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48f143ea44d0acfb1a0a66d9814ae0227f198665 | wikidoc | ABHD6 | ABHD6
alpha/beta-Hydrolase domain containing 6 (ABHD6), also known as monoacylglycerol lipase ABHD6 or 2-arachidonoylglycerol hydrolase is an enzyme that in humans is encoded by the ABHD6 gene.
# Function
ABHD6 is a serine hydrolyzing enzyme that possesses typical α/β-hydrolase family domains. ABHD6 was first studied because of its over-expression in certain forms of tumours.
ABHD6 has been linked to regulation of the endocannabinoid system as it controls the accumulation of 2-arachidonoylglycerol (2-AG) at the cannabinoid receptors.
ABHD6 accounts for about 4% of 2-AG brain hydrolysis. Together, monoacylglycerol lipase (MAGL), ABHD12, and ABHD6 control about 99% of 2-AG signalling in the brain, and each enzyme exhibits a distinct subcellular distribution, suggesting that they regulate distinct pools of 2-AG in the nervous system. | ABHD6
alpha/beta-Hydrolase domain containing 6 (ABHD6), also known as monoacylglycerol lipase ABHD6 or 2-arachidonoylglycerol hydrolase is an enzyme that in humans is encoded by the ABHD6 gene.
# Function
ABHD6 is a serine hydrolyzing enzyme that possesses typical α/β-hydrolase family domains. ABHD6 was first studied because of its over-expression in certain forms of tumours.[1]
ABHD6 has been linked to regulation of the endocannabinoid system as it controls the accumulation of 2-arachidonoylglycerol (2-AG) at the cannabinoid receptors.[2]
ABHD6 accounts for about 4% of 2-AG brain hydrolysis.[3] Together, monoacylglycerol lipase (MAGL), ABHD12, and ABHD6 control about 99% of 2-AG signalling in the brain,[3][4] and each enzyme exhibits a distinct subcellular distribution, suggesting that they regulate distinct pools of 2-AG in the nervous system.[5] | https://www.wikidoc.org/index.php/ABHD6 | |
8d416bc2e41bb50535a71612375a220674b69542 | wikidoc | ACAA2 | ACAA2
3-Ketoacyl-CoA thiolase, mitochondrial also known as acetyl-Coenzyme A acyltransferase 2 is an enzyme that in humans is encoded by the ACAA2 gene.
Acetyl-Coenzyme A acyltransferase 2 is an acetyl-CoA C-acyltransferase enzyme.
# Structure
The ACAA2 gene encodes a 41.9 kDa protein that is composed of 397 amino acids and contains 88 observed peptides.
# Function
The encoded protein catalyzes the last step of the mitochondrial fatty acid beta oxidation spiral. Unlike most mitochondrial matrix proteins, it contains a non-cleavable amino-terminal targeting signal. ACAA2 has been shown to be a functional BNIP3 binding partner, which provides a possible link between fatty acid metabolism and cell apoptosis.
# Clinical significance
To date, mutations or variants have not been identified in any clinical diseases. However, the ACAA2 locus has been associated with abnormal blood lipid levels, particularly HDL and LDL cholesterol levels; in addition, this locus has also been correlated with an individual’s risk for coronary artery disease. | ACAA2
3-Ketoacyl-CoA thiolase, mitochondrial also known as acetyl-Coenzyme A acyltransferase 2 is an enzyme that in humans is encoded by the ACAA2 gene.[1][2]
Acetyl-Coenzyme A acyltransferase 2 is an acetyl-CoA C-acyltransferase enzyme.
# Structure
The ACAA2 gene encodes a 41.9 kDa protein that is composed of 397 amino acids and contains 88 observed peptides.[3][4]
# Function
The encoded protein catalyzes the last step of the mitochondrial fatty acid beta oxidation spiral. Unlike most mitochondrial matrix proteins, it contains a non-cleavable amino-terminal targeting signal.[1] ACAA2 has been shown to be a functional BNIP3 binding partner, which provides a possible link between fatty acid metabolism and cell apoptosis.[5]
# Clinical significance
To date, mutations or variants have not been identified in any clinical diseases. However, the ACAA2 locus has been associated with abnormal blood lipid levels, particularly HDL and LDL cholesterol levels;[6] in addition, this locus has also been correlated with an individual’s risk for coronary artery disease.[7] | https://www.wikidoc.org/index.php/ACAA2 | |
0a284d677f7f10c12a6f11c384504b6b01a8a7b5 | wikidoc | ACACB | ACACB
Acetyl-CoA carboxylase 2 also known as ACC-beta or ACC2 is an enzyme that in humans is encoded by the ACACB gene.
# Function
Acetyl-CoA carboxylase (ACC) is a complex multifunctional enzyme system. ACC is a biotin-containing enzyme which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. ACC-beta is thought to control fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine palmitoyltransferase I, the rate-limiting step in fatty acid uptake and oxidation by mitochondria. ACC-beta may be involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis.
# Clinical implications
Human acetyl-CoA carboxylase has recently become a target in the design of new anti-obesity drugs. However, when the gene for ACC2 was knocked out in mice, no change in body weight was observed relative to normal mice. This result suggests inhibition of ACC2 by drugs may be an ineffective method of treating obesity. | ACACB
Acetyl-CoA carboxylase 2 also known as ACC-beta or ACC2 is an enzyme that in humans is encoded by the ACACB gene.[1][2]
# Function
Acetyl-CoA carboxylase (ACC) is a complex multifunctional enzyme system. ACC is a biotin-containing enzyme which catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, the rate-limiting step in fatty acid synthesis. ACC-beta is thought to control fatty acid oxidation by means of the ability of malonyl-CoA to inhibit carnitine palmitoyltransferase I, the rate-limiting step in fatty acid uptake and oxidation by mitochondria. ACC-beta may be involved in the regulation of fatty acid oxidation, rather than fatty acid biosynthesis.[1]
# Clinical implications
Human acetyl-CoA carboxylase has recently become a target in the design of new anti-obesity drugs.[3] However, when the gene for ACC2 was knocked out in mice, no change in body weight was observed relative to normal mice.[4] This result suggests inhibition of ACC2 by drugs may be an ineffective method of treating obesity. | https://www.wikidoc.org/index.php/ACACB | |
dc63cb8127047adfe58fd5c86379cbde6313d2ae | wikidoc | ACAD8 | ACAD8
Isobutyryl-CoA dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ACAD8 gene on chromosome 11.
The protein encoded by ACAD8 is a mitochondrial protein belongs to the acyl-CoA dehydrogenase family of enzymes, which function to catalyze the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branched-chain amino acids. ACAD8 functions in catabolism of the branched-chain amino acid valine.
# Structure
ACAD8 functions as a homotetramer and has an overall structure is similar to other acyl-CoA dehydrogenases. The functional protein contains an NH2-terminal alpha-helical domain, a medial beta-strand domain and a C-terminal alpha-helical domain.
# Clinical significance
Mutations in ACAD8 have been linked to isobutyryl-CoA dehydrogenase deficiency. Most patients with isobutyryl-CoA dehydrogenase deficiency are asymptotic, but children have also been observed to develop dilated cardiomyopathy.
# Function
ACAD8 is an isobutyryl-CoA dehydrogenase that functions in the catabolism of branched-chain amino acids including valine, and shows high reactivity toward isobutyryl-CoA. ACAD8 is responsible for the third step in the breakdown of valine and converts isobutyryl-CoA into methylacrylyl-CoA. | ACAD8
Isobutyryl-CoA dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ACAD8 gene on chromosome 11.[1][2]
The protein encoded by ACAD8 is a mitochondrial protein belongs to the acyl-CoA dehydrogenase family of enzymes, which function to catalyze the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branched-chain amino acids. ACAD8 functions in catabolism of the branched-chain amino acid valine.
# Structure
ACAD8 functions as a homotetramer and has an overall structure is similar to other acyl-CoA dehydrogenases. The functional protein contains an NH2-terminal alpha-helical domain, a medial beta-strand domain and a C-terminal alpha-helical domain.[3]
# Clinical significance
Mutations in ACAD8 have been linked to isobutyryl-CoA dehydrogenase deficiency.[4] Most patients with isobutyryl-CoA dehydrogenase deficiency are asymptotic, but children have also been observed to develop dilated cardiomyopathy.[5]
# Function
ACAD8 is an isobutyryl-CoA dehydrogenase that functions in the catabolism of branched-chain amino acids including valine, and shows high reactivity toward isobutyryl-CoA.[4] ACAD8 is responsible for the third step in the breakdown of valine and converts isobutyryl-CoA into methylacrylyl-CoA. | https://www.wikidoc.org/index.php/ACAD8 | |
fd67c5f13345be2355ae4b996073f6254f838c1b | wikidoc | ACAD9 | ACAD9
Acyl-CoA dehydrogenase family member 9, mitochondrial is an enzyme that in humans is encoded by the ACAD9 gene. Mitochondrial Complex I Deficiency with varying clinical manifestations has been associated with mutations in ACAD9.
# Structure
The ACAD9 gene contains an open reading frame of 1866 base pairs; this gene encodes a protein with 621 amino acid residues. Alignment of the ACAD9 protein sequence with that of other human ACAD proteins showed that ACAD-9 protein displays 46–27% identity, and 56–38% similarity with the eight members of the ACAD family, including ACADVL, ACADS, ACADM, ACADL, IVD, GCD, ACADSB, and ACD8. The calculated molecular weight of the ACAD9 is 68.8 kDa.
# Function
The ACAD9 enzyme catalyzes a crucial step in fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid. LVCAD is specific to very long-chain fatty acids, typically C16-acylCoA and longer. It has been observed that ACAD9 can catalyze acyl-CoAs with very long chains. The specific activity of ACAD9 towards palmitoyl-CoA (C16:0) is three times higher than that towards stearoyl-CoA (C18:0). ACAD-9 has little activity on n-octanoyl-CoA (C8:0), n-butyryl-CoA (C4:0) or isovaleryl-CoA (C5:0).
In contrast with ACADVL, ACAD9 is also involved in assembly of the oxidative phosphorylation complex I. ACAD9 binds complex I assembly factors NDUFAF1 and Ecsit and is specifically required for the assembly of complex I. Furthermore, ACAD9 mutations result in complex I deficiency and not in disturbed long-chain fatty acid oxidation.
# Clinical significance
Mutations in the ACAD9 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders. Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible. However, the majority of cases are caused by mutations in nuclear-encoded genes. It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.
A few cases specific to ACAD9 have been reported. Some cases presented with episodic liver dysfunction during otherwise mild illnesses or cardiomyopathy, along with chronic neurologic dysfunction. Brain findings were notable for generalized edema with diffuse ventricular compression, acute left tonsillar herniation, and diffuse multifocal acute damage in the hippocampus. In addition, some abnormalities consistent with nonacute changes were seen, including a subacute right cerebellar hemispheric infarct and reduction in the number of neurons in several areas. In one patient, whose clinical manifestations of hypotonia, cardiomyopathy, and lactic acidosis, a vigorous treatment with riboflavin allowed the individual to have normal psychomotor development and no cognitive impairment at 5 years of age. Exercise-induced rhabdomyolysis, mitochondrial encephalomyopathy, and hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules have also been observed in patients with ACAD9 mutations.
# Interactions
ACAD9 is part of the mitochondrial complex I assembly (MCIA) complex. The complex comprises at least TMEM126B, NDUFAF1, ECSIT, and ACAD9, which interacts directly with NDUFAF1 and ECSIT. | ACAD9
Acyl-CoA dehydrogenase family member 9, mitochondrial is an enzyme that in humans is encoded by the ACAD9 gene.[1][2] Mitochondrial Complex I Deficiency with varying clinical manifestations has been associated with mutations in ACAD9.[3]
# Structure
The ACAD9 gene contains an open reading frame of 1866 base pairs; this gene encodes a protein with 621 amino acid residues. Alignment of the ACAD9 protein sequence with that of other human ACAD proteins showed that ACAD-9 protein displays 46–27% identity, and 56–38% similarity with the eight members of the ACAD family, including ACADVL, ACADS, ACADM, ACADL, IVD, GCD, ACADSB, and ACD8. The calculated molecular weight of the ACAD9 is 68.8 kDa.[1]
# Function
The ACAD9 enzyme catalyzes a crucial step in fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid. LVCAD is specific to very long-chain fatty acids, typically C16-acylCoA and longer.[4] It has been observed that ACAD9 can catalyze acyl-CoAs with very long chains. The specific activity of ACAD9 towards palmitoyl-CoA (C16:0) is three times higher than that towards stearoyl-CoA (C18:0). ACAD-9 has little activity on n-octanoyl-CoA (C8:0), n-butyryl-CoA (C4:0) or isovaleryl-CoA (C5:0).[1]
In contrast with ACADVL, ACAD9 is also involved in assembly of the oxidative phosphorylation complex I. ACAD9 binds complex I assembly factors NDUFAF1 and Ecsit and is specifically required for the assembly of complex I. Furthermore, ACAD9 mutations result in complex I deficiency and not in disturbed long-chain fatty acid oxidation.[5]
# Clinical significance
Mutations in the ACAD9 gene are associated with Mitochondrial Complex I Deficiency, which is autosomal recessive. This deficiency is the most common enzymatic defect of the oxidative phosphorylation disorders.[6][7] Mitochondrial complex I deficiency shows extreme genetic heterogeneity and can be caused by mutation in nuclear-encoded genes or in mitochondrial-encoded genes. There are no obvious genotype-phenotype correlations, and inference of the underlying basis from the clinical or biochemical presentation is difficult, if not impossible.[8] However, the majority of cases are caused by mutations in nuclear-encoded genes.[9][10] It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease.[11]
A few cases specific to ACAD9 have been reported. Some cases presented with episodic liver dysfunction during otherwise mild illnesses or cardiomyopathy, along with chronic neurologic dysfunction. Brain findings were notable for generalized edema with diffuse ventricular compression, acute left tonsillar herniation, and diffuse multifocal acute damage in the hippocampus. In addition, some abnormalities consistent with nonacute changes were seen, including a subacute right cerebellar hemispheric infarct and reduction in the number of neurons in several areas.[12] In one patient, whose clinical manifestations of hypotonia, cardiomyopathy, and lactic acidosis, a vigorous treatment with riboflavin allowed the individual to have normal psychomotor development and no cognitive impairment at 5 years of age.[13] Exercise-induced rhabdomyolysis, mitochondrial encephalomyopathy, and hyperplasia in liver, cardiac myocytes, skeletal muscle, and renal tubules have also been observed in patients with ACAD9 mutations.[14][15][3]
# Interactions
ACAD9 is part of the mitochondrial complex I assembly (MCIA) complex. The complex comprises at least TMEM126B, NDUFAF1, ECSIT, and ACAD9, which interacts directly with NDUFAF1 and ECSIT.[5] | https://www.wikidoc.org/index.php/ACAD9 | |
beda98a1337f8df310d37d8f20f94d478624dbcb | wikidoc | ACADL | ACADL
Acyl-CoA dehydrogenase, long chain is a protein that in humans is encoded by the ACADL gene.
ACADL is a gene that encodes LCAD - acyl-CoA dehydrogenase, long chain - which is a member of the acyl-CoA dehydrogenase family. The acyl-CoA dehydrogenase family is primarily responsible for beta-oxidation of fatty acids within the mitochondria. LCAD dysfunction is associated with lowered fatty acid oxidation capacity and decreased heat generation. As a result, LCAD deficiency has been correlated with increased cardiac hypertrophy, pulmonary disease, and overall insulin resistance.
# Structure
Acadl is a single-copy, nuclear encoded gene approximately 35 kb in size. The gene contains 11 coding exons ranging in size from 67 bp to 275 bp, interrupted by 10 introns ranging in size from 1.0 kb to 6.6 kb in size. The Acadl 5' regulatory region, like other members of the Acad family, lacks a TATA or CAAT box and is GC rich. This region does contain multiple, putative cis-acting DNA elements recognized by either SP1 or members of the steroid-thyroid family of nuclear receptors, which has been shown with other members of the ACAD gene family to be important in regulated expression.
# Function
The LCAD enzyme catalyzes most of fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid. LCAD works on long-chain fatty acids, typically between C12 and C16-acylCoA. LCAD is essential for oxidizing unsaturated fatty acids such as oleic acid, but seems redundant in the oxidation of saturated fatty acids.
Fatty acid oxidation has proven to spare glucose in fasting conditions, and is also required for amino acid metabolism, which is essential for the maintenance of adequate glucose production. LCAD is regulated by a reversible acetylation mechanism by SIRT3, in which the active form of the enzyme is deacetylated, and hyperacetylation reduces the enzymatic activity.
# Animal studies
In mice, LCAD deficient mice have been shown to expend less energy, and are also subject to hypothermia, which can be explained by the fact that a reduced rate of fatty acid oxidation is correlated with a lowered capacity to generate heat. Indeed, when LCAD mice are exposed to the cold, the expression of fatty acid oxidation genes was elevated in liver.
As ACADL is a mitochondrial protein, and a member of the beta-oxidation family, there are many instances in which its deficiency is correlated with mitochondrial dysfunction and the diseases that manifest as a result. The ACADL gene has been correlated with protecting against diabetes. In corroboration, primary defects in mitochondrial fatty acid oxidation capacity, as illustrated by LCAD knockout mice, can lead to diacylglycerol accumulation, otherwise known as steatosis, as well as PKCepsilon activation, and hepatic insulin resistance. In animals with very long-chain acyl-CoA dehydrogenase deficiency, LCAD and MCAD work to compensate for the reduced fatty acid oxidation capacity; this compensation is modest, however, and the fatty acid oxidation levels do not return completely to wild type levels. Additionally, LCAD has been shown to have no mechanism that compensates for its deficiency.
In the heart, LCAD knockout mice rely more heavily on glucose oxidation, concurrently while there is a large need for replenishment of metabolic intermediates, or analplerosis. During fasting, the increased glucose usage cannot maintain homeostasis in LCAD knockout mice. LCAD knockout mice displayed a higher level of cardiac hypertrophy, as indicated by increased left ventricular wall thickness and an increased about of metabolic cardiomyopathy. The knockout mice also had increased triglyceride levels in the myocardium, which is a detrimental disease phenotype. Carnitine supplementation did lower the triglyceride levels in these knockout mice, but did not have any effect on hypertrophy or cardiac performance.
The ACADL gene has also been linked to pathophysiology of pulmonary disease. In humans, this protein was shown to be localized to the human alveolar type II pneumocytes, which synthesize and secrete pulmonary surfactant. Mice that were lacking LCAD (-/-) had dysfunctional or reduced amounts of pulmonary surfactant, which is required to prevent infection; the mice who did not have this protein also displayed a significantly reduced lung capacity in a variety of tests.
# Clinical significance
As LCAD deficiency has not yet been found in humans, it has also been postulated that LCAD confers a critical role in development of the blastocoele in human embryos. | ACADL
Acyl-CoA dehydrogenase, long chain is a protein that in humans is encoded by the ACADL gene.[1]
ACADL is a gene that encodes LCAD - acyl-CoA dehydrogenase, long chain - which is a member of the acyl-CoA dehydrogenase family. The acyl-CoA dehydrogenase family is primarily responsible for beta-oxidation of fatty acids within the mitochondria. LCAD dysfunction is associated with lowered fatty acid oxidation capacity and decreased heat generation. As a result, LCAD deficiency has been correlated with increased cardiac hypertrophy, pulmonary disease, and overall insulin resistance.[1]
# Structure
Acadl is a single-copy, nuclear encoded gene approximately 35 kb in size. The gene contains 11 coding exons ranging in size from 67 bp to 275 bp, interrupted by 10 introns ranging in size from 1.0 kb to 6.6 kb in size. The Acadl 5' regulatory region, like other members of the Acad family, lacks a TATA or CAAT box and is GC rich. This region does contain multiple, putative cis-acting DNA elements recognized by either SP1 or members of the steroid-thyroid family of nuclear receptors, which has been shown with other members of the ACAD gene family to be important in regulated expression.[2]
# Function
The LCAD enzyme catalyzes most of fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid. LCAD works on long-chain fatty acids, typically between C12 and C16-acylCoA. LCAD is essential for oxidizing unsaturated fatty acids such as oleic acid, but seems redundant in the oxidation of saturated fatty acids.[3]
Fatty acid oxidation has proven to spare glucose in fasting conditions, and is also required for amino acid metabolism, which is essential for the maintenance of adequate glucose production.[4] LCAD is regulated by a reversible acetylation mechanism by SIRT3, in which the active form of the enzyme is deacetylated, and hyperacetylation reduces the enzymatic activity.[5]
# Animal studies
In mice, LCAD deficient mice have been shown to expend less energy, and are also subject to hypothermia, which can be explained by the fact that a reduced rate of fatty acid oxidation is correlated with a lowered capacity to generate heat.[6] Indeed, when LCAD mice are exposed to the cold, the expression of fatty acid oxidation genes was elevated in liver.[7]
As ACADL is a mitochondrial protein, and a member of the beta-oxidation family, there are many instances in which its deficiency is correlated with mitochondrial dysfunction and the diseases that manifest as a result. The ACADL gene has been correlated with protecting against diabetes.[8] In corroboration, primary defects in mitochondrial fatty acid oxidation capacity, as illustrated by LCAD knockout mice, can lead to diacylglycerol accumulation, otherwise known as steatosis, as well as PKCepsilon activation, and hepatic insulin resistance.[9] In animals with very long-chain acyl-CoA dehydrogenase deficiency, LCAD and MCAD work to compensate for the reduced fatty acid oxidation capacity; this compensation is modest, however, and the fatty acid oxidation levels do not return completely to wild type levels.[10] Additionally, LCAD has been shown to have no mechanism that compensates for its deficiency.[3]
In the heart, LCAD knockout mice rely more heavily on glucose oxidation, concurrently while there is a large need for replenishment of metabolic intermediates, or analplerosis. During fasting, the increased glucose usage cannot maintain homeostasis in LCAD knockout mice.[11] LCAD knockout mice displayed a higher level of cardiac hypertrophy, as indicated by increased left ventricular wall thickness and an increased about of metabolic cardiomyopathy.[12] The knockout mice also had increased triglyceride levels in the myocardium, which is a detrimental disease phenotype.[13] Carnitine supplementation did lower the triglyceride levels in these knockout mice, but did not have any effect on hypertrophy or cardiac performance.[14]
The ACADL gene has also been linked to pathophysiology of pulmonary disease. In humans, this protein was shown to be localized to the human alveolar type II pneumocytes, which synthesize and secrete pulmonary surfactant. Mice that were lacking LCAD (-/-) had dysfunctional or reduced amounts of pulmonary surfactant, which is required to prevent infection; the mice who did not have this protein also displayed a significantly reduced lung capacity in a variety of tests.[5]
# Clinical significance
As LCAD deficiency has not yet been found in humans, it has also been postulated that LCAD confers a critical role in development of the blastocoele in human embryos.[15] | https://www.wikidoc.org/index.php/ACADL | |
3cfa5e72e0be2c3a9d49006a885cacf9496d4483 | wikidoc | ACADM | ACADM
ACADM (acyl-Coenzyme A dehydrogenase, C-4 to C-12 straight chain) is a gene that provides instructions for making an enzyme called acyl-coenzyme A dehydrogenase that is important for breaking down (degrading) a certain group of fats called medium-chain fatty acids.
These fatty acids are found in foods such as milk and certain oils, and they are also stored in the body's fat tissue. Medium-chain fatty acids are also produced when larger fatty acids are degraded.
The acyl-coenzyme A dehydrogenase for medium-chain fatty acids (ACADM) enzyme is essential for converting these particular fatty acids to energy, especially during periods without food (fasting). The ACADM enzyme functions in mitochondria, the energy-producing centers within cells. It is found in the mitochondria of several types of tissues, particularly the liver.
The ACADM gene is located on the short (p) arm of chromosome 1 at position 31, from base pair 75,902,302 to base pair 75,941,203.
# Structure
The protein encoded by the ACADM gene is 50.8 kDa in size, and composed of 454 amino acids.
# Function
The LCAD enzyme catalyzes most of fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid. MCAD works on long-chain fatty acids, typically between C4 and C12-acylCoA. Fatty acid oxidation has proven to spare glucose in fasting conditions, and is also required for amino acid metabolism, which is essential for the maintenance of adequate glucose production.
# Clinical significance
Medium-chain acyl-coenzyme A dehydrogenase deficiency can be caused by mutations in the ACADM gene. More than 30 ACADM gene mutations that cause medium-chain acyl-coenzyme A dehydrogenase deficiency have been identified. Many of these mutations switch an amino acid building block in the ACADM enzyme. The most common amino acid substitution replaces lysine with glutamic acid at position 329 in the enzyme's chain of amino acids (also written as Lys329Glu or K329E). This mutation and other amino acid substitutions alter the enzyme's structure, reducing or abolishing its activity. Other mutations delete or duplicate part of the ACADM gene, which leads to an unstable enzyme that cannot function.
With a shortage (deficiency) of functional ACADM enzyme, medium-chain fatty acids cannot be degraded and processed. As a result, these fats are not converted into energy, which can lead to characteristic symptoms of this disorder, such as lack of energy (lethargy) and low blood sugar. Levels of medium-chain fatty acids or partially degraded fatty acids may build up in tissues and can damage the liver and brain, causing more serious complications. | ACADM
ACADM (acyl-Coenzyme A dehydrogenase, C-4 to C-12 straight chain) is a gene that provides instructions for making an enzyme called acyl-coenzyme A dehydrogenase that is important for breaking down (degrading) a certain group of fats called medium-chain fatty acids.
These fatty acids are found in foods such as milk and certain oils, and they are also stored in the body's fat tissue. Medium-chain fatty acids are also produced when larger fatty acids are degraded.
The acyl-coenzyme A dehydrogenase for medium-chain fatty acids (ACADM) enzyme is essential for converting these particular fatty acids to energy, especially during periods without food (fasting). The ACADM enzyme functions in mitochondria, the energy-producing centers within cells. It is found in the mitochondria of several types of tissues, particularly the liver.
The ACADM gene is located on the short (p) arm of chromosome 1 at position 31, from base pair 75,902,302 to base pair 75,941,203.
# Structure
The protein encoded by the ACADM gene is 50.8 kDa in size, and composed of 454 amino acids.[1][2]
# Function
The LCAD enzyme catalyzes most of fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid. MCAD works on long-chain fatty acids, typically between C4 and C12-acylCoA.[3] Fatty acid oxidation has proven to spare glucose in fasting conditions, and is also required for amino acid metabolism, which is essential for the maintenance of adequate glucose production.[4]
# Clinical significance
Medium-chain acyl-coenzyme A dehydrogenase deficiency can be caused by mutations in the ACADM gene. More than 30 ACADM gene mutations that cause medium-chain acyl-coenzyme A dehydrogenase deficiency have been identified.[5] Many of these mutations switch an amino acid building block in the ACADM enzyme. The most common amino acid substitution replaces lysine with glutamic acid at position 329 in the enzyme's chain of amino acids (also written as Lys329Glu or K329E).[6] This mutation and other amino acid substitutions alter the enzyme's structure, reducing or abolishing its activity. Other mutations delete or duplicate part of the ACADM gene, which leads to an unstable enzyme that cannot function.
With a shortage (deficiency) of functional ACADM enzyme, medium-chain fatty acids cannot be degraded and processed. As a result, these fats are not converted into energy, which can lead to characteristic symptoms of this disorder, such as lack of energy (lethargy) and low blood sugar. Levels of medium-chain fatty acids or partially degraded fatty acids may build up in tissues and can damage the liver and brain, causing more serious complications.[7] | https://www.wikidoc.org/index.php/ACADM | |
c684adfa181f209a1af99b17ada2d728d20469cc | wikidoc | ACADS | ACADS
Acyl-CoA dehydrogenase, C-2 to C-3 short chain is an enzyme that in humans is encoded by the ACADS gene. This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. The ACADS gene associated with short-chain acyl-coenzyme A dehydrogenase deficiency.
# Structure
The ACADS gene is approximately 13 kb in length and has 10 exons. The coding sequence of this gene is 1239 bp long. The encoded protein has 412 amino acids, and its size is 44.3 kDa (Human) or 44.9 KDa (Mouse).
# Function
The SCAD enzyme catalyzes the first part of fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid through dehydrogenation of the flavoenzyme. SCAD is specific to short-chain fatty acids, between C2 and C3-acylCoA. The final result of beta-oxidation is acetyl-CoA. When there are defects that result in SCAD being misfolded, there is an increased production of reactive oxygen species (ROS); the increased ROS forces the mitochondria to undergo fission, and the mitochondrial reticulum takes on a grain-like structure.
# Clinical significance
Mutations of the ACADS gene are associated with deficiency of the short-chain acyl-coenzyme A dehydrogenase protein (SCADD); this is also known as butyryl-CoA dehydrogenase deficiency. Many mutations have been identified in specific populations, and large-scale studies have been performed to determine the allelic and genotypic frequency for the defective gene. As short-chain acyl-CoA dehydrogenase is involved in beta-oxidation, a deficiency in this enzyme is marked by an increased amount of fatty acids. This deficiency is characterized by the presence of increased butyrylcarnitine (C4) in blood plasma, and increased ethylmalonic acid (EMA) concentrations in urine. Genotypes of individuals with this deficiency have it as a result of a mutation, variant, or a combination of the two. Among one population with the disease, three subgroups have been identified: one group has a failure to thrive, feeding difficulties, and hypotonia; another group had seizures; finally, one group had hypotonia and no seizures. Other studies showed that the deficiency may be asymptomatic in some individuals under normal conditions, with symptoms presenting under physiological stress conditions such as fasting or illness. The treatment of this deficiency can sometimes be unclear, because it can sometimes be asymptomatic. The treatment for this disease is similar to treatment of other fatty acid oxidation disorders, by trying to restore biochemical and physiologic homeostasis, by promoting anabolism and providing alternative sources of energy.
Flavin adenine dinucleotide supplementation has also been identified as a therapy for this deficiency, because it is an essential cofactor for proper function of SCAD. SCAD deficiency is inherited in an autosomal recessive manner. Carrier testing can be performed for at-risk family members, and prenatal testing is also a possibility.
The ACADS gene has also been implicated in delaying the onset of Prader-Willi Syndrome, which is characterized by hypotonia, growth failure, and neurodevelopmental delays in the first years of life, and hyperphagia and obesity much later.
In Genome Wide Association Studies (GWAS), SCAD has been associated with a reduced amount of insulin release shown by an oral glucose tolerance test, or OGTT. | ACADS
Acyl-CoA dehydrogenase, C-2 to C-3 short chain is an enzyme that in humans is encoded by the ACADS gene.[1] This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. The ACADS gene associated with short-chain acyl-coenzyme A dehydrogenase deficiency.[2][1]
# Structure
The ACADS gene is approximately 13 kb in length and has 10 exons. The coding sequence of this gene is 1239 bp long.[3] The encoded protein has 412 amino acids, and its size is 44.3 kDa (Human) or 44.9 KDa (Mouse).[4][5]
# Function
The SCAD enzyme catalyzes the first part of fatty acid beta-oxidation by forming a C2-C3 trans-double bond in the fatty acid through dehydrogenation of the flavoenzyme. SCAD is specific to short-chain fatty acids, between C2 and C3-acylCoA. The final result of beta-oxidation is acetyl-CoA.[6] When there are defects that result in SCAD being misfolded, there is an increased production of reactive oxygen species (ROS); the increased ROS forces the mitochondria to undergo fission, and the mitochondrial reticulum takes on a grain-like structure.[7]
# Clinical significance
Mutations of the ACADS gene are associated with deficiency of the short-chain acyl-coenzyme A dehydrogenase protein (SCADD); this is also known as butyryl-CoA dehydrogenase deficiency. Many mutations have been identified in specific populations, and large-scale studies have been performed to determine the allelic and genotypic frequency for the defective gene.[8][9] As short-chain acyl-CoA dehydrogenase is involved in beta-oxidation, a deficiency in this enzyme is marked by an increased amount of fatty acids. This deficiency is characterized by the presence of increased butyrylcarnitine (C4) in blood plasma, and increased ethylmalonic acid (EMA) concentrations in urine. Genotypes of individuals with this deficiency have it as a result of a mutation, variant, or a combination of the two.[10] Among one population with the disease, three subgroups have been identified: one group has a failure to thrive, feeding difficulties, and hypotonia; another group had seizures; finally, one group had hypotonia and no seizures.[11] Other studies showed that the deficiency may be asymptomatic in some individuals under normal conditions, with symptoms presenting under physiological stress conditions such as fasting or illness.[12] The treatment of this deficiency can sometimes be unclear, because it can sometimes be asymptomatic. The treatment for this disease is similar to treatment of other fatty acid oxidation disorders, by trying to restore biochemical and physiologic homeostasis, by promoting anabolism and providing alternative sources of energy.
[10] Flavin adenine dinucleotide supplementation has also been identified as a therapy for this deficiency, because it is an essential cofactor for proper function of SCAD.[13] SCAD deficiency is inherited in an autosomal recessive manner. Carrier testing can be performed for at-risk family members, and prenatal testing is also a possibility.
[10]
The ACADS gene has also been implicated in delaying the onset of Prader-Willi Syndrome, which is characterized by hypotonia, growth failure, and neurodevelopmental delays in the first years of life, and hyperphagia and obesity much later.[14]
In Genome Wide Association Studies (GWAS), SCAD has been associated with a reduced amount of insulin release shown by an oral glucose tolerance test, or OGTT.[15] | https://www.wikidoc.org/index.php/ACADS | |
afb93843293f432abc6d3723110b570885bb77f7 | wikidoc | ACAT1 | ACAT1
Acetyl-CoA acetyltransferase, mitochondrial, also known as acetoacetyl-CoA thiolase, is an enzyme that in humans is encoded by the ACAT1 (Acetyl-Coenzyme A acetyltransferase 1) gene.
Acetyl-Coenzyme A acetyltransferase 1 is an acetyl-CoA C-acetyltransferase enzyme.
# Structure
The gene spans approx. 27 kb and contains twelve exons interrupted by eleven introns. The region flanking the 5’ end of the gene lacks a TATA box, but contains many GC’s and also has two CAAT boxes. The gene also may have a binding site for the transcription factor Sp1, and has sequences resembling the binding sites of several other transcription factors. Additionally, there is a 101-bp DNA fragment immediately upstream from the cap site that has promoter activity.
The human ACAT1 gene produces a chimeric mRNA through trans-splicing, a process in which separate transcripts from chromosomes 1 and 7 are spliced together. The chimeric mRNA transcript uses two sections to initiate translation: AUG(1397-1399) and GGC(1274-1276). Initiation of the first codon (AUG) results in the translation of a 50-kDa ACAT1, and initiation of the other (GGC) produces another enzymatically active 56-kDa isoform respectively; the 56kDa isoform is naturally present in human cells, including human monocyte-derived macrophages.
The resulting transcript encodes ACAT1, which is a 45.1 kDa protein composed of 427 amino acids. It is also a homotetrameric protein that has nine transmembrane domains (TMDs). One active residue is a Histidine at the 460th position, which is in the 7th TMD. ACAT1 has seven free Cysteine residues, but they do not affect catalytic activity. There are two functional sections of this protein, TMD7 and TMD8; one side is involved in substrate binding and catalysis, while the other is involved in subunit interactions and binding.
# Function
This gene encodes a mitochondrially localized enzyme that catalyzes the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA. The ACAT1 enzyme has a few unique properties. First, it is activated by potassium ions binding near the CoA binding site and the catalytic site. This binding causes a structural change in the active site loop. Additionally, this enzyme is able to use 2-methyl-branched acetoacetyl-CoA as a substrate, making it a unique thiolase. ACAT1 is regulated at both transcriptional and translational levels. ACAT1 enzyme activity is enhanced ACAT1’s expression is promoted transcriptionally by leptin, angiotensin II, and insulin in human monocytes/macrophages. Insulin-mediated regulation also involves ERK, p38MAPK, and JNK signaling pathways.
# Clinical significance
## Ketothiolase deficiency
Mutations of the ACAT1 gene are associated with a deficiency in the encoded protein mitochondrial acetoacetyl-CoA thiolase; this is also known as ketothiolase deficiency. Many mutations have been identified in specific populations, and large scale studies have been performed to determine the allelic and genotypic frequency for the defective gene. As mitochondrial acetoacetyl-CoA thiolase is involved in beta-oxidation, a deficiency in this enzyme is marked by an increased amount of cholesterol compounds. Additionally, the isoleucine amino acid pathway is affected, such that proper metabolism of it is halted. This deficiency belongs to a more general class of disorders known as organic acidemias, in which the dysfunction of a specific step of amino acid catabolism results in the excretion of non-amino acids in the urine. This deficiency specifically presents as ketosis, acidosis, as well as hypoglycemia, but there are other clinical manifestations as well. The characteristics of organic acidemia disorders are vomiting, poor feeding, neurologic symptoms such as seizures and abnormal tone, and lethargy progressing to coma, which are all manifestations of toxic encephalopathy. The clinical outcome of infants with these disorders is largely determined by the time of diagnosis, with the potential outcome greatly improving if the disease is diagnosed in the first ten days of life. Ketothiolase deficiency is diagnosed by performing GC-MS and quantitative amino acid analysis in the urine; the diagnostic markers are 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine. The disease is managed by trying to restore biochemical and physiologic homeostasis; common therapies include restricting diet to avoid the precursor amino acids and use of compounds to either dispose of toxic metabolites or increase enzyme activity. This disease is inherited in an autosomal recessive manner, meaning that carriers of the gene do not show symptoms of the disease.
## Cancer
Additionally, expression of ACAT1 has been associated with manifestations of prostate cancer, in that ACAT1 is more significantly expressed in aggressive prostate cancer tissue samples when compared to its expression in benign cells.
## Possible drug target
Over-expression of ACAT-1 is associated with more aggressive pancreatic cancer, and an ACAT-1 inhibitor avasimibe (previously developed for treatment of atherosclerosis) is being studied in cancer cell lines and an orthotopic mouse model. | ACAT1
Acetyl-CoA acetyltransferase, mitochondrial, also known as acetoacetyl-CoA thiolase, is an enzyme that in humans is encoded by the ACAT1 (Acetyl-Coenzyme A acetyltransferase 1) gene.[1]
Acetyl-Coenzyme A acetyltransferase 1 is an acetyl-CoA C-acetyltransferase enzyme.
# Structure
The gene spans approx. 27 kb and contains twelve exons interrupted by eleven introns. The region flanking the 5’ end of the gene lacks a TATA box, but contains many GC’s and also has two CAAT boxes. The gene also may have a binding site for the transcription factor Sp1, and has sequences resembling the binding sites of several other transcription factors. Additionally, there is a 101-bp DNA fragment immediately upstream from the cap site that has promoter activity.[2]
The human ACAT1 gene produces a chimeric mRNA through trans-splicing, a process in which separate transcripts from chromosomes 1 and 7 are spliced together. The chimeric mRNA transcript uses two sections to initiate translation: AUG(1397-1399) and GGC(1274-1276). Initiation of the first codon (AUG) results in the translation of a 50-kDa ACAT1, and initiation of the other (GGC) produces another enzymatically active 56-kDa isoform respectively; the 56kDa isoform is naturally present in human cells, including human monocyte-derived macrophages.[3]
The resulting transcript encodes ACAT1, which is a 45.1 kDa protein composed of 427 amino acids.[4][5] It is also a homotetrameric protein that has nine transmembrane domains (TMDs). One active residue is a Histidine at the 460th position, which is in the 7th TMD. ACAT1 has seven free Cysteine residues, but they do not affect catalytic activity. There are two functional sections of this protein, TMD7 and TMD8; one side is involved in substrate binding and catalysis, while the other is involved in subunit interactions and binding.[6]
# Function
This gene encodes a mitochondrially localized enzyme that catalyzes the reversible formation of acetoacetyl-CoA from two molecules of acetyl-CoA.[1] The ACAT1 enzyme has a few unique properties. First, it is activated by potassium ions binding near the CoA binding site and the catalytic site. This binding causes a structural change in the active site loop. Additionally, this enzyme is able to use 2-methyl-branched acetoacetyl-CoA as a substrate, making it a unique thiolase.[7] ACAT1 is regulated at both transcriptional and translational levels. ACAT1 enzyme activity is enhanced ACAT1’s expression is promoted transcriptionally by leptin,[8] angiotensin II,[9] and insulin in human monocytes/macrophages.[10] Insulin-mediated regulation also involves ERK, p38MAPK, and JNK signaling pathways.[11]
# Clinical significance
## Ketothiolase deficiency
Mutations of the ACAT1 gene are associated with a deficiency in the encoded protein mitochondrial acetoacetyl-CoA thiolase; this is also known as ketothiolase deficiency. Many mutations have been identified in specific populations, and large scale studies have been performed to determine the allelic and genotypic frequency for the defective gene.[12] As mitochondrial acetoacetyl-CoA thiolase is involved in beta-oxidation, a deficiency in this enzyme is marked by an increased amount of cholesterol compounds. Additionally, the isoleucine amino acid pathway is affected, such that proper metabolism of it is halted. This deficiency belongs to a more general class of disorders known as organic acidemias, in which the dysfunction of a specific step of amino acid catabolism results in the excretion of non-amino acids in the urine. This deficiency specifically presents as ketosis, acidosis, as well as hypoglycemia, but there are other clinical manifestations as well. The characteristics of organic acidemia disorders are vomiting, poor feeding, neurologic symptoms such as seizures and abnormal tone, and lethargy progressing to coma, which are all manifestations of toxic encephalopathy. The clinical outcome of infants with these disorders is largely determined by the time of diagnosis, with the potential outcome greatly improving if the disease is diagnosed in the first ten days of life. Ketothiolase deficiency is diagnosed by performing GC-MS and quantitative amino acid analysis in the urine; the diagnostic markers are 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, and tiglylglycine. The disease is managed by trying to restore biochemical and physiologic homeostasis; common therapies include restricting diet to avoid the precursor amino acids and use of compounds to either dispose of toxic metabolites or increase enzyme activity. This disease is inherited in an autosomal recessive manner, meaning that carriers of the gene do not show symptoms of the disease.[13]
## Cancer
Additionally, expression of ACAT1 has been associated with manifestations of prostate cancer, in that ACAT1 is more significantly expressed in aggressive prostate cancer tissue samples when compared to its expression in benign cells.[14][15]
## Possible drug target
Over-expression of ACAT-1 is associated with more aggressive pancreatic cancer, and an ACAT-1 inhibitor avasimibe (previously developed for treatment of atherosclerosis) is being studied in cancer cell lines and an orthotopic mouse model.[16] | https://www.wikidoc.org/index.php/ACAT1 | |
328e5eba9e65386e8bf488d238162edce796b6a6 | wikidoc | ACER1 | ACER1
Alkaline ceramidase 1 also known as ACER1 is a ceramidase enzyme which in humans is encoded by the ACER1 gene.
# Function
ACER1 mediates cellular differentiation by controlling the generation of sphingosine (SPH) and sphingosine-1-phosphate (S1P).
# Model organisms
Model organisms have been used in the study of ACER1 function. A conditional knockout mouse line called Acer1tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping - in-depth bone and cartilage phenotyping | ACER1
Alkaline ceramidase 1 also known as ACER1 is a ceramidase enzyme which in humans is encoded by the ACER1 gene.[1]
# Function
ACER1 mediates cellular differentiation by controlling the generation of sphingosine (SPH) and sphingosine-1-phosphate (S1P).[1]
# Model organisms
Model organisms have been used in the study of ACER1 function. A conditional knockout mouse line called Acer1tm1a(EUCOMM)Wtsi was generated at the Wellcome Trust Sanger Institute.[5] Male and female animals underwent a standardized phenotypic screen[2] to determine the effects of deletion.[6][7][8][9] Additional screens performed: - In-depth immunological phenotyping[3] - in-depth bone and cartilage phenotyping[4] | https://www.wikidoc.org/index.php/ACER1 | |
fee2415110deeef485bfc3f4d6639b50e69b2418 | wikidoc | ACKR3 | ACKR3
Atypical chemokine receptor 3 also known as C-X-C chemokine receptor type 7 (CXCR-7) and G-protein coupled receptor 159 (GPR159) is a protein that in humans is encoded by the ACKR3 gene.
This gene encodes a member of the G protein-coupled receptor family. This protein was earlier thought to be a receptor for vasoactive intestinal peptide (VIP) and was considered to be an orphan receptor. It is now classified as a chemokine receptor able to bind the chemokines CXCL12/SDF-1 and CXCL11. The protein is also a coreceptor for human immunodeficiency viruses (HIV). Translocations involving this gene and HMGA2 on chromosome 12 have been observed in lipomas. Alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. Whereas some reports claim that the receptor induces signaling following ligand binding, recent findings in zebrafish suggest that CXCR7 functions primarily by sequestering the chemokine CXCL12.
However, another recent study has provided evidence that ligand binding to CXCR7 activates MAP kinases through Beta-arrestins, and thus has functions beyond ligand sequestration. | ACKR3
Atypical chemokine receptor 3 also known as C-X-C chemokine receptor type 7 (CXCR-7) and G-protein coupled receptor 159 (GPR159) is a protein that in humans is encoded by the ACKR3 gene.[1][2]
This gene encodes a member of the G protein-coupled receptor family. This protein was earlier thought to be a receptor for vasoactive intestinal peptide (VIP) and was considered to be an orphan receptor. It is now classified as a chemokine receptor able to bind the chemokines CXCL12/SDF-1 and CXCL11. The protein is also a coreceptor for human immunodeficiency viruses (HIV). Translocations involving this gene and HMGA2 on chromosome 12 have been observed in lipomas. Alternatively spliced transcript variants encoding the same protein isoform have been found for this gene. Whereas some reports claim that the receptor induces signaling following ligand binding, recent findings in zebrafish suggest that CXCR7 functions primarily by sequestering the chemokine CXCL12.[2]
However, another recent study has provided evidence that ligand binding to CXCR7 activates MAP kinases through Beta-arrestins, and thus has functions beyond ligand sequestration.[3] | https://www.wikidoc.org/index.php/ACKR3 | |
88fc28fde85b8e8beb9f6545f73e4208ad760f4b | wikidoc | ACOT1 | ACOT1
Acyl-CoA thioesterase 1 is a protein that in humans is encoded by the ACOT1 gene.
# Structure
The ACOT1 gene is located on the 14th chromosome, with its specific localization being 14q24.3. It contains 7 exons.
The protein encoded by this gene contains 410 amino acids, and forms a homodimer with another chain. The protein contains a StAR-related transfer domain, which is a domain responsible for binding to lipids. There are 4 known ligands that bind to this homodimer: polyethylene glycol, chlorine, glycerol, and a form of TCEP.
# Function
The protein encoded by the ACOT1 gene is part of a family of Acyl-CoA thioesterases, which catalyze the hydrolysis of various Coenzyme A esters of various molecules to the free acid plus CoA. These enzymes have also been referred to in the literature as acyl-CoA hydrolases, acyl-CoA thioester hydrolases, and palmitoyl-CoA hydrolases. The reaction carried out by these enzymes is as follows:
CoA ester + H2O → free acid + coenzyme A
These enzymes use the same substrates as long-chain acyl-CoA synthetases, but have a unique purpose in that they generate the free acid and CoA, as opposed to long-chain acyl-CoA synthetases, which ligate fatty acids to CoA, to produce the CoA ester. The role of the ACOT- family of enzymes is not well understood; however, it has been suggested that they play a crucial role in regulating the intracellular levels of CoA esters, Coenzyme A, and free fatty acids. Recent studies have shown that Acyl-CoA esters have many more functions than simply an energy source. These functions include allosteric regulation of enzymes such as acetyl-CoA carboxylase, hexokinase IV, and the citrate condensing enzyme. Long-chain acyl-CoAs also regulate opening of ATP-sensitive potassium channels and activation of Calcium ATPases, thereby regulating insulin secretion. A number of other cellular events are also mediated via acyl-CoAs, for example signal transduction through protein kinase C, inhibition of retinoic acid-induced apoptosis, and involvement in budding and fusion of the endomembrane system. Acyl-CoAs also mediate protein targeting to various membranes and regulation of G Protein α subunits, because they are substrates for protein acylation. In the mitochondria, acyl-CoA esters are involved in the acylation of mitochondrial NAD+ dependent dehydrogenases; because these enzymes are responsible for amino acid catabolism, this acylation renders the whole process inactive. This mechanism may provide metabolic crosstalk and act to regulate the NADH/NAD+ ratio in order to maintain optimal mitochondrial beta oxidation of fatty acids. The role of CoA esters in lipid metabolism and numerous other intracellular processes are well defined, and thus it is hypothesized that ACOT- enzymes play a role in modulating the processes these metabolites are involved in. | ACOT1
Acyl-CoA thioesterase 1 is a protein that in humans is encoded by the ACOT1 gene.[1]
# Structure
The ACOT1 gene is located on the 14th chromosome, with its specific localization being 14q24.3. It contains 7 exons.[1]
The protein encoded by this gene contains 410 amino acids, and forms a homodimer with another chain.[2] The protein contains a StAR-related transfer domain, which is a domain responsible for binding to lipids. There are 4 known ligands that bind to this homodimer: polyethylene glycol, chlorine, glycerol, and a form of TCEP.[3]
# Function
The protein encoded by the ACOT1 gene is part of a family of Acyl-CoA thioesterases, which catalyze the hydrolysis of various Coenzyme A esters of various molecules to the free acid plus CoA. These enzymes have also been referred to in the literature as acyl-CoA hydrolases, acyl-CoA thioester hydrolases, and palmitoyl-CoA hydrolases. The reaction carried out by these enzymes is as follows:
CoA ester + H2O → free acid + coenzyme A
These enzymes use the same substrates as long-chain acyl-CoA synthetases, but have a unique purpose in that they generate the free acid and CoA, as opposed to long-chain acyl-CoA synthetases, which ligate fatty acids to CoA, to produce the CoA ester.[4] The role of the ACOT- family of enzymes is not well understood; however, it has been suggested that they play a crucial role in regulating the intracellular levels of CoA esters, Coenzyme A, and free fatty acids. Recent studies have shown that Acyl-CoA esters have many more functions than simply an energy source. These functions include allosteric regulation of enzymes such as acetyl-CoA carboxylase,[5] hexokinase IV,[6] and the citrate condensing enzyme. Long-chain acyl-CoAs also regulate opening of ATP-sensitive potassium channels and activation of Calcium ATPases, thereby regulating insulin secretion.[7] A number of other cellular events are also mediated via acyl-CoAs, for example signal transduction through protein kinase C, inhibition of retinoic acid-induced apoptosis, and involvement in budding and fusion of the endomembrane system.[8][9][10] Acyl-CoAs also mediate protein targeting to various membranes and regulation of G Protein α subunits, because they are substrates for protein acylation.[11] In the mitochondria, acyl-CoA esters are involved in the acylation of mitochondrial NAD+ dependent dehydrogenases; because these enzymes are responsible for amino acid catabolism, this acylation renders the whole process inactive. This mechanism may provide metabolic crosstalk and act to regulate the NADH/NAD+ ratio in order to maintain optimal mitochondrial beta oxidation of fatty acids.[12] The role of CoA esters in lipid metabolism and numerous other intracellular processes are well defined, and thus it is hypothesized that ACOT- enzymes play a role in modulating the processes these metabolites are involved in.[13] | https://www.wikidoc.org/index.php/ACOT1 | |
9825d9a21f95c15d7e1dde92dca3114ac0a5105c | wikidoc | ACOT2 | ACOT2
Acyl-CoA thioesterase 2, also known as ACOT2, is an enzyme which in humans is encoded by the ACOT2 gene.
Acyl-CoA thioesterases, such as ACOT2, are a group of enzymes that hydrolyze Coenzyme A (CoA) esters, such as acyl-CoAs, bile CoAs, and CoA esters of prostaglandins, to the corresponding free acid and CoA. ACOT2 shows high acyl-CoA thioesterase activity on medium- and long-chain acyl-CoAs, with an optimal pH of 8.5. It is most active on myristoyl-CoA but also shows high activity on palmitoyl-CoA, stearoyl-CoA, and arachidoyl-CoA.
# Function
The protein encoded by the ACOT2 gene is part of a family of Acyl-CoA thioesterases, which catalyze the hydrolysis of various Coenzyme A esters of various molecules to the free acid plus CoA. These enzymes have also been referred to in the literature as acyl-CoA hydrolases, acyl-CoA thioester hydrolases, and palmitoyl-CoA hydrolases. The reaction carried out by these enzymes is as follows:
CoA ester + H2O → free acid + coenzyme A
These enzymes use the same substrates as long-chain acyl-CoA synthetases, but have a unique purpose in that they generate the free acid and CoA, as opposed to long-chain acyl-CoA synthetases, which ligate fatty acids to CoA, to produce the CoA ester. The role of the ACOT- family of enzymes is not well understood; however, it has been suggested that they play a crucial role in regulating the intracellular levels of CoA esters, Coenzyme A, and free fatty acids. Recent studies have shown that Acyl-CoA esters have many more functions than simply an energy source. These functions include allosteric regulation of enzymes such as acetyl-CoA carboxylase, hexokinase IV, and the citrate condensing enzyme. Long-chain acyl-CoAs also regulate opening of ATP-sensitive potassium channels and activation of Calcium ATPases, thereby regulating insulin secretion. A number of other cellular events are also mediated via acyl-CoAs, for example signal transduction through protein kinase C, inhibition of retinoic acid-induced apoptosis, and involvement in budding and fusion of the endomembrane system. Acyl-CoAs also mediate protein targeting to various membranes and regulation of G Protein α subunits, because they are substrates for protein acylation. In the mitochondria, acyl-CoA esters are involved in the acylation of mitochondrial NAD+ dependent dehydrogenases; because these enzymes are responsible for amino acid catabolism, this acylation renders the whole process inactive. This mechanism may provide metabolic crosstalk and act to regulate the NADH/NAD+ ratio in order to maintain optimal mitochondrial beta oxidation of fatty acids. The role of CoA esters in lipid metabolism and numerous other intracellular processes are well defined, and thus it is hypothesized that ACOT- enzymes play a role in modulating the processes these metabolites are involved in. | ACOT2
Acyl-CoA thioesterase 2, also known as ACOT2, is an enzyme which in humans is encoded by the ACOT2 gene.[1][2][3]
Acyl-CoA thioesterases, such as ACOT2, are a group of enzymes that hydrolyze Coenzyme A (CoA) esters, such as acyl-CoAs, bile CoAs, and CoA esters of prostaglandins, to the corresponding free acid and CoA.[4] ACOT2 shows high acyl-CoA thioesterase activity on medium- and long-chain acyl-CoAs, with an optimal pH of 8.5. It is most active on myristoyl-CoA but also shows high activity on palmitoyl-CoA, stearoyl-CoA, and arachidoyl-CoA.[2]
# Function
The protein encoded by the ACOT2 gene is part of a family of Acyl-CoA thioesterases, which catalyze the hydrolysis of various Coenzyme A esters of various molecules to the free acid plus CoA. These enzymes have also been referred to in the literature as acyl-CoA hydrolases, acyl-CoA thioester hydrolases, and palmitoyl-CoA hydrolases. The reaction carried out by these enzymes is as follows:
CoA ester + H2O → free acid + coenzyme A
These enzymes use the same substrates as long-chain acyl-CoA synthetases, but have a unique purpose in that they generate the free acid and CoA, as opposed to long-chain acyl-CoA synthetases, which ligate fatty acids to CoA, to produce the CoA ester.[5] The role of the ACOT- family of enzymes is not well understood; however, it has been suggested that they play a crucial role in regulating the intracellular levels of CoA esters, Coenzyme A, and free fatty acids. Recent studies have shown that Acyl-CoA esters have many more functions than simply an energy source. These functions include allosteric regulation of enzymes such as acetyl-CoA carboxylase,[6] hexokinase IV,[7] and the citrate condensing enzyme. Long-chain acyl-CoAs also regulate opening of ATP-sensitive potassium channels and activation of Calcium ATPases, thereby regulating insulin secretion.[8] A number of other cellular events are also mediated via acyl-CoAs, for example signal transduction through protein kinase C, inhibition of retinoic acid-induced apoptosis, and involvement in budding and fusion of the endomembrane system.[9][10][11] Acyl-CoAs also mediate protein targeting to various membranes and regulation of G Protein α subunits, because they are substrates for protein acylation.[12] In the mitochondria, acyl-CoA esters are involved in the acylation of mitochondrial NAD+ dependent dehydrogenases; because these enzymes are responsible for amino acid catabolism, this acylation renders the whole process inactive. This mechanism may provide metabolic crosstalk and act to regulate the NADH/NAD+ ratio in order to maintain optimal mitochondrial beta oxidation of fatty acids.[13] The role of CoA esters in lipid metabolism and numerous other intracellular processes are well defined, and thus it is hypothesized that ACOT- enzymes play a role in modulating the processes these metabolites are involved in.[14] | https://www.wikidoc.org/index.php/ACOT2 | |
1f5b247c1628ed06f6275331c6931cd8b3d99cdb | wikidoc | ACOT4 | ACOT4
Acyl-coenzyme A thioesterase 4 is an enzyme that in humans is encoded by the ACOT4 gene.
# Function
The protein encoded by the ACOT4 gene is part of a family of Acyl-CoA thioesterases, which catalyze the hydrolysis of various Coenzyme A esters of various molecules to the free acid plus CoA. These enzymes have also been referred to in the literature as acyl-CoA hydrolases, acyl-CoA thioester hydrolases, and palmitoyl-CoA hydrolases. The reaction carried out by these enzymes is as follows:
CoA ester + H2O → free acid + coenzyme A
These enzymes use the same substrates as long-chain acyl-CoA synthetases, but have a unique purpose in that they generate the free acid and CoA, as opposed to long-chain acyl-CoA synthetases, which ligate fatty acids to CoA, to produce the CoA ester. The role of the ACOT- family of enzymes is not well understood; however, it has been suggested that they play a crucial role in regulating the intracellular levels of CoA esters, Coenzyme A, and free fatty acids. Recent studies have shown that Acyl-CoA esters have many more functions than simply an energy source. These functions include allosteric regulation of enzymes such as acetyl-CoA carboxylase, hexokinase IV, and the citrate condensing enzyme. Long-chain acyl-CoAs also regulate opening of ATP-sensitive potassium channels and activation of Calcium ATPases, thereby regulating insulin secretion. A number of other cellular events are also mediated via acyl-CoAs, for example signal transduction through protein kinase C, inhibition of retinoic acid-induced apoptosis, and involvement in budding and fusion of the endomembrane system. Acyl-CoAs also mediate protein targeting to various membranes and regulation of G Protein α subunits, because they are substrates for protein acylation. In the mitochondria, acyl-CoA esters are involved in the acylation of mitochondrial NAD+ dependent dehydrogenases; because these enzymes are responsible for amino acid catabolism, this acylation renders the whole process inactive. This mechanism may provide metabolic crosstalk and act to regulate the NADH/NAD+ ratio in order to maintain optimal mitochondrial beta oxidation of fatty acids. The role of CoA esters in lipid metabolism and numerous other intracellular processes are well defined, and thus it is hypothesized that ACOT- enzymes play a role in modulating the processes these metabolites are involved in. | ACOT4
Acyl-coenzyme A thioesterase 4 is an enzyme that in humans is encoded by the ACOT4 gene.[1][2][3]
# Function
The protein encoded by the ACOT4 gene is part of a family of Acyl-CoA thioesterases, which catalyze the hydrolysis of various Coenzyme A esters of various molecules to the free acid plus CoA. These enzymes have also been referred to in the literature as acyl-CoA hydrolases, acyl-CoA thioester hydrolases, and palmitoyl-CoA hydrolases. The reaction carried out by these enzymes is as follows:
CoA ester + H2O → free acid + coenzyme A
These enzymes use the same substrates as long-chain acyl-CoA synthetases, but have a unique purpose in that they generate the free acid and CoA, as opposed to long-chain acyl-CoA synthetases, which ligate fatty acids to CoA, to produce the CoA ester.[4] The role of the ACOT- family of enzymes is not well understood; however, it has been suggested that they play a crucial role in regulating the intracellular levels of CoA esters, Coenzyme A, and free fatty acids. Recent studies have shown that Acyl-CoA esters have many more functions than simply an energy source. These functions include allosteric regulation of enzymes such as acetyl-CoA carboxylase,[5] hexokinase IV,[6] and the citrate condensing enzyme. Long-chain acyl-CoAs also regulate opening of ATP-sensitive potassium channels and activation of Calcium ATPases, thereby regulating insulin secretion.[7] A number of other cellular events are also mediated via acyl-CoAs, for example signal transduction through protein kinase C, inhibition of retinoic acid-induced apoptosis, and involvement in budding and fusion of the endomembrane system.[8][9][10] Acyl-CoAs also mediate protein targeting to various membranes and regulation of G Protein α subunits, because they are substrates for protein acylation.[11] In the mitochondria, acyl-CoA esters are involved in the acylation of mitochondrial NAD+ dependent dehydrogenases; because these enzymes are responsible for amino acid catabolism, this acylation renders the whole process inactive. This mechanism may provide metabolic crosstalk and act to regulate the NADH/NAD+ ratio in order to maintain optimal mitochondrial beta oxidation of fatty acids.[12] The role of CoA esters in lipid metabolism and numerous other intracellular processes are well defined, and thus it is hypothesized that ACOT- enzymes play a role in modulating the processes these metabolites are involved in.[13] | https://www.wikidoc.org/index.php/ACOT4 | |
7cea8166c80b6c8f86b4b792e3b327222fd3cf18 | wikidoc | ACOT6 | ACOT6
Acyl-CoA thioesterase 6 is a protein that in humans is encoded by the ACOT6 gene. The protein, also known as C14orf42, is an enzyme with thioesterase activity.
# Function
The protein encoded by the ACOT1 gene is part of a family of Acyl-CoA thioesterases, which catalyze the hydrolysis of various Coenzyme A esters of various molecules to the free acid plus CoA. These enzymes have also been referred to in the literature as acyl-CoA hydrolases, acyl-CoA thioester hydrolases, and palmitoyl-CoA hydrolases. The reaction carried out by these enzymes is as follows:
CoA ester + H2O → free acid + coenzyme A
These enzymes use the same substrates as long-chain acyl-CoA synthetases, but have a unique purpose in that they generate the free acid and CoA, as opposed to long-chain acyl-CoA synthetases, which ligate fatty acids to CoA, to produce the CoA ester. The role of the ACOT- family of enzymes is not well understood; however, it has been suggested that they play a crucial role in regulating the intracellular levels of CoA esters, Coenzyme A, and free fatty acids. Recent studies have shown that Acyl-CoA esters have many more functions than simply an energy source. These functions include allosteric regulation of enzymes such as acetyl-CoA carboxylase, hexokinase IV, and the citrate condensing enzyme. Long-chain acyl-CoAs also regulate opening of ATP-sensitive potassium channels and activation of Calcium ATPases, thereby regulating insulin secretion. A number of other cellular events are also mediated via acyl-CoAs, for example signal transduction through protein kinase C, inhibition of retinoic acid-induced apoptosis, and involvement in budding and fusion of the endomembrane system. Acyl-CoAs also mediate protein targeting to various membranes and regulation of G Protein α subunits, because they are substrates for protein acylation. In the mitochondria, acyl-CoA esters are involved in the acylation of mitochondrial NAD+ dependent dehydrogenases; because these enzymes are responsible for amino acid catabolism, this acylation renders the whole process inactive. This mechanism may provide metabolic crosstalk and act to regulate the NADH/NAD+ ratio in order to maintain optimal mitochondrial beta oxidation of fatty acids. The role of CoA esters in lipid metabolism and numerous other intracellular processes are well defined, and thus it is hypothesized that ACOT- enzymes play a role in modulating the processes these metabolites are involved in.
# Model organisms
Model organisms have been used in the study of ACOT6 function. A conditional knockout mouse line, called Acot6tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on mutant mice but no significant abnormalities were observed. | ACOT6
Acyl-CoA thioesterase 6 is a protein that in humans is encoded by the ACOT6 gene.[1] The protein, also known as C14orf42, is an enzyme with thioesterase activity.[1]
# Function
The protein encoded by the ACOT1 gene is part of a family of Acyl-CoA thioesterases, which catalyze the hydrolysis of various Coenzyme A esters of various molecules to the free acid plus CoA. These enzymes have also been referred to in the literature as acyl-CoA hydrolases, acyl-CoA thioester hydrolases, and palmitoyl-CoA hydrolases. The reaction carried out by these enzymes is as follows:
CoA ester + H2O → free acid + coenzyme A
These enzymes use the same substrates as long-chain acyl-CoA synthetases, but have a unique purpose in that they generate the free acid and CoA, as opposed to long-chain acyl-CoA synthetases, which ligate fatty acids to CoA, to produce the CoA ester.[2] The role of the ACOT- family of enzymes is not well understood; however, it has been suggested that they play a crucial role in regulating the intracellular levels of CoA esters, Coenzyme A, and free fatty acids. Recent studies have shown that Acyl-CoA esters have many more functions than simply an energy source. These functions include allosteric regulation of enzymes such as acetyl-CoA carboxylase,[3] hexokinase IV,[4] and the citrate condensing enzyme. Long-chain acyl-CoAs also regulate opening of ATP-sensitive potassium channels and activation of Calcium ATPases, thereby regulating insulin secretion.[5] A number of other cellular events are also mediated via acyl-CoAs, for example signal transduction through protein kinase C, inhibition of retinoic acid-induced apoptosis, and involvement in budding and fusion of the endomembrane system.[6][7][8] Acyl-CoAs also mediate protein targeting to various membranes and regulation of G Protein α subunits, because they are substrates for protein acylation.[9] In the mitochondria, acyl-CoA esters are involved in the acylation of mitochondrial NAD+ dependent dehydrogenases; because these enzymes are responsible for amino acid catabolism, this acylation renders the whole process inactive. This mechanism may provide metabolic crosstalk and act to regulate the NADH/NAD+ ratio in order to maintain optimal mitochondrial beta oxidation of fatty acids.[10] The role of CoA esters in lipid metabolism and numerous other intracellular processes are well defined, and thus it is hypothesized that ACOT- enzymes play a role in modulating the processes these metabolites are involved in.[11]
# Model organisms
Model organisms have been used in the study of ACOT6 function. A conditional knockout mouse line, called Acot6tm1a(KOMP)Wtsi[16][17] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[18][19][20]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[14][21] Twenty four tests were carried out on mutant mice but no significant abnormalities were observed.[14] | https://www.wikidoc.org/index.php/ACOT6 | |
42ce2593a3c22b18cd05d39f0743b0fabed6a3e2 | wikidoc | ACRRM | ACRRM
ACRRM is the Australian College of Rural and Remote Medicine. It has a current membership of around 2,500 including fellows, registrars, practitioners and students.
# History
ACRRM was established in 1997
ACRRM received initial accreditation from the Australian Medical Council (AMC) in February 2007, and was included in the Australian Medicare legislation in April 2007.
# Initial Accreditation by the AMC
Initial accreditation enables ACRRM to now work towards a full assessment by an AMC accreditation team in the future. The AMC assesses and accredits training programs in the recognised medical specialties. Rural and remote medicine is not a recognised medical specialty. The initial accreditation relates to ACRRM as a standards body and provider of specific training and professional development programs for the specialty of general practice.
# Australian Legislation and Regulations governing Medicare and the recognition of General Practitioners
This was a Regulatory change rather than Legislative change that enables practitioners who 'meet ACRRM's fellowship standards' to gain Vocational Recognition as a General Practitioner in Australia. Medical practitioners who 'meet the ACRRM's fellowship standards' can be vocationally recognised General Practitioners in Australia and deliver services that attract a Medicare rebate.
Australia has a socialised health care system offering Australians and designated other foreign nationals access to subsidised health care through universal health insurance. A portion of the charge (in many instances the complete charge) for medical services is rebated through the Australian Government via Medicare.
The Federal Government enacted Legislation in 1973 - The Health Insurance Act 1973 - legislating the universal health insurance.
Gazetted underneath this Act is The Health Insurance Regulations 1975.
Australian Acts require passage through the Parliament. Australian Regulations can be changed by authority of the Minister of the relevant Department and the Governor-General of Australia. The distinction is significant as parliamentary review is the more robust mechanism.
The Act and Regulations define how a doctor can be recognised as a General Practitioner in Australia and, therefore, deliver services that attract Medicare rebates. This is Vocational Recognition of General Practitioners. There are three current pathways.
1/ Section 3EA of The Health Insurance Act 1973 allows doctors to gain a 'determination' as a General Practitioner if they are General Practitioners if they are 'Fellows of the Royal Australian College of General Practitioners'.
2/ Section 3F of The Health Insurance act 1973 allows doctors to gain a determination as a General Practitioner if they meet the requirements set out by Medicare Australia. This is the Vocational Register. This list is held by the CEO of Medicare Australia.
3/ The third pathway relevant to ACRRM is not held in the Legislation but in the Regulations. Section 6DA of The Health Insurance Regulations 1975. This section of the Regulations allows doctors to seek a determination that they are a General Practitioner if they 'meet ACRRM fellowship standards'.
This regulation was added in April 2007 by the authority of the Governor General.
## Legislated standards for ACRRM Fellowship
### Recognition process by the Australian Medical Council
The Australian Medical Council has two distinct processes regarding medical specialties in Australia. The first is the Recognition of Medical Specialties. The second is Accreditation of Medical Specialist Education and Training and Professional Development Programs..
The Australian College of Rural and Remote Medicine initially sought recognition of Rural and Remote Medicine as a unique medical specialty in Australia through the Australian Medical Council (AMC).
This application was hotly debated with the AMC receiving 326 submission for it's deliberations. The application was rejected and the Hon Tony Abbott MHR did 'not consider that a case has been made for rural and remote medicine to be a medical specialty.'
The Review Group considers that:
'applying a broad definition of general practice, the practice of rural and remote medicine is largely general practice'
In addition:
'There is as yet no other instance in Australia of two organisations defining the standards of medical practice and the standards for training and assessment in one medical specialty.....the AMC had agreed this should be possible.'
With this in mind, the Minister for Health and Ageing Tony Abbott MHR released 1 million dollars to the Australian College of Rural and Remote Medicine to develop an accredited training program for rural general practitioners on the 22nd of December 2005.
### Regulations governing ACRRM
The regulations under the Health Insurance Regulation 1975, cited above, describe four criteria for eligibility for a determination to be recognised as a general practitioner in Australia via ACRRM. They are split into two subgroupings.
The two groups under this section of the Regulations (section 6DB(1)) are:
- doctors who successfully complete accredited training.
- doctors who have been assessed by the ACRRM as having training and experience equivalent to successful completion of accredited training.
It is important to note that the Australian Medical council only offers advice to the Minister for Health and Ageing.
In this context, the advice received was for initial accreditation. The press release lists a series of specified areas that need to be addressed to achieve full accreditation - mostly regarding an assessment that ACRRM is yet to deliver.
The true impetus for ACRRM's inclusion came from adept and effective lobbying by ACRRM of the state Health Ministers who released the following:
COAG noted that, in order to attract more general practitioners with procedural skills to rural areas, and subject to the Australian College of Rural and Remote Medicine’s training programme being accredited by the Australian Medical Council, the Commonwealth will provide rural medicine with formal recognition under Medicare as a generalist discipline by April 2007.
While clearly confused about rural medicine, what awards offer procedural training and how the Medicare Legislation and Regulations work, this is powerful and insurmountable political pressure for the Federal Government to have acted rapidly on any positive advice from the AMC.
The two groups under this section of the Regulations (section 6DB(2)) are:
- doctors who have been assessed by the ACRRM, using an assessment model approved by the Department, as having training and experience equivalent to successful completion of accredited training.
- doctors who are vocationally registered general practitioners.
The inclusion of this section is notable as it fell outside of the AMC's brief and advice. This inclusion was a decision of the Department of Health and Ageing.
There is precedent for the Government to pass into law recognition of doctors in certain medical specialties outside of the professional College structures and professional advice from the regulatory bodies. The inclusion of section 3F of the Health Insurance Act is an example
However, at that time a distinction was made between this group of doctors under 3F and Fellows of the RACGP under section 3EA, such that the RACGP current holds a position that Vocational Registration does not lead directly to their Fellowship (FRACGP)
Pre-determination FACRRM, delivered under various Grandfather and Pioneer Clauses, was a peer recognition document that sought doctors to document their contribution to Rural and Remote Medicine (noting that most were awarded at a time when ACRRM was seeking recognition for Rural and Remote Medicine as a medical specialty). This was a reasonable effort to bolster membership and representative input into this organisation. ACRRM approached the new Directors of Rural Medical Schools and University Departments of Rural Health. There is evidence that advocacy groups within the ACRRM sought to increase numbers of females who were under represented at that stage at a Rural Female Doctors weekend in Western Victoria in 2003.
An argument suggests that the criteria for pre-determination FACRRMs is an evolved version of the criteria set down for the Vocational Register. Further evolution can be seen in the 16 point scheme laid down by ACRRM as a means to fulfill the government's request to allow recognition for:
'doctors who have been assessed by the ACRRM, using an assessment model approved by the Department, as having training and experience equivalent to successful completion of accredited training.'
The professional risk, however, is the linking of the government driven additions and the professional driven inclusions. The intimate linking of the two within the Health Insurance Regulation 1975, may mean that ACRRM will not be able to develop a set of standard beyond the Government and enshrines Vocational Registration as an equivalent standard to ACRRM's standard.
The trainee organisation, the General Practice Registrars Australia, have commented on the problem but failed to see that the recognition of non-VR GPs under the new Regulations is a modified additional round of grandfathering into recognition but denying this path to anyone who does not wish to be a member or Fellow of ACRRM. | ACRRM
Template:Primarysources
ACRRM is the Australian College of Rural and Remote Medicine. It has a current membership of around 2,500 including fellows, registrars, practitioners and students.[1]
# History
ACRRM was established in 1997
ACRRM received initial accreditation from the Australian Medical Council (AMC) in February 2007, and was included in the Australian Medicare legislation in April 2007.[2]
# Initial Accreditation by the AMC
Initial accreditation enables ACRRM to now work towards a full assessment by an AMC accreditation team in the future. The AMC assesses and accredits training programs in the recognised medical specialties. Rural and remote medicine is not a recognised medical specialty. The initial accreditation relates to ACRRM as a standards body and provider of specific training and professional development programs for the specialty of general practice. [3]
# Australian Legislation and Regulations governing Medicare and the recognition of General Practitioners
This was a Regulatory change rather than Legislative change that enables practitioners who 'meet ACRRM's fellowship standards' to gain Vocational Recognition as a General Practitioner in Australia. Medical practitioners who 'meet the ACRRM's fellowship standards' can be vocationally recognised General Practitioners in Australia and deliver services that attract a Medicare rebate.
Australia has a socialised health care system offering Australians and designated other foreign nationals access to subsidised health care through universal health insurance. A portion of the charge (in many instances the complete charge) for medical services is rebated through the Australian Government via Medicare.
The Federal Government enacted Legislation in 1973 - The Health Insurance Act 1973 - legislating the universal health insurance.[4]
Gazetted underneath this Act is The Health Insurance Regulations 1975.[5]
Australian Acts require passage through the Parliament. Australian Regulations can be changed by authority of the Minister of the relevant Department and the Governor-General of Australia. The distinction is significant as parliamentary review is the more robust mechanism.
The Act and Regulations define how a doctor can be recognised as a General Practitioner in Australia and, therefore, deliver services that attract Medicare rebates. This is Vocational Recognition of General Practitioners. There are three current pathways.
1/ Section 3EA of The Health Insurance Act 1973 allows doctors to gain a 'determination' as a General Practitioner if they are General Practitioners if they are 'Fellows of the Royal Australian College of General Practitioners'.
2/ Section 3F of The Health Insurance act 1973 allows doctors to gain a determination as a General Practitioner if they meet the requirements set out by Medicare Australia. This is the Vocational Register. This list is held by the CEO of Medicare Australia.
3/ The third pathway relevant to ACRRM is not held in the Legislation but in the Regulations. Section 6DA of The Health Insurance Regulations 1975. This section of the Regulations allows doctors to seek a determination that they are a General Practitioner if they 'meet ACRRM fellowship standards'.
This regulation was added in April 2007 by the authority of the Governor General.[6]
## Legislated standards for ACRRM Fellowship
### Recognition process by the Australian Medical Council
The Australian Medical Council has two distinct processes regarding medical specialties in Australia. The first is the Recognition of Medical Specialties.[7] The second is Accreditation of Medical Specialist Education and Training and Professional Development Programs.[8].
The Australian College of Rural and Remote Medicine initially sought recognition of Rural and Remote Medicine as a unique medical specialty in Australia through the Australian Medical Council (AMC).
This application was hotly debated with the AMC receiving 326 submission for it's deliberations. The application was rejected and the Hon Tony Abbott MHR did 'not consider that a case has been made for rural and remote medicine to be a medical specialty.'[9]
The Review Group considers that:
'applying a broad definition of general practice, the practice of rural and remote medicine is largely general practice'[10]
In addition:
'There is as yet no other instance in Australia of two organisations defining the standards of medical practice and the standards for training and assessment in one medical specialty.....the AMC had agreed this should be possible.'[11]
With this in mind, the Minister for Health and Ageing Tony Abbott MHR released 1 million dollars to the Australian College of Rural and Remote Medicine to develop an accredited training program for rural general practitioners on the 22nd of December 2005.[12]
### Regulations governing ACRRM
The regulations under the Health Insurance Regulation 1975, cited above, describe four criteria for eligibility for a determination to be recognised as a general practitioner in Australia via ACRRM. They are split into two subgroupings.
The two groups under this section of the Regulations (section 6DB(1)) are:
- doctors who successfully complete accredited training.
- doctors who have been assessed by the ACRRM as having training and experience equivalent to successful completion of accredited training.
It is important to note that the Australian Medical council only offers advice to the Minister for Health and Ageing.
In this context, the advice received was for initial accreditation.[13] The press release lists a series of specified areas that need to be addressed to achieve full accreditation - mostly regarding an assessment that ACRRM is yet to deliver.
The true impetus for ACRRM's inclusion came from adept and effective lobbying by ACRRM of the state Health Ministers who released the following:[14]
COAG noted that, in order to attract more general practitioners with procedural skills to rural areas, and subject to the Australian College of Rural and Remote Medicine’s training programme being accredited by the Australian Medical Council, the Commonwealth will provide rural medicine with formal recognition under Medicare as a generalist discipline by April 2007.
While clearly confused about rural medicine, what awards offer procedural training and how the Medicare Legislation and Regulations work, this is powerful and insurmountable political pressure for the Federal Government to have acted rapidly on any positive advice from the AMC.
The two groups under this section of the Regulations (section 6DB(2)) are:
- doctors who have been assessed by the ACRRM, using an assessment model approved by the Department, as having training and experience equivalent to successful completion of accredited training.
- doctors who are vocationally registered general practitioners.[15]
The inclusion of this section is notable as it fell outside of the AMC's brief and advice. This inclusion was a decision of the Department of Health and Ageing.
There is precedent for the Government to pass into law recognition of doctors in certain medical specialties outside of the professional College structures and professional advice from the regulatory bodies. The inclusion of section 3F of the Health Insurance Act is an example [16]
However, at that time a distinction was made between this group of doctors under 3F and Fellows of the RACGP under section 3EA, such that the RACGP current holds a position that Vocational Registration does not lead directly to their Fellowship (FRACGP) [17]
Pre-determination FACRRM, delivered under various Grandfather and Pioneer Clauses, was a peer recognition document that sought doctors to document their contribution to Rural and Remote Medicine (noting that most were awarded at a time when ACRRM was seeking recognition for Rural and Remote Medicine as a medical specialty). This was a reasonable effort to bolster membership and representative input into this organisation. ACRRM approached the new Directors of Rural Medical Schools and University Departments of Rural Health. There is evidence that advocacy groups within the ACRRM sought to increase numbers of females who were under represented at that stage at a Rural Female Doctors weekend in Western Victoria in 2003.
An argument suggests that the criteria for pre-determination FACRRMs is an evolved version of the criteria set down for the Vocational Register.[18] Further evolution can be seen in the 16 point scheme [19] laid down by ACRRM as a means to fulfill the government's request to allow recognition for:
'doctors who have been assessed by the ACRRM, using an assessment model approved by the Department, as having training and experience equivalent to successful completion of accredited training.'[20]
The professional risk, however, is the linking of the government driven additions and the professional driven inclusions. The intimate linking of the two within the Health Insurance Regulation 1975, may mean that ACRRM will not be able to develop a set of standard beyond the Government and enshrines Vocational Registration as an equivalent standard to ACRRM's standard.
The trainee organisation, the General Practice Registrars Australia, have commented on the problem but failed to see that the recognition of non-VR GPs under the new Regulations is a modified additional round of grandfathering into recognition but denying this path to anyone who does not wish to be a member or Fellow of ACRRM.[21] | https://www.wikidoc.org/index.php/ACRRM | |
83c452fed6276326421b02b2a3d62be3c5d211ad | wikidoc | ACSF3 | ACSF3
Acyl-CoA synthetase family member 3 is an enzyme that in humans is encoded by the ACSF3 gene.
# Structure
The ACSF3 gene is located on the 16th chromosome, with its specific location being 16q24.3. The gene contains 17 exons. ASCL4 encodes a 64.1 kDa protein that is composed of 576 amino acids; 20 peptides have been observed through mass spectrometry data.
# Function
This gene encodes a member of the acetyl—CoA synthetase family of enzymes that activate fatty acids by catalyzing the formation of a thioester linkage between fatty acids and coenzyme A. The encoded protein is localized to mitochondria, has high specificity for malonate and methylmalonate and possesses malonyl-CoA synthetase activity.
# Clinical significance
Mutations in this gene have been shown to cause combined malonic and methylmalonic aciduria. Combined malonic and methylmalonic aciduria (CMAMMA) is a condition characterized by high levels of malonic acid and methylmalonic acid, because deficiencies in this gene cause these metabolites to not be broken down. The disease is typically diagnosed by either genetic testing or higher levels of methylmalonic acid than malonic acid in the urine, although both are elevated. The disorder typically presents symptoms early in childhood, first starting with high levels of acid in the blood (ketoacidosis). The disorder can also present as involuntary muscle tensing (dystonia), weak muscle tone (hypotonia), developmental delay, an inability to grow and gain weight at the expected rate (failure to thrive), low blood sugar (hypoglycemia), and coma. Some affected children can even have microcephaly. Other people with CMAMMA do not develop signs and symptoms until adulthood. These individuals usually have neurological problems, such as seizures, loss of memory, a decline in thinking ability, or psychiatric diseases. | ACSF3
Acyl-CoA synthetase family member 3 is an enzyme that in humans is encoded by the ACSF3 gene.[1]
# Structure
The ACSF3 gene is located on the 16th chromosome, with its specific location being 16q24.3. The gene contains 17 exons.[1] ASCL4 encodes a 64.1 kDa protein that is composed of 576 amino acids; 20 peptides have been observed through mass spectrometry data.[2][3]
# Function
This gene encodes a member of the acetyl—CoA synthetase family of enzymes that activate fatty acids by catalyzing the formation of a thioester linkage between fatty acids and coenzyme A. The encoded protein is localized to mitochondria, has high specificity for malonate and methylmalonate and possesses malonyl-CoA synthetase activity.[1]
# Clinical significance
Mutations in this gene have been shown to cause combined malonic and methylmalonic aciduria.[4] Combined malonic and methylmalonic aciduria (CMAMMA) is a condition characterized by high levels of malonic acid and methylmalonic acid, because deficiencies in this gene cause these metabolites to not be broken down. The disease is typically diagnosed by either genetic testing or higher levels of methylmalonic acid than malonic acid in the urine, although both are elevated. The disorder typically presents symptoms early in childhood, first starting with high levels of acid in the blood (ketoacidosis). The disorder can also present as involuntary muscle tensing (dystonia), weak muscle tone (hypotonia), developmental delay, an inability to grow and gain weight at the expected rate (failure to thrive), low blood sugar (hypoglycemia), and coma. Some affected children can even have microcephaly. Other people with CMAMMA do not develop signs and symptoms until adulthood. These individuals usually have neurological problems, such as seizures, loss of memory, a decline in thinking ability, or psychiatric diseases.[1] | https://www.wikidoc.org/index.php/ACSF3 | |
dba1bf4067e914a31441effb1638b5a21a66ca86 | wikidoc | ACSL1 | ACSL1
Long-chain-fatty-acid—CoA ligase 1 is an enzyme that in humans is encoded by the ACSL1 gene.
# Structure
## Gene
The ACSL4 gene is located on the 4th chromosome, with its specific location being 4q35.1. The gene contains 28 exons.
The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation.
In melanocytic cells ACSL1 gene expression may be regulated by MITF.
# Function
The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. Several transcript variants encoding different isoforms have been found for this gene. This specific protein is most commonly found in mitochondria and peroxisomes.
# Clinical significance
ACSL1 was shown to be involved in nonspecific mental retardation and fatty-acid metabolism. Since the ACSL4 gene is highly expressed in brain, where it encodes a brain specific isoform, an ASCL1 mutation may be an efficient diagnostic tool in mentally retarded males.
# Interactions
ACSL1 expression is regulated by SHP2 activity. Additionally, ACSL4 interacts with ACSL3, APP, DSE, ELAVL1, HECW2, MINOS1, PARK2, SPG20, SUMO2, TP53, TUBGCP3, UBC, UBD, and YWHAQ. | ACSL1
Long-chain-fatty-acid—CoA ligase 1 is an enzyme that in humans is encoded by the ACSL1 gene.[1][2][3]
# Structure
## Gene
The ACSL4 gene is located on the 4th chromosome, with its specific location being 4q35.1. The gene contains 28 exons.[3]
The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation.[3]
In melanocytic cells ACSL1 gene expression may be regulated by MITF.[4]
# Function
The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation.[3] Several transcript variants encoding different isoforms have been found for this gene. This specific protein is most commonly found in mitochondria and peroxisomes.[5]
# Clinical significance
ACSL1 was shown to be involved in nonspecific mental retardation and fatty-acid metabolism.[6] Since the ACSL4 gene is highly expressed in brain, where it encodes a brain specific isoform, an ASCL1 mutation may be an efficient diagnostic tool in mentally retarded males.[7]
# Interactions
ACSL1 expression is regulated by SHP2 activity.[8] Additionally, ACSL4 interacts with ACSL3, APP, DSE, ELAVL1, HECW2, MINOS1, PARK2, SPG20, SUMO2, TP53, TUBGCP3, UBC, UBD, and YWHAQ.[3] | https://www.wikidoc.org/index.php/ACSL1 | |
2fc6468b62b7cb224e2fcfba5ab6b255e03ac4b4 | wikidoc | ACSL4 | ACSL4
Long-chain-fatty-acid—CoA ligase 4 is an enzyme that in humans is encoded by the ACSL4 gene.
The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme preferentially utilizes arachidonate as substrate. The absence of this enzyme may contribute to the mental retardation or Alport syndrome. Alternative splicing of this gene generates 2 transcript variants.
# Structure
The ACSL4 gene is located on the X-chromosome, with its specific location being Xq22.3-q23. The gene contains 17 exons. ASCL4 encodes a 74.4 kDa protein, FACL4, which is composed of 670 amino acids; 17 peptides have been observed through mass spectrometry data.
# Function
Fatty acid-CoA ligase 4 (FACL4), the protein encoded by the ACSL4 gene, is an acyl-CoA synthetase, which is an essential class of lipid metabolism enzymes, and ACSL4 is distinguished by its preference for arachidonic acid. The enzyme controls the level of this fatty acid in cells; because AA is known to induce apoptosis, the enzyme modulates apoptosis. Overexpression of ACSL4 results in a higher rate of arachidonoyl-CoA synthesis, increased 20:4 incorporation into phosphatidylethanolamine, phosphatidylinositol, and triacylglycerol, and reduced cellular levels of unesterified 20:4. Additionally, ACSL4 regulates PGE₂ release from human smooth muscle cells. ACSL4 may regulate a number of processes dependent on the release of arachidonic acid-derived lipid mediators in the arterial wall.
# Clinical significance
The most common SNP (C to T substitution) in the first intron of the FACL4 gene is associated with altered FA composition of plasma phosphatidylcholines in patients with Metabolic Syndrome.
It has been implicated in many mechanisms of carcinogenesis and neuronal development.
## Cancer
In breast cancer, ACSL4 can serve as both a biomarker for and mediator of an aggressive breast cancer phenotype. ACSL4 also is positively correlated with a unique subtype of triple negative breast cancer (TNBC), which is characterized by the absence of androgen receptor (AR) and therefore referred to as quadruple negative breast cancer (QNBC).
The encoded protein FACL4 also plays a role in the growth of hepatic cancer cells. Inhibiting FACL4 leads to inhibition of human liver tumor cells, as marked by an increased level of apoptosis. It has also been suggested that modulation of FACL4 expression/activity is an approach for treatment of hepatic cell carcinoma (HCC).
The FACL4 pathway is also important in colon carcinogenesis; the development of selective inhibitors for FACL4 may be a worthy effort in the prevention and treatment of colon cancer. FACL4 up-regulation appears to occur during the transformation from the cancer from adenoma to adenocarcinoma. Additionally, some colon tumor promoters significantly induced FACL4 expression.
## Neuronal development
FACL4 was the gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism. Since the ASCL4 gene is highly expressed in brain, where it encodes a brain specific isoform, a FACL4 mutation may be an efficient diagnostic tool in mentally retarded males. FACL4was discovered to bedeleted in a family with Alport syndrome and elliptocytosis.
# Interactions
ACSL4 expression is regulated by SHP2 activity. Additionally, ACSL4 interacts with ACSL3, APP, DSE, ELAVL1, HECW2, MINOS1, PARK2, SPG20, SUMO2, TP53, TUBGCP3, UBC, UBD, and YWHAQ. | ACSL4
Long-chain-fatty-acid—CoA ligase 4 is an enzyme that in humans is encoded by the ACSL4 gene.[1][2][3]
The protein encoded by this gene is an isozyme of the long-chain fatty-acid-coenzyme A ligase family. Although differing in substrate specificity, subcellular localization, and tissue distribution, all isozymes of this family convert free long-chain fatty acids into fatty acyl-CoA esters, and thereby play a key role in lipid biosynthesis and fatty acid degradation. This isozyme preferentially utilizes arachidonate as substrate. The absence of this enzyme may contribute to the mental retardation or Alport syndrome. Alternative splicing of this gene generates 2 transcript variants.[3]
# Structure
The ACSL4 gene is located on the X-chromosome, with its specific location being Xq22.3-q23. The gene contains 17 exons.[3] ASCL4 encodes a 74.4 kDa protein, FACL4, which is composed of 670 amino acids; 17 peptides have been observed through mass spectrometry data.[4][5]
# Function
Fatty acid-CoA ligase 4 (FACL4), the protein encoded by the ACSL4 gene, is an acyl-CoA synthetase, which is an essential class of lipid metabolism enzymes, and ACSL4 is distinguished by its preference for arachidonic acid.[6] The enzyme controls the level of this fatty acid in cells; because AA is known to induce apoptosis, the enzyme modulates apoptosis.[7] Overexpression of ACSL4 results in a higher rate of arachidonoyl-CoA synthesis, increased 20:4 incorporation into phosphatidylethanolamine, phosphatidylinositol, and triacylglycerol, and reduced cellular levels of unesterified 20:4. Additionally, ACSL4 regulates PGE₂ release from human smooth muscle cells. ACSL4 may regulate a number of processes dependent on the release of arachidonic acid-derived lipid mediators in the arterial wall.[8]
# Clinical significance
The most common SNP (C to T substitution) in the first intron of the FACL4 gene is associated with altered FA composition of plasma phosphatidylcholines in patients with Metabolic Syndrome.[9]
It has been implicated in many mechanisms of carcinogenesis and neuronal development.[6]
## Cancer
In breast cancer, ACSL4 can serve as both a biomarker for and mediator of an aggressive breast cancer phenotype. ACSL4 also is positively correlated with a unique subtype of triple negative breast cancer (TNBC), which is characterized by the absence of androgen receptor (AR) and therefore referred to as quadruple negative breast cancer (QNBC).[10]
The encoded protein FACL4 also plays a role in the growth of hepatic cancer cells. Inhibiting FACL4 leads to inhibition of human liver tumor cells, as marked by an increased level of apoptosis.[11] It has also been suggested that modulation of FACL4 expression/activity is an approach for treatment of hepatic cell carcinoma (HCC).[7]
The FACL4 pathway is also important in colon carcinogenesis; the development of selective inhibitors for FACL4 may be a worthy effort in the prevention and treatment of colon cancer. FACL4 up-regulation appears to occur during the transformation from the cancer from adenoma to adenocarcinoma. Additionally, some colon tumor promoters significantly induced FACL4 expression.[12]
## Neuronal development
FACL4 was the gene shown to be involved in nonspecific mental retardation and fatty-acid metabolism.[13] Since the ASCL4 gene is highly expressed in brain, where it encodes a brain specific isoform, a FACL4 mutation may be an efficient diagnostic tool in mentally retarded males.[14] FACL4was discovered to bedeleted in a family with Alport syndrome and elliptocytosis.[15]
# Interactions
ACSL4 expression is regulated by SHP2 activity.[16] Additionally, ACSL4 interacts with ACSL3, APP, DSE, ELAVL1, HECW2, MINOS1, PARK2, SPG20, SUMO2, TP53, TUBGCP3, UBC, UBD, and YWHAQ.[3] | https://www.wikidoc.org/index.php/ACSL4 | |
c3b286aa6dcde1c48be602690c07591ce1f735ae | wikidoc | ACSS2 | ACSS2
Acyl-coenzyme A synthetase short-chain family member 2 is an enzyme that in humans is encoded by the ACSS2 gene.
# Function
This gene encodes a cytosolic enzyme that catalyzes the activation of acetate for use in lipid synthesis and energy generation. The protein acts as a monomer and produces acetyl-CoA from acetate in a reaction that requires ATP. It is also essential for the production of Crotonyl-CoA which activates its target genes by crotonylation of histone tails. Expression of this gene is regulated by sterol regulatory element-binding proteins, transcription factors that activate genes required for the synthesis of cholesterol and unsaturated fatty acids. Two transcript variants encoding different isoforms have been found for this gene.
Metabolic production of acetyl-CoA is linked to histone acetylation and gene regulation. In mouse neurons, Mews et al. identified a major role for the ACSS2 pathway to regulate histone acetylation and neuronal gene expression. Histone acetylation in mature neurons is associated strongly with memory formation. Chromatin becomes acetylated in specific regions of the brain, such as the hippocampus, in response to neuronal activity or behavioral training in rodent. Such acetylation correlates with the increased expression of a set of 'immediate early' genes, which encode proteins that broadly mediate changes in the strength of connections between neurons, therefore facilitating memory consolidation. In the mouse hippocampus, ACSS2 binds directly to immediate early genes to 'fuel' local histone acetylation and, in turn, their induction for long-term spatial memory. | ACSS2
Acyl-coenzyme A synthetase short-chain family member 2 is an enzyme that in humans is encoded by the ACSS2 gene.[1][2]
# Function
This gene encodes a cytosolic enzyme that catalyzes the activation of acetate for use in lipid synthesis and energy generation. The protein acts as a monomer and produces acetyl-CoA from acetate in a reaction that requires ATP. It is also essential for the production of Crotonyl-CoA which activates its target genes by crotonylation of histone tails. Expression of this gene is regulated by sterol regulatory element-binding proteins, transcription factors that activate genes required for the synthesis of cholesterol and unsaturated fatty acids. Two transcript variants encoding different isoforms have been found for this gene.[2]
Metabolic production of acetyl-CoA is linked to histone acetylation and gene regulation. In mouse neurons, Mews et al.[3] identified a major role for the ACSS2 pathway to regulate histone acetylation and neuronal gene expression. Histone acetylation in mature neurons is associated strongly with memory formation. Chromatin becomes acetylated in specific regions of the brain, such as the hippocampus, in response to neuronal activity or behavioral training in rodent.[4] Such acetylation correlates with the increased expression of a set of 'immediate early' genes,[5] which encode proteins that broadly mediate changes in the strength of connections between neurons, therefore facilitating memory consolidation.[6] In the mouse hippocampus, ACSS2 binds directly to immediate early genes to 'fuel' local histone acetylation and, in turn, their induction for long-term spatial memory. | https://www.wikidoc.org/index.php/ACSS2 | |
28b454407af68fd025251fd0b707fa1e116625c7 | wikidoc | ACTA2 | ACTA2
Alpha-actin-2 also known as actin, aortic smooth muscle or alpha smooth muscle actin (α-SMA, SMactin, alpha-SM-actin, ASMA) is a protein that in humans is encoded by the ACTA2 gene located on 10q22-q24.
Actin alpha 2, the human aortic smooth muscle actin gene, is one of six different actin isoforms which have been identified. Actins are highly conserved proteins that are involved in cell motility, structure and integrity. Alpha actins are a major constituent of the contractile apparatus. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, Moyamoya disease, and multisystemic smooth muscle dysfunction syndrome.
Alpha-smooth muscle actin (α-SMA) is commonly used as a marker of myofibroblast formation. | ACTA2
Alpha-actin-2 also known as actin, aortic smooth muscle or alpha smooth muscle actin (α-SMA, SMactin, alpha-SM-actin, ASMA) is a protein that in humans is encoded by the ACTA2 gene located on 10q22-q24.[1][2]
Actin alpha 2, the human aortic smooth muscle actin gene, is one of six different actin isoforms which have been identified. Actins are highly conserved proteins that are involved in cell motility, structure and integrity. Alpha actins are a major constituent of the contractile apparatus. Mutations in this gene cause a variety of vascular diseases, such as thoracic aortic disease, coronary artery disease, stroke, Moyamoya disease, and multisystemic smooth muscle dysfunction syndrome.[1]
Alpha-smooth muscle actin (α-SMA) is commonly used as a marker of myofibroblast formation.[3] | https://www.wikidoc.org/index.php/ACTA2 | |
8c5729886aff96f5d457d934660fdc2fcae6a55f | wikidoc | ACTC1 | ACTC1
ACTC1 encodes cardiac muscle alpha actin. This isoform differs from the alpha actin that is expressed in skeletal muscle, ACTA1. Alpha cardiac actin is the major protein of the thin filament in cardiac sarcomeres, which are responsible for muscle contraction and generation of force to support the pump function of the heart.
# Structure
Cardiac alpha actin is a 42.0 kDa protein composed of 377 amino acids. Cardiac alpha actin is a filamentous protein extending from a complex mesh with cardiac alpha-actinin (ACTN2) at Z-lines towards the center of the sarcomere. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to four others. The atomic structure of monomeric actin was solved by Kabsch et al., and closely thereafter this same group published the structure of the actin filament. Actins are highly conserved proteins; the alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. Cardiac (ACTC1) and skeletal (ACTA1) alpha actins differ by only four amino acids (Asp4Glu, Glu5Asp, Leu301Met, Ser360Thr; cardiac/skeletal). The actin monomer has two asymmetric domains; the larger inner domain comprised by sub-domains 3 and 4, and the smaller outer domain by sub-domains 1 and 2. Both the amino and carboxy-termini lie in sub-domain 1 of the outer domain.
# Function
Actin is a dynamic structure that can adapt two states of flexibility, with the greatest difference between the states occurring as a result of movement within sub-domain 2. Myosin binding increases the flexibility of actin, and cross-linking studies have shown that myosin subfragment-1 binds to actin amino acid residues 48-67 within actin sub-domain 2, which may account for this effect.
It has been suggested that the ACTC1 gene has a role during development. Experiments in chick embryos found an association between ACTC1 knockdown and a reduction in the atrial septa.
# Clinical significance
Polymorphisms in ACTC1 have been linked to Dilated Cardiomyopathy in a small number of Japanese patients. Further studies in patients from South Africa found no association. The E101K missense mutation has been associated with Hypertrophic Cardiomyopathy and Left Ventricular Noncompaction. Another mutation has in the ACTC1 gene has been associated with atrial septal defects. | ACTC1
ACTC1 encodes cardiac muscle alpha actin.[1][2] This isoform differs from the alpha actin that is expressed in skeletal muscle, ACTA1. Alpha cardiac actin is the major protein of the thin filament in cardiac sarcomeres, which are responsible for muscle contraction and generation of force to support the pump function of the heart.
# Structure
Cardiac alpha actin is a 42.0 kDa protein composed of 377 amino acids.[3][4] Cardiac alpha actin is a filamentous protein extending from a complex mesh with cardiac alpha-actinin (ACTN2) at Z-lines towards the center of the sarcomere. Polymerization of globular actin (G-actin) leads to a structural filament (F-actin) in the form of a two-stranded helix. Each actin can bind to four others. The atomic structure of monomeric actin was solved by Kabsch et al.,[5] and closely thereafter this same group published the structure of the actin filament.[6] Actins are highly conserved proteins; the alpha actins are found in muscle tissues and are a major constituent of the contractile apparatus. Cardiac (ACTC1) and skeletal (ACTA1) alpha actins differ by only four amino acids (Asp4Glu, Glu5Asp, Leu301Met, Ser360Thr; cardiac/skeletal). The actin monomer has two asymmetric domains; the larger inner domain comprised by sub-domains 3 and 4, and the smaller outer domain by sub-domains 1 and 2. Both the amino and carboxy-termini lie in sub-domain 1 of the outer domain.
# Function
Actin is a dynamic structure that can adapt two states of flexibility, with the greatest difference between the states occurring as a result of movement within sub-domain 2.[7] Myosin binding increases the flexibility of actin,[8] and cross-linking studies have shown that myosin subfragment-1 binds to actin amino acid residues 48-67 within actin sub-domain 2, which may account for this effect.[9]
It has been suggested that the ACTC1 gene has a role during development. Experiments in chick embryos found an association between ACTC1 knockdown and a reduction in the atrial septa.[10]
# Clinical significance
Polymorphisms in ACTC1 have been linked to Dilated Cardiomyopathy in a small number of Japanese patients.[11] Further studies in patients from South Africa found no association.[12] The E101K missense mutation has been associated with Hypertrophic Cardiomyopathy[13][14][15][16] and Left Ventricular Noncompaction.[17] Another mutation has in the ACTC1 gene has been associated with atrial septal defects.[10] | https://www.wikidoc.org/index.php/ACTC1 | |
ab6042d27a520592f131257291b80a6dbab3301a | wikidoc | ACTG1 | ACTG1
Gamma-actin is a protein that in humans is encoded by the ACTG1 gene. Gamma-actin is widely expressed in cellular cytoskeletons of many tissues; in adult striated muscle cells, gamma-actin is localized to Z-discs and costamere structures, which are responsible for force transduction and transmission in muscle cells. Mutations in ACTG1 have been associated with nonsyndromic hearing loss and Baraitser-Winter syndrome, as well as susceptibility of adolescent patients to vincristine toxicity.
# Structure
Human gamma-actin is 41.8 kDa in molecular weight and 375 amino acids in length. Actins are highly conserved proteins that are involved in various types of cell motility, and maintenance of the cytoskeleton. In vertebrates, three main groups of actin isoforms, alpha, beta and gamma have been identified.
The alpha actins are found in muscle tissues and are a major constituent of the sarcomere contractile apparatus. The beta and gamma actins co-exist in most cell types as components of the cytoskeleton, and as mediators of internal cell motility. Actin, gamma 1, encoded by this gene, is found in non-muscle cells in the cytoplasm, and in muscle cells at costamere structures, or transverse points of cell-cell adhesion that run perpendicular to the long axis of myocytes.
# Function
In myocytes, sarcomeres adhere to the sarcolemma via costameres, which align at Z-discs and M-lines. The two primary cytoskeletal components of costameres are desmin intermediate filaments and gamma-actin microfilaments. It has been shown that gamma-actin interacting with another costameric protein dystrophin is critical for costameres forming mechanically strong links between the cytoskeleton and the sarcolemmal membrane. Additional studies have shown that gamma-actin colocalizes with alpha-actinin and GFP-labeled gamma actin localized to Z-discs, whereas GFP-alpha-actin localized to pointed ends of thin filaments, indicating that gamma actin specifically localizes to Z-discs in striated muscle cells.
During development of myocytes, gamma actin is thought to play a role in the organization and assembly of developing sarcomeres, evidenced in part by its early colocalization with alpha-actinin. Gamma-actin is eventually replaced by sarcomeric alpha-actin isoforms, with low levels of gamma-actin persisting in adult myocytes which associate with Z-disc and costamere domains.
Insights into the function of gamma-actin in muscle have come from studies employing transgenesis. In a skeletal muscle-specific knockout of gamma-actin in mice, these animals showed no detectable abnormalities in development; however, knockout mice showed muscle weakness and fiber necrosis, along with decreased isometric twitch force, disrupted intrafibrillar and interfibrillar connections among myocytes, and myopathy.
# Clinical Significance
An autosomal dominant mutation in ACTG1 in the DFNA20/26 locus at 17q25-qter was identified in patients with hearing loss. A Thr278Ile mutation was identified in helix 9 of gamma-actin protein, which is predicted to alter protein structure. This study identified the first disease causing mutation in gamma-actin and underlies the importance of gamma-actin as structural elements of the inner ear hair cells. Since then, other ACTG1 mutations have been linked to nonsyndromic hearing loss, including Met305Thr.
A missense mutation in ACTG1 at Ser155Phe has also been identified in patients with Baraitser-Winter syndrome, which is a developmental disorder characterized by congenital ptosis, excessively-arched eyebrows, hypertelorism, ocular colobomata, lissencephaly, short stature, seizures and hearing loss.
Differential expression of ACTG1 mRNA was also identified in patients with Sporadic Amyotrophic Lateral Sclerosis, a devastating disease with unknown causality, using a sophisticated bioinformatics approach employing Affymetrix long-oligonucleotide BaFL methods.
Single nucleotide polymorphisms in ACTG1 have been associated with vincristine toxicity, which is part of the standard treatment regimen for childhood acute lymphoblastic leukemia. Neurotoxicity was more frequent in patients that were ACTG1 Gly310Ala mutation carriers, suggesting that this may play a role in patient outcomes from vincristine treatment.
# Interactions
ACTG1 has been shown to interact with:
- CAP1,
- DMD,
- TMSB4X, and
- plectin. | ACTG1
Gamma-actin is a protein that in humans is encoded by the ACTG1 gene.[1] Gamma-actin is widely expressed in cellular cytoskeletons of many tissues; in adult striated muscle cells, gamma-actin is localized to Z-discs and costamere structures, which are responsible for force transduction and transmission in muscle cells. Mutations in ACTG1 have been associated with nonsyndromic hearing loss and Baraitser-Winter syndrome, as well as susceptibility of adolescent patients to vincristine toxicity.
# Structure
Human gamma-actin is 41.8 kDa in molecular weight and 375 amino acids in length.[2] Actins are highly conserved proteins that are involved in various types of cell motility, and maintenance of the cytoskeleton. In vertebrates, three main groups of actin isoforms, alpha, beta and gamma have been identified.[3]
The alpha actins are found in muscle tissues and are a major constituent of the sarcomere contractile apparatus. The beta and gamma actins co-exist in most cell types as components of the cytoskeleton, and as mediators of internal cell motility. Actin, gamma 1, encoded by this gene, is found in non-muscle cells in the cytoplasm, and in muscle cells at costamere structures, or transverse points of cell-cell adhesion that run perpendicular to the long axis of myocytes.[4][5][6]
# Function
In myocytes, sarcomeres adhere to the sarcolemma via costameres, which align at Z-discs and M-lines.[7] The two primary cytoskeletal components of costameres are desmin intermediate filaments and gamma-actin microfilaments.[8] It has been shown that gamma-actin interacting with another costameric protein dystrophin is critical for costameres forming mechanically strong links between the cytoskeleton and the sarcolemmal membrane.[9][10] Additional studies have shown that gamma-actin colocalizes with alpha-actinin and GFP-labeled gamma actin localized to Z-discs, whereas GFP-alpha-actin localized to pointed ends of thin filaments, indicating that gamma actin specifically localizes to Z-discs in striated muscle cells.[11][12][13]
During development of myocytes, gamma actin is thought to play a role in the organization and assembly of developing sarcomeres, evidenced in part by its early colocalization with alpha-actinin.[14] Gamma-actin is eventually replaced by sarcomeric alpha-actin isoforms,[15][16][17] with low levels of gamma-actin persisting in adult myocytes which associate with Z-disc and costamere domains.[11][18][19]
Insights into the function of gamma-actin in muscle have come from studies employing transgenesis. In a skeletal muscle-specific knockout of gamma-actin in mice, these animals showed no detectable abnormalities in development; however, knockout mice showed muscle weakness and fiber necrosis, along with decreased isometric twitch force, disrupted intrafibrillar and interfibrillar connections among myocytes, and myopathy.[20]
# Clinical Significance
An autosomal dominant mutation in ACTG1 in the DFNA20/26 locus at 17q25-qter was identified in patients with hearing loss. A Thr278Ile mutation was identified in helix 9 of gamma-actin protein, which is predicted to alter protein structure. This study identified the first disease causing mutation in gamma-actin and underlies the importance of gamma-actin as structural elements of the inner ear hair cells.[21] Since then, other ACTG1 mutations have been linked to nonsyndromic hearing loss, including Met305Thr.[22]
A missense mutation in ACTG1 at Ser155Phe has also been identified in patients with Baraitser-Winter syndrome, which is a developmental disorder characterized by congenital ptosis, excessively-arched eyebrows, hypertelorism, ocular colobomata, lissencephaly, short stature, seizures and hearing loss.[23][24]
Differential expression of ACTG1 mRNA was also identified in patients with Sporadic Amyotrophic Lateral Sclerosis, a devastating disease with unknown causality, using a sophisticated bioinformatics approach employing Affymetrix long-oligonucleotide BaFL methods.[25]
Single nucleotide polymorphisms in ACTG1 have been associated with vincristine toxicity, which is part of the standard treatment regimen for childhood acute lymphoblastic leukemia. Neurotoxicity was more frequent in patients that were ACTG1 Gly310Ala mutation carriers, suggesting that this may play a role in patient outcomes from vincristine treatment.[26]
# Interactions
ACTG1 has been shown to interact with:
- CAP1,[27]
- DMD,[9]
- TMSB4X,[28][29] and
- plectin.[30] | https://www.wikidoc.org/index.php/ACTG1 | |
5d453e6e78ce51bc11af6fbc45c8d43f8f8a707c | wikidoc | ACVR1 | ACVR1
Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ACVR1 gene; also known as ALK-2 (activin receptor-like kinase-2). ACVR1 has been linked to the 2q23-24 region of the genome. This protein is important in the bone morphogenic protein (BMP) pathway which is responsible for the development and repair of the skeletal system. While knock-out models with this gene are in progress, the ACVR1 gene has been connected to Fibrodysplasia Ossificans Progressiva, a disease characterized by the formation of heterotopic bone throughout the body.
# Function
Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I ( I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. This gene encodes activin A type I receptor which signals a particular transcriptional response in concert with activin type II receptors.
# Signaling
ACVR1 transduces signals of BMPs. BMPs bind either ACVR2A/ACVR2B or a BMPR2 and then form a complex with ACVR1. These go on to recruit the R-SMADs SMAD1, SMAD2, SMAD3 or SMAD6.
# Clinical significance
A mutation in the gene ACVR1 (= ALK2) is responsible for the fibrodysplasia ossificans progressiva. ACVR1 encodes activin receptor type-1, a BMP type-1 receptor. The mutation causes the ACVR1 protein to have the amino acid histidine substituted for the amino acid arginine at position 206. This causes the protein ALK2 to change in the critical glycine-serine activation domain of the protein which will cause the protein to bind its inhibitory ligand (FKBP12) less tightly, and activate its SMAD pathway specific proteins more effectively than usual. The result is the BMP pathway will trigger when it should not, and bone will form in soft tissues throughout the body. This causes endothelial cells to transform to mesenchymal stem cells and then to bone.
Mutations in the ACVR1 gene have also been linked to cancer, especially diffuse intrinsic pontine glioma (DIPG). | ACVR1
Activin A receptor, type I (ACVR1) is a protein which in humans is encoded by the ACVR1 gene; also known as ALK-2 (activin receptor-like kinase-2).[1] ACVR1 has been linked to the 2q23-24 region of the genome.[2] This protein is important in the bone morphogenic protein (BMP) pathway which is responsible for the development and repair of the skeletal system. While knock-out models with this gene are in progress, the ACVR1 gene has been connected to Fibrodysplasia Ossificans Progressiva, a disease characterized by the formation of heterotopic bone throughout the body.[2]
# Function
Activins are dimeric growth and differentiation factors which belong to the transforming growth factor-beta (TGF beta) superfamily of structurally related signaling proteins. Activins signal through a heteromeric complex of receptor serine kinases which include at least two type I ( I and IB) and two type II (II and IIB) receptors. These receptors are all transmembrane proteins, composed of a ligand-binding extracellular domain with cysteine-rich region, a transmembrane domain, and a cytoplasmic domain with predicted serine/threonine specificity. Type I receptors are essential for signaling; and type II receptors are required for binding ligands and for expression of type I receptors. Type I and II receptors form a stable complex after ligand binding, resulting in phosphorylation of type I receptors by type II receptors. This gene encodes activin A type I receptor which signals a particular transcriptional response in concert with activin type II receptors.[3]
# Signaling
ACVR1 transduces signals of BMPs. BMPs bind either ACVR2A/ACVR2B or a BMPR2 and then form a complex with ACVR1. These go on to recruit the R-SMADs SMAD1, SMAD2, SMAD3 or SMAD6.[4]
# Clinical significance
A mutation in the gene ACVR1 (= ALK2) is responsible for the fibrodysplasia ossificans progressiva.[5] ACVR1 encodes activin receptor type-1, a BMP type-1 receptor. The mutation causes the ACVR1 protein to have the amino acid histidine substituted for the amino acid arginine at position 206.[6] This causes the protein ALK2 to change in the critical glycine-serine activation domain of the protein which will cause the protein to bind its inhibitory ligand (FKBP12) less tightly, and activate its SMAD pathway specific proteins more effectively than usual.[2] The result is the BMP pathway will trigger when it should not, and bone will form in soft tissues throughout the body. This causes endothelial cells to transform to mesenchymal stem cells and then to bone.[7]
Mutations in the ACVR1 gene have also been linked to cancer, especially diffuse intrinsic pontine glioma (DIPG).[8][9][10] | https://www.wikidoc.org/index.php/ACVR1 | |
ed350c1dff2c2accfd068e7c2ba2cb5f0f86b1ae | wikidoc | AD-36 | AD-36
AD-36 is one of 51 types of adenoviruses known to infect humans. It was first shown to be associated with obesity in chickens by Dr. Nikhil Dhurandhar.
There has been a positive correlation between body fat and the presence of AD-36 antibodies in the blood. Previous research showed that chicken or mice injected with similar types of viruses show a statistically significant weight gain.
A 2.5 fold increase in fat storage was not uncommon, among the test subjects. There is, however, a distinctive signature of the viral weight gain, in addition to the obvious anti-bodies that can now be tested for, the weight gain is unusual in that lipids, triglycerides, and cholesterol are markedly absent, or at least very low, in the blood of the victim. This is distinct from normal obesity, where these chemicals are usually found in the blood in abundance, as a natural tendency in the cause and effect chain. Currently, no one knows where these chemicals are going, but the current hypothesis is that they are being stored within cells, instead of excreted via the blood stream.
It was noted the following in the experiment:
AD-36 has been found to increase adiposity in chickens among other non-human subjects. This is not to be mistaken for the sole, or even leading, cause of obesity if any cause at all. It is fact that this causes and increase in fat but not for any known amount of time, and certainly not for many years.
Recent testing has been completed on several other human adenoviruses including AD-37 and AD-2. AD-37 showed similar correlations with the increase in fat tissue as it inducted human stem cells into fat cells. However, AD-37 had the reverse effect on cholesterol (increasing it) from that of AD-36. The most important discovery of these experiments (AD-36 in 2004 and AD-37 in 2007) was notes that AD-2 actually lowered the body fat in the test subjects. It is important to understand that the virus is not the only cause of obesity and that further research is needed in order to even prove that it causes any kind of long term obesity. | AD-36
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AD-36 is one of 51 types of adenoviruses known to infect humans. It was first shown to be associated with obesity in chickens by Dr. Nikhil Dhurandhar.[1][2]
There has been a positive correlation between body fat and the presence of AD-36 antibodies in the blood[citation needed]. Previous research showed that chicken or mice injected with similar types of viruses show a statistically significant weight gain.[1]
A 2.5 fold increase in fat storage was not uncommon, among the test subjects[citation needed]. There is, however, a distinctive signature of the viral weight gain, in addition to the obvious anti-bodies that can now be tested for, the weight gain is unusual in that lipids, triglycerides, and cholesterol are markedly absent, or at least very low, in the blood of the victim.[citation needed] This is distinct from normal obesity, where these chemicals are usually found in the blood in abundance, as a natural tendency in the cause and effect chain.[citation needed] Currently, no one knows where these chemicals are going, but the current hypothesis[citation needed] is that they are being stored within cells, instead of excreted via the blood stream.
It was noted the following in the experiment:
AD-36 has been found to increase adiposity in chickens among other non-human subjects. This is not to be mistaken for the sole, or even leading, cause of obesity if any cause at all. It is fact that this causes and increase in fat but not for any known amount of time, and certainly not for many years.
Recent testing has been completed on several other human adenoviruses including AD-37 and AD-2. AD-37 showed similar correlations with the increase in fat tissue as it inducted human stem cells into fat cells.[citation needed] However, AD-37 had the reverse effect on cholesterol (increasing it) from that of AD-36. The most important discovery of these experiments (AD-36 in 2004 and AD-37 in 2007) was notes that AD-2 actually lowered the body fat in the test subjects. It is important to understand that the virus is not the only cause of obesity and that further research is needed in order to even prove that it causes any kind of long term obesity.[citation needed] | https://www.wikidoc.org/index.php/AD-36 | |
89701d60762d7c644e68c989a353b620ed53b904 | wikidoc | PSEN2 | PSEN2
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Presenilin-2 is a protein that in humans is encoded by the PSEN2 gene.
# Function
Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Two alternative transcripts of PSEN2 have been identified.
In melanocytic cells PSEN2 gene expression may be regulated by MITF.
# Interactions
PSEN2 has been shown to interact with:
- BCL2-like 1,
- CAPN1,
- CIB1,
- Calsenilin,
- FHL2,
- FLNB,
- KCNIP4,
- Nicastrin, and
- UBQLN1. | PSEN2
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Presenilin-2 is a protein that in humans is encoded by the PSEN2 gene.[1]
# Function
Alzheimer's disease (AD) patients with an inherited form of the disease carry mutations in the presenilin proteins (PSEN1; PSEN2) or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (main component of amyloid deposits found in AD brains). Presenilins are postulated to regulate APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is thought that the presenilins are involved in the cleavage of the Notch receptor, such that they either directly regulate gamma-secretase activity or themselves are protease enzymes. Two alternative transcripts of PSEN2 have been identified.[2]
In melanocytic cells PSEN2 gene expression may be regulated by MITF.[3]
# Interactions
PSEN2 has been shown to interact with:
- BCL2-like 1,[4]
- CAPN1,[5]
- CIB1,[6]
- Calsenilin,[7][8]
- FHL2,[9]
- FLNB,[10]
- KCNIP4,[11]
- Nicastrin,[12][13] and
- UBQLN1.[14] | https://www.wikidoc.org/index.php/AD4 | |
f383a3b36c6fda1c1b9cb7c82f6a49647ecbc8d9 | wikidoc | ADAM7 | ADAM7
Disintegrin and metalloproteinase domain-containing protein 7 is a protein that in humans is encoded by the ADAM7 gene. ADAM7 is an 85-kDa enzyme that is a member of the transmembrane ADAM (A Disintegrin and Metalloprotease) protein family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. ADAM7 is important for the maturation of sperm cells in mammals. ADAM7 is also denoted as: ADAM_7, ADAM-7, EAPI, GP-83, and GP83.
# Function
The functions of ADAM7 directly relate to sperm maturation and fertilization. Sperm are immobile until traversing the epididymis, in which the sperm interact with many proteins secreted by epithelial cells of the epididymis. Lacking protease activity, ADAM7 may play roles in protein-protein interactions and cell adhesion processes including sperm-egg fusion. ADAM7 is secreted by epididymis cells and transferred to the maturing sperm's surface. As determined through mouse gene knock-out studies, the amount of ADAM7 secreted is directly linked to ADAM2 and ADAM3 protein levels. Complex formation between ADAM7, Calnexin, Hspa5, and Itm2b have been shown to act as a molecular chaperone after ADAM7 is incorporated into the membrane of sperm cells. Furthermore, complex formation with Itm2b is increased during sperm capacitation leading to a conformation change in ADAM7. As such, the ADAM7 protein plays an important function involved in sperm capacitation, although this function is not entirely understood.
# Mechanism of secretion and membrane transfer
ADAM7 is synthesized in epididymis cells and transferred to the membrane of immature sperm cells as they traverse the epididymis during ejaculation. Epithelial cells of the epididymis incorporate ADAM7 into their membrane normally like other integral membrane protein. Portions of the membrane are secreted as exosome vesicles. Secretion in this manner is an apocrine secretion in which apical blebs containing a portion of the epididymis cell are released from the cell. The apical blebs then encounter the immature sperm cell membrane within the convoluted tubules of the epididymis. The apical bleb and immature sperm cell membrane then fuse, ultimately incorporating ADAM7 into the sperm cell membrane.
# Physical characteristics
Human ADAM7 contains a sequence of 756 amino acids. Numerous mammalian orthologs are currently known. The largest portion of ADAM7 resides in the extracellular space. A short helical transmembrane sequence anchors the sequence while a short cytoplasmic sequence exists. This is consistent and expected as the protein has a secretory function.
# Localization
ADAM7 expression is localized in mammalian epididymis cells. Expression of ADAM7 is higher in the head (Caput) of the epididymis and decreases in cells towards the distal epididymis. ADAM7 is also present in mature sperm cell membranes of mice. Thus, ADAM7 is synthesized in the epididymis and transferred to the maturing sperm cell membrane. mRNA transcripts are highly expressed in testes leydig cells as well.
# Model Organisms
Due to the large mammalian homology, ADAM7 is primarily studied in Mus Musculus. | ADAM7
Disintegrin and metalloproteinase domain-containing protein 7 is a protein that in humans is encoded by the ADAM7 gene.[1] ADAM7 is an 85-kDa enzyme that is a member of the transmembrane ADAM (A Disintegrin and Metalloprotease) protein family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. ADAM7 is important for the maturation of sperm cells in mammals. ADAM7 is also denoted as: ADAM_7, ADAM-7, EAPI, GP-83, and GP83.
# Function
The functions of ADAM7 directly relate to sperm maturation and fertilization. Sperm are immobile until traversing the epididymis, in which the sperm interact with many proteins secreted by epithelial cells of the epididymis.[2] Lacking protease activity, ADAM7 may play roles in protein-protein interactions and cell adhesion processes including sperm-egg fusion. ADAM7 is secreted by epididymis cells and transferred to the maturing sperm's surface. As determined through mouse gene knock-out studies, the amount of ADAM7 secreted is directly linked to ADAM2 and ADAM3 protein levels.[3] Complex formation between ADAM7, Calnexin, Hspa5, and Itm2b have been shown to act as a molecular chaperone after ADAM7 is incorporated into the membrane of sperm cells. Furthermore, complex formation with Itm2b is increased during sperm capacitation leading to a conformation change in ADAM7.[3] As such, the ADAM7 protein plays an important function involved in sperm capacitation, although this function is not entirely understood.
# Mechanism of secretion and membrane transfer
ADAM7 is synthesized in epididymis cells and transferred to the membrane of immature sperm cells as they traverse the epididymis during ejaculation. Epithelial cells of the epididymis incorporate ADAM7 into their membrane normally like other integral membrane protein.[2] Portions of the membrane are secreted as exosome vesicles. Secretion in this manner is an apocrine secretion in which apical blebs containing a portion of the epididymis cell are released from the cell. The apical blebs then encounter the immature sperm cell membrane within the convoluted tubules of the epididymis. The apical bleb and immature sperm cell membrane then fuse, ultimately incorporating ADAM7 into the sperm cell membrane.[4][5]
# Physical characteristics
Human ADAM7 contains a sequence of 756 amino acids.[6] Numerous mammalian orthologs are currently known.[7] The largest portion of ADAM7 resides in the extracellular space. A short helical transmembrane sequence anchors the sequence while a short cytoplasmic sequence exists. This is consistent and expected as the protein has a secretory function.[8]
# Localization
ADAM7 expression is localized in mammalian epididymis cells. Expression of ADAM7 is higher in the head (Caput) of the epididymis and decreases in cells towards the distal epididymis.[9] ADAM7 is also present in mature sperm cell membranes of mice.[10] Thus, ADAM7 is synthesized in the epididymis and transferred to the maturing sperm cell membrane. mRNA transcripts are highly expressed in testes leydig cells as well.[11]
# Model Organisms
Due to the large mammalian homology, ADAM7 is primarily studied in Mus Musculus. | https://www.wikidoc.org/index.php/ADAM7 | |
65b262a7637b6e92401d333fccdbb2b07fcae891 | wikidoc | ADCK3 | ADCK3
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aarF domain containing kinase 3 is a protein that in humans is encoded by the ADCK3 gene.
This gene encodes a mitochondrial protein similar to yeast ABC1, which functions in an electron-transferring membrane protein complex in the respiratory chain. It is not related to the family of ABC transporter proteins. Expression of this gene is induced by the tumor suppressor p53 and in response to DNA damage, and inhibiting its expression partially suppresses p53-induced apoptosis. Alternatively spliced transcript variants have been found; however, their full-length nature has not been determined. | ADCK3
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aarF domain containing kinase 3 is a protein that in humans is encoded by the ADCK3 gene.[1]
This gene encodes a mitochondrial protein similar to yeast ABC1, which functions in an electron-transferring membrane protein complex in the respiratory chain. It is not related to the family of ABC transporter proteins. Expression of this gene is induced by the tumor suppressor p53 and in response to DNA damage, and inhibiting its expression partially suppresses p53-induced apoptosis. Alternatively spliced transcript variants have been found; however, their full-length nature has not been determined.[1] | https://www.wikidoc.org/index.php/ADCK3 | |
08c8f7aa1347740c18c135be3dfe6bc8322657ea | wikidoc | ADCY1 | ADCY1
Adenylyl cyclase type 1 is an enzyme that in humans is encoded by the ADCY1 gene.
This gene encodes a form of adenylyl cyclase expressed in brain. A similar protein in mice is involved in pattern formation of the brain.
# Function
ADCY1 is a calmodulin-sensitive adenylyl cyclase. In terms of function, It may be involved in regulatory processes in the central
nervous system; specifically, it may play a role in memory acquisition and learning. It is inhibited by the G protein beta and gamma subunit complex. | ADCY1
Adenylyl cyclase type 1 is an enzyme that in humans is encoded by the ADCY1 gene.[1][2]
This gene encodes a form of adenylyl cyclase expressed in brain. A similar protein in mice is involved in pattern formation of the brain.[2]
# Function
ADCY1 is a calmodulin-sensitive adenylyl cyclase. In terms of function, It may be involved in regulatory processes in the central
nervous system; specifically, it may play a role in memory acquisition and learning. It is inhibited by the G protein beta and gamma subunit complex.[3] | https://www.wikidoc.org/index.php/ADCY1 | |
4b19ff836bff6154671b1fe6930e702909cba6fd | wikidoc | ADCY2 | ADCY2
Adenylyl cyclase type 2 is an enzyme typically expressed in the brain of humans, that is encoded by the ADCY2 gene. It belongs to the adenylyl cyclase class-3 or guanylyl cyclase family because it contains two guanylate cyclase domains. ADCY2 is one of ten different mammalian isoforms of adenylyl cyclases. ADCY2 can be found on chromosome 5 and the "MIR2113-POU3F2" region of chromosome 6, with a length of 1091 amino-acids. An essential cofactor for ADCY2 is magnesium; two ions bind per subunit.
# Structure
Structurally, ADCY2 are transmembrane proteins with twelve transmembrane segments. The protein is organized with six transmembrane segments followed by the C1 cytoplasmic domain. Then another six membrane segments, and then a second cytoplasmic domain called C2. The important parts for function are the N-terminus and the C1 and C2 regions. The C1a and C2a subdomains are homologous and form an intramolecular 'dimer' that forms the active site.
This structure displays significant homology with human brain adenylyl cyclase 1(HBA C1 or ADCY1) in the highly conserved adenylyl cyclases domain found in the 3’ cytoplasmic domain of all mammalian adenylyl cyclases. Outside this domain homology is not similar suggesting that this corresponding mRNA originates from a different gene. In situ hybridization confirms a heterogeneous population of adenylyl cyclase mRNAs is expressed in the brain.
# Function
This gene encodes a member of the family of adenylyl cyclases, which are membrane-associated enzymes that catalyze the formation of the secondary messenger cyclic adenosine monophosphate (cAMP) from ATP. ADCY2 has also been found to accelerate phosphor-acidification, along with glycogen synthesis and breakdown. This enzyme is insensitive to Ca2+/calmodulin, and is stimulated by the G protein beta and gamma subunit complex. Therefore, ADCY2 is highly regulated by G-proteins, calcium, calmodulin, pyrophosphate, and post-translational modifications.
Recently, it has been discover that ADCY2 can activated by a Raf kinase-mediated serine phosphorylation. In aggregate, Raf kinase associates with adenylyl cyclases and is isoform-selective, which includes adenylyl cyclase type 2.
In human embryonic kidney cells, ADCY2 is stimulated by activation of Gq-coupled muscarinic receptors through protein kinase C (PKC) to generate localized cAMP. Once the agonist binding to the Gq-coupled muscarinic receptor, A-kinase-anchoring protein (AKAP) recruits PKC to activate ADCY2 to produce cAMP. The cAMP formed is degraded by phosphodiesterase 4 (PDE4) activated by an AKAP-anchored protein kinase A.
# Clinical significance
Polymorphisms of the ADCY2 gene have been associated with COPD and lung function.
Perturbations in adenylyl cyclase activity have been implicated in alcohol and opioid addiction and is associated with human diseases, including thyroid adenoma, Anthrax, precocious puberty in males and chondrodysplasia punctata diseases. During these diseases, ADCY2 undergoes a super-related pathway where protein kinase A (PKA) activation occurs in glucagon signaling and IP3 signaling. This enzyme may play a role in bipolar disorder along with other brain-expressed genes including NCALD, WDR60, SCN7A, and SPAG16.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
# Model organisms
Model organisms have been used in the study of ADCY2 function. A conditional knockout mouse line called Adcy2tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Additional screens performed: - In-depth immunological phenotyping - in-depth bone and cartilage phenotyping | ADCY2
Adenylyl cyclase type 2 is an enzyme typically expressed in the brain of humans, that is encoded by the ADCY2 gene.[1][2] It belongs to the adenylyl cyclase class-3 or guanylyl cyclase family because it contains two guanylate cyclase domains.[3] ADCY2 is one of ten different mammalian isoforms of adenylyl cyclases. ADCY2 can be found on chromosome 5 and the "MIR2113-POU3F2" region of chromosome 6, with a length of 1091 amino-acids. An essential cofactor for ADCY2 is magnesium; two ions bind per subunit.[3]
# Structure
Structurally, ADCY2 are transmembrane proteins with twelve transmembrane segments. The protein is organized with six transmembrane segments followed by the C1 cytoplasmic domain. Then another six membrane segments, and then a second cytoplasmic domain called C2. The important parts for function are the N-terminus and the C1 and C2 regions. The C1a and C2a subdomains are homologous and form an intramolecular 'dimer' that forms the active site.
This structure displays significant homology with human brain adenylyl cyclase 1(HBA C1 or ADCY1) in the highly conserved adenylyl cyclases domain found in the 3’ cytoplasmic domain of all mammalian adenylyl cyclases. Outside this domain homology is not similar suggesting that this corresponding mRNA originates from a different gene. In situ hybridization confirms a heterogeneous population of adenylyl cyclase mRNAs is expressed in the brain.[4]
# Function
This gene encodes a member of the family of adenylyl cyclases, which are membrane-associated enzymes that catalyze the formation of the secondary messenger cyclic adenosine monophosphate (cAMP) from ATP. ADCY2 has also been found to accelerate phosphor-acidification, along with glycogen synthesis and breakdown.[5] This enzyme is insensitive to Ca2+/calmodulin, and is stimulated by the G protein beta and gamma subunit complex.[2] Therefore, ADCY2 is highly regulated by G-proteins, calcium, calmodulin, pyrophosphate, and post-translational modifications.
Recently, it has been discover that ADCY2 can activated by a Raf kinase-mediated serine phosphorylation.[6] In aggregate, Raf kinase associates with adenylyl cyclases and is isoform-selective, which includes adenylyl cyclase type 2.
In human embryonic kidney cells, ADCY2 is stimulated by activation of Gq-coupled muscarinic receptors through protein kinase C (PKC) to generate localized cAMP. Once the agonist binding to the Gq-coupled muscarinic receptor, A-kinase-anchoring protein (AKAP) recruits PKC to activate ADCY2 to produce cAMP. The cAMP formed is degraded by phosphodiesterase 4 (PDE4) activated by an AKAP-anchored protein kinase A.[7]
# Clinical significance
Polymorphisms of the ADCY2 gene have been associated with COPD and lung function.[8]
Perturbations in adenylyl cyclase activity have been implicated in alcohol and opioid addiction and is associated with human diseases, including thyroid adenoma, Anthrax, precocious puberty in males and chondrodysplasia punctata diseases.[9] During these diseases, ADCY2 undergoes a super-related pathway where protein kinase A (PKA) activation occurs in glucagon signaling and IP3 signaling. This enzyme may play a role in bipolar disorder along with other brain-expressed genes including NCALD, WDR60, SCN7A, and SPAG16.[10]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "NicotineDopaminergic_WP1602"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em}
# Model organisms
Model organisms have been used in the study of ADCY2 function. A conditional knockout mouse line called Adcy2tm1a(KOMP)Wtsi was generated at the Wellcome Trust Sanger Institute.[11] Male and female animals underwent a standardized phenotypic screen[12] to determine the effects of deletion.[13][14][15][16] Additional screens performed: - In-depth immunological phenotyping[17] - in-depth bone and cartilage phenotyping[18] | https://www.wikidoc.org/index.php/ADCY2 | |
7273bc8797a819a58d07f43329e94fc738752e79 | wikidoc | ADCY3 | ADCY3
Adenylyl cyclase type 3 is an enzyme that in humans is encoded by the ADCY3 gene.
# Function
This gene encodes adenylyl cyclase 3, which is a membrane-associated enzyme and catalyzes the formation of the secondary messenger cyclic adenosine monophosphate (cAMP).
The ADCY3 subtype likely mediates odorant detection (possibly) via modulation of intracellular cAMP concentration. | ADCY3
Adenylyl cyclase type 3 is an enzyme that in humans is encoded by the ADCY3 gene.[1][2]
# Function
This gene encodes adenylyl cyclase 3, which is a membrane-associated enzyme and catalyzes the formation of the secondary messenger cyclic adenosine monophosphate (cAMP).[2]
The ADCY3 subtype likely mediates odorant detection (possibly) via modulation of intracellular cAMP concentration.[3] | https://www.wikidoc.org/index.php/ADCY3 | |
5959137ea0dbc793147301e117b7a72c7f80f25d | wikidoc | ADH1B | ADH1B
Alcohol dehydrogenase 1B is an enzyme that in humans is encoded by the ADH1B gene.
The protein encoded by this gene is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol (beverage alcohol), retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. The encoded protein, known as ADH1B or beta-ADH, can form homodimers and heterodimers with ADH1A and ADH1C subunits, exhibits high activity for ethanol oxidation and plays a major role in ethanol catabolism (oxidizing ethanol into acetaldehyde). The acetaldehyde is further metabolized to acetate by aldehyde dehydrogenase genes. Three genes encoding the closely related alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster.
The human gene is located on chromosome 4 in 4q22.
Previously ADH1B was called ADH2. There are more genes in the family of alcohol dehydrogenase. These genes are now referred to as ADH1A, ADH1C, and ADH4, ADH5, ADH6 and ADH7.
# Variants
A single nucleotide polymorphism (SNP) in ADH1B is rs1229984, that changes arginine to histidine at residue 47 of the mature protein; standard nomenclature now includes the initiating methionine, so the position is officially 48.
The 'typical' variant of this has been referred to as ADH2(1) or ADH2*1 while the 'atypical' has been referred to as, e.g., ADH2(2), ADH2*2, ADH1B*48His.
This SNP is associated with the risk for alcohol dependence, alcohol use disorders and alcohol consumption, with the atypical genotype having reduced risk of alcoholism.
Another SNP is rs2066702 . originally called position 369. This SNP is at high frequencies in populations from Africa, and also reduces risk for alcohol dependence.
# Role in pathology
A marked decrease of ADH1B mRNA was detected in corneal fibroblasts taken from persons suffering from keratoconus. | ADH1B
Alcohol dehydrogenase 1B is an enzyme that in humans is encoded by the ADH1B gene.[1][2]
The protein encoded by this gene is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol (beverage alcohol), retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. The encoded protein, known as ADH1B or beta-ADH, can form homodimers and heterodimers with ADH1A and ADH1C subunits, exhibits high activity for ethanol oxidation[3][4] and plays a major role in ethanol catabolism (oxidizing ethanol into acetaldehyde). The acetaldehyde is further metabolized to acetate by aldehyde dehydrogenase genes. Three genes encoding the closely related alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster.[5]
The human gene is located on chromosome 4 in 4q22.
Previously ADH1B was called ADH2. There are more genes in the family of alcohol dehydrogenase. These genes are now referred to as ADH1A, ADH1C, and ADH4, ADH5, ADH6 and ADH7.[6]
# Variants
A single nucleotide polymorphism (SNP) in ADH1B is rs1229984, that changes arginine to histidine at residue 47 of the mature protein;[7] standard nomenclature now includes the initiating methionine, so the position is officially 48.
The 'typical' variant of this has been referred to as ADH2(1) or ADH2*1 while the 'atypical' has been referred to as, e.g., ADH2(2), ADH2*2, ADH1B*48His.
This SNP is associated with the risk for alcohol dependence, alcohol use disorders and alcohol consumption, with the atypical genotype having reduced risk of alcoholism.[8][9][10]
Another SNP is rs2066702 [Arg370Cys].[11] originally called position 369. This SNP is at high frequencies in populations from Africa, and also reduces risk for alcohol dependence[12].
# Role in pathology
A marked decrease of ADH1B mRNA was detected in corneal fibroblasts taken from persons suffering from keratoconus.[13] | https://www.wikidoc.org/index.php/ADH1B | |
04db6d8238badbc669ebd2f3126eec676cae29f2 | wikidoc | ADRM1 | ADRM1
Proteasomal ubiquitin receptor ADRM1 is a protein that in humans is encoded by the ADRM1 gene. Recent evidences on proteasome complex structure confirmed that the protein encoded by gene ADRM1, also known as 26S Proteasome regulatory subunit Rpn13 (systematic nomenclature for proteasome subunits), is a subunit of 19S proteasome complex.
# Gene
The gene ADRM1 encodes one of the non-ATPase subunits of the 19S regulator base, subunit Rpn13. The human PSMD4 gene has 10 exons and locates at chromosome band 20q13.33.The human protein Proteasomal ubiquitin receptor ADRM1 is 42 kDa in size and composed of 407 amino acids. The calculated theoretical pI of this protein is 4.95.
# Structure
The protein encoded by this gene is an integral plasma membrane protein which promotes cell adhesion. The encoded protein is thought to undergo O-linked glycosylation. Expression of this gene has been shown to be induced by gamma interferon in some cancer cells. Two transcript variants encoding the same protein have been found for this gene.
## Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, and Rpn10. Thus, Proteasomal ubiquitin receptor ADRM1 (Rpn13) is an important component of forming the base subcomplex of 19S regulatory particle. Traditional view of Rpn13 is that it is rather an associating partner of proteasome complex than a constitutive subunit. However, emerging evidences suggested that Rpn13 is a novel subunit of 19S. A recent study provided new evidences of 19S complex structure via an integrative approach combining data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. In the newly established sub complex model of 19S base, Rpn2 is rigid protein located on the side of ATPase ring, supporting as the connection between the lid and base. Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located further in the distal part of the 19S complex, indicating that they were recruited to the complex late during the assembly process.
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis, proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex. Rpn13 is one essential subunit of 19S regulatory particle and it contributes to the assembly of the "base" subcomplex. In the base sub complex, Rpn13, as a ubiquitin receptor, offers a docking position for ubiquitinated substrate. Evidence showed that ubiquitination of Rpn13 subunit can significantly reduced the proteasome's ability to bind and degrade ubiquitin-conjugated proteins. Investigation employing biochemical and unbiased AQUA-MS methodologies offered evidences showing that, although the vast majority (if not all) of the double-capped 26S proteasomes, both 19S complexes, contain the ubiquitin receptor Rpn10, only one of these 19S particles contains the additional ubiquitin receptor Rpn13, thereby defining asymmetry in the 26S proteasome. Such structural asymmetry might be the molecular foundation for the one-directional substrate feeding process of proteasome complex. | ADRM1
Proteasomal ubiquitin receptor ADRM1 is a protein that in humans is encoded by the ADRM1 gene.[1][2] Recent evidences on proteasome complex structure confirmed that the protein encoded by gene ADRM1, also known as 26S Proteasome regulatory subunit Rpn13 (systematic nomenclature for proteasome subunits), is a subunit of 19S proteasome complex.[3][4]
# Gene
The gene ADRM1 encodes one of the non-ATPase subunits of the 19S regulator base, subunit Rpn13. The human PSMD4 gene has 10 exons and locates at chromosome band 20q13.33.The human protein Proteasomal ubiquitin receptor ADRM1 is 42 kDa in size and composed of 407 amino acids. The calculated theoretical pI of this protein is 4.95.[5]
# Structure
The protein encoded by this gene is an integral plasma membrane protein which promotes cell adhesion. The encoded protein is thought to undergo O-linked glycosylation. Expression of this gene has been shown to be induced by gamma interferon in some cancer cells. Two transcript variants encoding the same protein have been found for this gene.[2]
## Complex assembly
26S proteasome complex is usually consisted of a 20S core particle (CP, or 20S proteasome) and one or two 19S regulatory particles (RP, or 19S proteasome) on either one side or both side of the barrel-shaped 20S. The CP and RPs pertain distinct structural characteristics and biological functions. In brief, 20S sub complex presents three types proteolytic activities, including caspase-like, trypsin-like, and chymotrypsin-like activities. These proteolytic active sites located in the inner side of a chamber formed by 4 stacked rings of 20S subunits, preventing random protein-enzyme encounter and uncontrolled protein degradation. The 19S regulatory particles can recognize ubiquitin-labeled protein as degradation substrate, unfold the protein to linear, open the gate of 20S core particle, and guide the substate into the proteolytic chamber. To meet such functional complexity, 19S regulatory particle contains at least 18 constitutive subunits. These subunits can be categorized into two classes based on the ATP dependence of subunits, ATP-dependent subunits and ATP-independent subunits. According to the protein interaction and topological characteristics of this multisubunit complex, the 19S regulatory particle is composed of a base and a lid subcomplex. The base consists of a ring of six AAA ATPases (Subunit Rpt1-6, systematic nomenclature) and four non-ATPase subunits (Rpn1, Rpn2, and Rpn10.[6] Thus, Proteasomal ubiquitin receptor ADRM1 (Rpn13) is an important component of forming the base subcomplex of 19S regulatory particle. Traditional view of Rpn13 is that it is rather an associating partner of proteasome complex than a constitutive subunit. However, emerging evidences suggested that Rpn13 is a novel subunit of 19S.[7][8] A recent study provided new evidences of 19S complex structure via an integrative approach combining data from cryoelectron microscopy, X-ray crystallography, residue-specific chemical cross-linking, and several proteomics techniques. In the newly established sub complex model of 19S base, Rpn2 is rigid protein located on the side of ATPase ring, supporting as the connection between the lid and base. Rpn1 is conformationally variable, positioned at the periphery of the ATPase ring. The ubiquitin receptors Rpn10 and Rpn13 are located further in the distal part of the 19S complex, indicating that they were recruited to the complex late during the assembly process.[3]
# Function
As the degradation machinery that is responsible for ~70% of intracellular proteolysis,[9] proteasome complex (26S proteasome) plays a critical roles in maintaining the homeostasis of cellular proteome. Accordingly, misfolded proteins and damaged protein need to be continuously removed to recycle amino acids for new synthesis; in parallel, some key regulatory proteins fulfill their biological functions via selective degradation; furthermore, proteins are digested into peptides for MHC class I antigen presentation. To meet such complicated demands in biological process via spatial and temporal proteolysis, protein substrates have to be recognized, recruited, and eventually hydrolyzed in a well controlled fashion. Thus, 19S regulatory particle pertains a series of important capabilities to address these functional challenges. To recognize protein as designated substrate, 19S complex has subunits that are capable to recognize proteins with a special degradative tag, the ubiquitinylation. It also have subunits that can bind with nucleotides (e.g., ATPs) in order to facilitate the association between 19S and 20S particles, as well as to cause confirmation changes of alpha subunit C-terminals that form the substate entrance of 20S complex. Rpn13 is one essential subunit of 19S regulatory particle and it contributes to the assembly of the "base" subcomplex. In the base sub complex, Rpn13, as a ubiquitin receptor, offers a docking position for ubiquitinated substrate. Evidence showed that ubiquitination of Rpn13 subunit can significantly reduced the proteasome's ability to bind and degrade ubiquitin-conjugated proteins.[10] Investigation employing biochemical and unbiased AQUA-MS methodologies offered evidences showing that, although the vast majority (if not all) of the double-capped 26S proteasomes, both 19S complexes, contain the ubiquitin receptor Rpn10, only one of these 19S particles contains the additional ubiquitin receptor Rpn13, thereby defining asymmetry in the 26S proteasome.[11] Such structural asymmetry might be the molecular foundation for the one-directional substrate feeding process of proteasome complex. | https://www.wikidoc.org/index.php/ADRM1 | |
cb6efc5ae63f794a2aa294bfffdc5c44fd6f3711 | wikidoc | AEBP2 | AEBP2
Adipocyte Enhancer-Binding Protein is a zinc finger protein that in humans is encoded by the evolutionarily well-conserved gene AEBP2. It was initially identified due to its binding capability to the promoter of the adipocyte P2 gene, and was therefore named Adipocyte Enhancer Binding Protein 2. AEBP2 is a potential targeting protein for the mammalian Polycomb Repression Complex 2 (PRC2).
# Function
AEBP2 is a DNA-binding transcriptional repressor. It may interact with and stimulate the activity of the PRC2 complex.
AEBP2 may regulate the migration and development of the neural crest cells through the PRC2-mediated epigenetic mechanism and is most likely a targeting protein for the mammalian PRC2 complex.
# Clinical significance
Diseases associated with AEBP2 include Waardenburg's syndrome, and Hirschsprung's disease. | AEBP2
Adipocyte Enhancer-Binding Protein is a zinc finger protein that in humans is encoded by the evolutionarily well-conserved gene AEBP2. It was initially identified due to its binding capability to the promoter[1] of the adipocyte P2 gene, and was therefore named Adipocyte Enhancer Binding Protein 2. AEBP2 is a potential targeting protein for the mammalian Polycomb Repression Complex 2 (PRC2).[2]
# Function
AEBP2 is a DNA-binding transcriptional repressor. It may interact with and stimulate the activity of the PRC2 complex.[3]
AEBP2 may regulate the migration and development of the neural crest cells through the PRC2-mediated epigenetic mechanism and is most likely a targeting protein for the mammalian PRC2 complex.[4]
# Clinical significance
Diseases associated with AEBP2 include Waardenburg's syndrome, and Hirschsprung's disease.[4] | https://www.wikidoc.org/index.php/AEBP2 | |
b83057b11563347c4286f4cc8d7115f245554c4e | wikidoc | AGG01 | AGG01
AGG01 is the tentative name of a new Penicillin-class antibiotic, recently discovered in the breast milk of the Tammar Wallaby, reportedly one hundred times more powerful than penicillin.
This compound was found to be effective against MRSA, E. coli, Streptococci, Salmonella, Bacillus subtilis, Pseudomonas spp., Proteus vulgaris, and Staphylococcus aureus.
AGG01 has not yet been classified as a Beta-lactam antibiotic.
AGG01 is a cationic peptide, which is a polycationic protein which is rich in positive residues of the amino acidss arginine and lysine, and which folds into an amphipathic structure (one which has both hydrophobic and hydrophilic areas). These features mean that it can interact with the anionic lipids in the bacterial membrane, such as phosphatidylglycerol. It inserts itself into the membrane, by competing with cross-linking proteins between each membrane layer, and then sets up trans-membrane protein channels which induce ion transport out of the cell. This causes huge leakage via osmosis through these 'pores’ and the general consensus is that the loss of these essential molecules is the mechanism by which bacteria are killed. The bacterial membrane has a different structure from the mammalian plasma membrane, so the protein can only kill pathogenic cells and not human ones. | AGG01
AGG01 is the tentative name of a new Penicillin-class antibiotic, recently discovered in the breast milk[1] of the Tammar Wallaby, reportedly one hundred times more powerful than penicillin.
This compound was found to be effective against MRSA, E. coli, Streptococci, Salmonella, Bacillus subtilis, Pseudomonas spp., Proteus vulgaris, and Staphylococcus aureus.
AGG01 has not yet been classified as a Beta-lactam antibiotic.
AGG01 is a cationic peptide, which is a polycationic protein which is rich in positive residues of the amino acidss arginine and lysine, and which folds into an amphipathic structure (one which has both hydrophobic and hydrophilic areas). These features mean that it can interact with the anionic lipids in the bacterial membrane, such as phosphatidylglycerol. It inserts itself into the membrane, by competing with cross-linking proteins between each membrane layer, and then sets up trans-membrane protein channels which induce ion transport out of the cell. This causes huge leakage via osmosis through these 'pores’ and the general consensus is that the loss of these essential molecules is the mechanism by which bacteria are killed. The bacterial membrane has a different structure from the mammalian plasma membrane, so the protein can only kill pathogenic cells and not human ones. | https://www.wikidoc.org/index.php/AGG01 | |
4bedb3e0559030555cd954252b622801436f7927 | wikidoc | AGGF1 | AGGF1
Angiogenic factor with G patch and FHA domains 1 is a protein that in humans is encoded by the AGGF1 gene.
AGGF1 is a human gene that functions as an angiogenic factor with a G-patch and forkhead-associated domain. This gene is predominantly expressed in activated, plump endothelial cells and acts to regulate angiogenesis and vascular development. AGGF1 is known to interact with a wide range of proteins involved in vascular development. Mutations to AGGF1 have been implicated in multiple cancers and is known to cause the rare congenital condition, Klippel-Trenaunay syndrome.
# Gene
The gene was originally named VG5Q, indicating that it was a vascular gene on chromosome 5, but the name was later changed to reflect its function, instead of just its location.
The AGGF1 gene promoter does not contain a TATA box and contains 2 transcription start sites that are -367 and -364 base pairs ahead of the base translation start site. The gene promoter contains over 50 CpG islands, which makes it a DNA methylation target. AGGF1 is regulated by 2 repressor sites and 2 activator sites. While the presence of 2 repressor and 2 activator sites is clear, the only known transcription factor that regulates AGGF1 is GATA1. GATA1 binds upstream of the AGGF1 gene promoter at -295 and -300, and the binding of GATA1 will lead to increased AGGF1 expression. For the gene to be fully expressed, both of the activator sites must be bound by the transcription factors, GATA1 and another unknown factor.
# Protein
To form a protein, an mRNA transcript must be transcribed from the DNA. For AGGF1, the mRNA transcript contains 14 exons and 34 807 nucleotides.
There are 714 amino acids present in this protein, and it has a molecular weight of 80997 Da. It contains a coiled coil domain at positions 18-88 and an OCRE domain at the N terminus. The G-patch domain is located at amino acids 619-663 while the forkhead-associated domain is located at amino acids 435-508. While it is known that these domains are present in the protein, their role in protein function remains unclear.
AGGF1 was the third haploinsufficient human gene identified. Haploinsufficiency means AGGF1 is "dose dependent" so any reductions in protein product can have phenotypic consequences on the vascular development of the organism.
# Expression
AGGF1 is largely expressed during early embryonic vein specification, and expression is increased when endothelial cells are activated. While AGGF1 is predominantly functional in endothelial, vascular smooth muscle cells, and osteoblasts, it also has activity in mast cells, cardiac cells, Kupffer cells and hematopoietic stem cells. AGGF1 mRNA has been detected in the heart, kidneys and limbs which indicates that the protein likely also functions in these organs. The proliferation of vascular smooth muscle cells is inhibited when AGGF1 is expressed. It has been found that AGGF1 is highly expressed in some malignant tumours which has implicated AGGF1 in cancer. In vitro models have shown that AGGF1 localizes to cell periphery and directly outside of the cell.
Depending on the mutation type, AGGF1 mutations can be lethal in either the heterozygous or homozygous genotype due to its haploinsufficiency. Mice models have shown that heterozygous mutations can cause fatality due to hemorrhaging while homozygous mutations can prevent proper stem cell differentiation.
# Homology
Aggf1 is not unique to humans. This gene is conserved across many species, such as chimpanzees, Rhesus monkeys, dogs, cows, mice, rats, chickens, and frogs. There are 212 organisms that have genes which are orthologs to AGGF1.
Within the human chromosome, there are pseudogenes related to AGGF1 are located on chromosomes 3, 4, 10 and 16 that have likely arisen due to translocation events.
# Function
AGGF1 functions to regulate angiogenesis and vascular development. Gene ontology has also implicated AGGF1 in cell adhesion, positive regulation of angiogenesis and endothelial cell proliferation. Additionally, AGGF1 has been shown to protect against inflammation and ischemic injuries. During embryongenesis, AGGF1 is required for hematopoietic stem cell specification and the differentiation of hematopoietic and endothelial cell lineages. Specifically, it regulates vascular endothelial cadherin (VE-cadherin) by inhibiting the phosphorylation of the cadherin and increasing its presence in the plasma membrane of endothelial cells. AGGF1 is critical to the specification of veins and multipotent hemanigioblasts, anti-inflammation, tumour angiogenesis, and inhibition of vascular permeability. Additionally, it activates autophagy in specific cell types, such as endothelial cells, cardiac HL1 and H9C2 cells, and vascular smooth muscle cells.
# Interactions
AGGF1 directly and indirectly interacts with many proteins. There are direct interactions between AGGF1 and TNFSF12, another secreted angiogenic factor, that leads to increased angiogenesis. AGGF1 acts upstream of hemangioblast genes such as scl, fil1, and etsrp. AGGF1 acts similarly to VEGF - another gene implicated in vascular growth. Additionally, AGGF1 is known to activate catalytic and regulatory subunits of PI3K. This leads to downstream activation of AKT, GSK3b and p70S6K signalling pathway which leads to vein specification and angiogenesis. AGGF1 also interacts with vein specific markers such at flt4, dab2, and ephB4. Ccl2 has also been shown to interact with AGGF1 in hepatocytes through blocking NF-κB/p65 from binding to Ccl2. AGGF1 activity is eliminated when Elk is overexpressed. AGGF1 regulates autophagy by regulating expression of JNK genes. SMAD7 and Aggf1 directly interact in the liver to inhibit fibrogenesis. The presence of DNMT3b will repress AGGF1 by acting on the promoter region of the gene.
# Clinical significance
## Klippel-Trenaunay Syndrome
Heterogeneous mutations in this gene causing deregulation of expression can lead to the vascular malformations associated with Klippel-Trenaunay syndrome (KTS). Due to the haploinsufficient nature of AGGF1, individuals who have even one mutant allele may have KTS. Studies done in mouse models have shown frequent haemorrhages and increased vascular permeability has been seen in mice who are heterozygous for Aggf1. A translocation between the chromosome 5 q-arm at region 13 in band 3 and the chromosome 11 p-arm at region 15 in band 1 has been implicated in KTS. This translocation affects the AGGF1 promoter so there is a 3 fold increase in protein production. Single nucleotide polymorphisms in intron 11 and exon 7 were associated with KTS susceptibility even though neither of these SNPs resulted in an amino acid change. At one point, the E133K allele was thought to be a mutational hotspot - due to altered phosphorylation - causing KTS, but it has since been found as much as 3.3% of the population are carriers for the mutation.
## Heart Disease
AGGF1 has also been implicated in treatment after vascular smooth muscle cell damage due to coronary artery disease and myocardial infarction. By blocking vascular permeability and regulating vascular smooth muscle cell phenotypic switching, AGGF1 protein therapy is currently being investigated as a new method of treating both of these diseases.
## Cancer
Aberrant AGGF1 has been implicated in multiple cancers and functions in tumour initiation and progression. For example, both hepatocellular carcinoma and gastric cancer survivability is related to the levels of AGGF1 expression in tumours. AGGF1 has been found to have higher expression in tumours than the surrounding tissues, and higher levels of AGGF1 are associated with a poor patient prognosis. | AGGF1
Angiogenic factor with G patch and FHA domains 1 is a protein that in humans is encoded by the AGGF1 gene.[1][2][3]
AGGF1 is a human gene that functions as an angiogenic factor with a G-patch and forkhead-associated domain.[4] This gene is predominantly expressed in activated, plump endothelial cells and acts to regulate angiogenesis and vascular development.[5] AGGF1 is known to interact with a wide range of proteins involved in vascular development.[6] Mutations to AGGF1 have been implicated in multiple cancers and is known to cause the rare congenital condition, Klippel-Trenaunay syndrome.[5][7][8]
# Gene
The gene was originally named VG5Q, indicating that it was a vascular gene on chromosome 5, but the name was later changed to reflect its function, instead of just its location.[9]
The AGGF1 gene promoter does not contain a TATA box and contains 2 transcription start sites that are -367 and -364 base pairs ahead of the base translation start site.[9] The gene promoter contains over 50 CpG islands, which makes it a DNA methylation target.[9] AGGF1 is regulated by 2 repressor sites and 2 activator sites.[9] While the presence of 2 repressor and 2 activator sites is clear, the only known transcription factor that regulates AGGF1 is GATA1.[9] GATA1 binds upstream of the AGGF1 gene promoter at -295 and -300, and the binding of GATA1 will lead to increased AGGF1 expression.[5][9] For the gene to be fully expressed, both of the activator sites must be bound by the transcription factors, GATA1 and another unknown factor.[9]
# Protein
To form a protein, an mRNA transcript must be transcribed from the DNA. For AGGF1, the mRNA transcript contains 14 exons and 34 807 nucleotides.[1]
There are 714 amino acids present in this protein, and it has a molecular weight of 80997 Da.[10] It contains a coiled coil domain at positions 18-88 and an OCRE domain at the N terminus.[10] The G-patch domain is located at amino acids 619-663 while the forkhead-associated domain is located at amino acids 435-508.[10] While it is known that these domains are present in the protein, their role in protein function remains unclear.
AGGF1 was the third haploinsufficient human gene identified.[5] Haploinsufficiency means AGGF1 is "dose dependent" so any reductions in protein product can have phenotypic consequences on the vascular development of the organism.
# Expression
AGGF1 is largely expressed during early embryonic vein specification, and expression is increased when endothelial cells are activated.[10][4] While AGGF1 is predominantly functional in endothelial, vascular smooth muscle cells, and osteoblasts, it also has activity in mast cells, cardiac cells, Kupffer cells and hematopoietic stem cells.[9][4][11][12] AGGF1 mRNA has been detected in the heart, kidneys and limbs which indicates that the protein likely also functions in these organs.[10] The proliferation of vascular smooth muscle cells is inhibited when AGGF1 is expressed.[13] It has been found that AGGF1 is highly expressed in some malignant tumours which has implicated AGGF1 in cancer.[13] In vitro models have shown that AGGF1 localizes to cell periphery and directly outside of the cell.[12]
Depending on the mutation type, AGGF1 mutations can be lethal in either the heterozygous or homozygous genotype due to its haploinsufficiency.[10] Mice models have shown that heterozygous mutations can cause fatality due to hemorrhaging while homozygous mutations can prevent proper stem cell differentiation.[10]
# Homology
Aggf1 is not unique to humans. This gene is conserved across many species, such as chimpanzees, Rhesus monkeys, dogs, cows, mice, rats, chickens, and frogs.[3] There are 212 organisms that have genes which are orthologs to AGGF1.[3]
Within the human chromosome, there are pseudogenes related to AGGF1 are located on chromosomes 3, 4, 10 and 16 that have likely arisen due to translocation events.[3]
# Function
AGGF1 functions to regulate angiogenesis and vascular development.[5] Gene ontology has also implicated AGGF1 in cell adhesion, positive regulation of angiogenesis and endothelial cell proliferation.[3] Additionally, AGGF1 has been shown to protect against inflammation and ischemic injuries.[11] During embryongenesis, AGGF1 is required for hematopoietic stem cell specification and the differentiation of hematopoietic and endothelial cell lineages.[10] Specifically, it regulates vascular endothelial cadherin (VE-cadherin) by inhibiting the phosphorylation of the cadherin and increasing its presence in the plasma membrane of endothelial cells.[5] AGGF1 is critical to the specification of veins and multipotent hemanigioblasts, anti-inflammation, tumour angiogenesis, and inhibition of vascular permeability.[14] Additionally, it activates autophagy in specific cell types, such as endothelial cells, cardiac HL1 and H9C2 cells, and vascular smooth muscle cells.[5][10][14]
# Interactions
AGGF1 directly and indirectly interacts with many proteins. There are direct interactions between AGGF1 and TNFSF12, another secreted angiogenic factor, that leads to increased angiogenesis.[12] AGGF1 acts upstream of hemangioblast genes such as scl, fil1, and etsrp.[6] AGGF1 acts similarly to VEGF - another gene implicated in vascular growth.[6] Additionally, AGGF1 is known to activate catalytic and regulatory subunits of PI3K.[5] This leads to downstream activation of AKT, GSK3b and p70S6K signalling pathway which leads to vein specification and angiogenesis.[5][6] AGGF1 also interacts with vein specific markers such at flt4, dab2, and ephB4.[15] Ccl2 has also been shown to interact with AGGF1 in hepatocytes through blocking NF-κB/p65 from binding to Ccl2.[16] AGGF1 activity is eliminated when Elk is overexpressed.[13] AGGF1 regulates autophagy by regulating expression of JNK genes.[13] SMAD7 and Aggf1 directly interact in the liver to inhibit fibrogenesis.[11] The presence of DNMT3b will repress AGGF1 by acting on the promoter region of the gene.[11]
# Clinical significance
## Klippel-Trenaunay Syndrome
Heterogeneous mutations in this gene causing deregulation of expression can lead to the vascular malformations associated with Klippel-Trenaunay syndrome (KTS).[5][9][15] Due to the haploinsufficient nature of AGGF1, individuals who have even one mutant allele may have KTS.[5] Studies done in mouse models have shown frequent haemorrhages and increased vascular permeability has been seen in mice who are heterozygous for Aggf1.[5] A translocation between the chromosome 5 q-arm at region 13 in band 3 and the chromosome 11 p-arm at region 15 in band 1 has been implicated in KTS.[1] This translocation affects the AGGF1 promoter so there is a 3 fold increase in protein production.[1] Single nucleotide polymorphisms in intron 11 and exon 7 were associated with KTS susceptibility even though neither of these SNPs resulted in an amino acid change.[1] At one point, the E133K allele was thought to be a mutational hotspot - due to altered phosphorylation - causing KTS, but it has since been found as much as 3.3% of the population are carriers for the mutation.[12][17]
## Heart Disease
AGGF1 has also been implicated in treatment after vascular smooth muscle cell damage due to coronary artery disease and myocardial infarction.[13] By blocking vascular permeability and regulating vascular smooth muscle cell phenotypic switching, AGGF1 protein therapy is currently being investigated as a new method of treating both of these diseases.[13]
## Cancer
Aberrant AGGF1 has been implicated in multiple cancers and functions in tumour initiation and progression.[8] For example, both hepatocellular carcinoma and gastric cancer survivability is related to the levels of AGGF1 expression in tumours.[7][8] AGGF1 has been found to have higher expression in tumours than the surrounding tissues, and higher levels of AGGF1 are associated with a poor patient prognosis.[7][8] | https://www.wikidoc.org/index.php/AGGF1 | |
759e5b3f4f11c5c693a8933bea764c26bdfc2802 | wikidoc | AIFM1 | AIFM1
Apoptosis-inducing factor 1, mitochondrial is a protein that in humans is encoded by the AIFM1 gene on the X chromosome. This protein localizes to the mitochondria, as well as the nucleus, where it carries out nuclear fragmentation as part of caspase-independent apoptosis.
# Structure
AIFM1 is expressed as a 613-residue precursor protein that containing a mitochondrial targeting sequence (MTS) at its N-terminal and two nuclear leading sequences (NLS). Once imported into the mitochondria, the first 54 residues of the N-terminal are cleaved to produce the mature protein, which inserts into the inner mitochondrial membrane. The mature protein incorporates the FAD cofactor and folds into three structural domains: the FAD-binding domain, the NAD-binding domain, and the C-terminal. While the C-terminal is responsible for the proapoptotic activity of AIFM1, the FAD-binding and NAD-binding domains share the classical Rossmann topology with other flavoproteins and the NAD(P)H dependent reductase activity.
Three alternative transcripts encoding different isoforms have been identified for this gene. Two alternatively spliced mRNA isoforms correspond to the inclusion/exclusion of the C-terminal and the reductase domains. A pseudogene that is thought to be related to this gene has been identified on chromosome 10.
# Function
This gene encodes a flavoprotein essential for nuclear disassembly in apoptotic cells that is found in the mitochondrial intermembrane space in healthy cells. Induction of apoptosis results in the cleavage of this protein at residue 102 by calpains and/or cathepsins into a soluble and proapoptogenic form that translocates to the nucleus, where it effects chromosome condensation and fragmentation. In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9. AIFM1 also contributes reductase activity in redox metabolism.
# Clinical significance
Mutations in the AIFM1 gene are correlated with Charcot-Marie-Tooth disease (Cowchock syndrome). At a cellular level, AIFM1 mutations result in deficiencies in oxidative phosphorylation, leading to severe mitochondrial encephalomyopathy. Clinical manifestations of this mutation are characterized by muscular atrophy, neuropathy, ataxia, psychomotor regression, hearing loss and seizures.
# Interactions
AIFM1 has been shown to interact with HSPA1A.
# Evolution
Phylogenetic analysis indicates that the divergence of the AIFM1 and other human AIFs (AIFM2a and AIFM3) sequences occurred before the divergence of eukaryotes.This conclusion is supported by domain architecture of these proteins. Both eukaryotic and eubacterial AIFM1 proteins contain additional domain AIF_C. | AIFM1
Apoptosis-inducing factor 1, mitochondrial is a protein that in humans is encoded by the AIFM1 gene on the X chromosome.[1][2] This protein localizes to the mitochondria, as well as the nucleus, where it carries out nuclear fragmentation as part of caspase-independent apoptosis.[3]
# Structure
AIFM1 is expressed as a 613-residue precursor protein that containing a mitochondrial targeting sequence (MTS) at its N-terminal and two nuclear leading sequences (NLS). Once imported into the mitochondria, the first 54 residues of the N-terminal are cleaved to produce the mature protein, which inserts into the inner mitochondrial membrane. The mature protein incorporates the FAD cofactor and folds into three structural domains: the FAD-binding domain, the NAD-binding domain, and the C-terminal. While the C-terminal is responsible for the proapoptotic activity of AIFM1, the FAD-binding and NAD-binding domains share the classical Rossmann topology with other flavoproteins and the NAD(P)H dependent reductase activity.[3]
Three alternative transcripts encoding different isoforms have been identified for this gene.[2] Two alternatively spliced mRNA isoforms correspond to the inclusion/exclusion of the C-terminal and the reductase domains.[3] A pseudogene that is thought to be related to this gene has been identified on chromosome 10.[2]
# Function
This gene encodes a flavoprotein essential for nuclear disassembly in apoptotic cells that is found in the mitochondrial intermembrane space in healthy cells. Induction of apoptosis results in the cleavage of this protein at residue 102 by calpains and/or cathepsins into a soluble and proapoptogenic form that translocates to the nucleus, where it effects chromosome condensation and fragmentation.[2][3] In addition, this gene product induces mitochondria to release the apoptogenic proteins cytochrome c and caspase-9.[2] AIFM1 also contributes reductase activity in redox metabolism.[3]
# Clinical significance
Mutations in the AIFM1 gene are correlated with Charcot-Marie-Tooth disease (Cowchock syndrome).[3][4] At a cellular level, AIFM1 mutations result in deficiencies in oxidative phosphorylation, leading to severe mitochondrial encephalomyopathy.[2] Clinical manifestations of this mutation are characterized by muscular atrophy, neuropathy, ataxia, psychomotor regression, hearing loss and seizures.[5]
# Interactions
AIFM1 has been shown to interact with HSPA1A.[6][7]
# Evolution
Phylogenetic analysis indicates that the divergence of the AIFM1 and other human AIFs (AIFM2a and AIFM3) sequences occurred before the divergence of eukaryotes.This conclusion is supported by domain architecture of these proteins. Both eukaryotic and eubacterial AIFM1 proteins contain additional domain AIF_C.[8] | https://www.wikidoc.org/index.php/AIFM1 | |
b559a7156015e46daafad1706121dace76129bf9 | wikidoc | AIFM2 | AIFM2
Apoptosis-inducing factor 2 (AIFM2), also known as apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), is a protein that in humans is encoded by the AIFM2 gene, also known as p53-responsive gene 3 (PRG3), on chromosome 10.
This gene encodes a flavoprotein oxidoreductase that binds single stranded DNA and is thought to contribute to apoptosis in the presence of bacterial and viral DNA. The expression of this gene is also found to be induced by tumor suppressor protein p53 in colon cancer cells.
# Function
The protein encoded by this gene has significant homology to NADH oxidoreductases and the apoptosis-inducing factor PDCD8/AIF. Overexpression of this gene has been shown to induce apoptosis. The expression of this gene is found to be induced by tumor suppressor protein p53 in colon cancer cells.
# Structure
AIFM2 can be found only both in prokaryotes and eukaryotes. Sequence analysis reveals that the AIFM2 gene promoter contains a consensus transcription initiator sequence instead of a TATA box. Though AIFM2 also lacks a recognizable mitochondrial localization sequence and cannot enter the mitochondria, it is found to adhere to the outer mitochondrial membrane (OMM), where it forms a ring-like structure. Two deletion mutations at the C-terminal (aa 1–185 and 1–300) result in nuclear localization and failure to effect cell death, suggesting that AIFM2 must be associated with the mitochondria in order to induce apoptosis. Moreover, domain mapping experiments reveal that only the C-terminal 187 aa is required for apoptotic induction. Meanwhile, mutations in the N-terminal putative FAD- and ADP-binding domains, which are responsible for its oxidoreductase function, do not affect its apoptotic function, thus indicating that these two functions operate independently. It assembles stoichiometrically and noncovalently with 6-hydroxy-FAD.
The AIFM2 gene contains a putative p53-binding element in intron 5, suggesting that its gene expression can be activated by p53.
# Function
This protein is a flavoprotein that functions as an NAD(P)H-dependent oxidoreductase and induces caspase- and p53-independent apoptosis. The exact mechanisms remain unknown, but AIFM2 is found to localize to the cytosol and the OMM. Thus, it may carry out this function by disrupting mitochondrial morphology and releasing proapoptotic factors. Also, under conditions of stress which activate p53-mediated apoptosis, such as hypoxia, AIMF2 may stabilize p53 by inhibiting its degradation and accelerate the apoptotic process. Under normal conditions (i.e., undetectable p53 expression), the AIMF2 gene is highly expressed in the heart, followed by liver and skeletal muscle, with low levels detected in the placenta, lung, kidney, and pancreas and the lowest in the brain. However, in organs such as the heart, there may be additional regulatory mechanisms to suppress its proapoptotic function. For instance, AIFM2 may be able to directly bind nuclear DNA and effect chromatin condensation, as with AIF. Furthermore, AIMF2 expressed at low levels may function as an oxidoreductase involved in metabolism. Hence, under normal cellular conditions, AIFM2 may promote cell survival rather than death by metabolic processes such as generating reactive oxygen species (ROS) to maintain survival signaling.
# Clinical significance
AIFM2 has been implicated in tumorigenesis as a p53-inducible gene. AIFM2 mRNA levels are observed to be downregulated in many human cancer tissues, though a previous study reported that AIFM2 mRNA transcripts were only detected in colon cancer and B-cell lymphoma cell lines. Furthermore, its DNA-binding ability contributes to its involvement in the apoptosis-inducing response to viral and bacterial infections, possibly through its role in ROS regulation.
# Evolution
The phylogenetic studies indicates that the divergence of the AIFM1 and other AIFs occurred before the divergence of eukaryotes.
# Interactions
AIFM2 is shown to interact with p53.
AIFM2 is not inhibited by Bcl-2.
AIFM2 can also bind the following coenzymes:
- 6-hydroxy-FAD,
- Flavin adenine dinucleotide (FAD),
- NADPH/NADP+,
- NADH/NAD+, and
- pyridine nucleotide coenzyme. | AIFM2
Apoptosis-inducing factor 2 (AIFM2), also known as apoptosis-inducing factor-homologous mitochondrion-associated inducer of death (AMID), is a protein that in humans is encoded by the AIFM2 gene, also known as p53-responsive gene 3 (PRG3), on chromosome 10.[1][2][3][4]
This gene encodes a flavoprotein oxidoreductase that binds single stranded DNA and is thought to contribute to apoptosis in the presence of bacterial and viral DNA. The expression of this gene is also found to be induced by tumor suppressor protein p53 in colon cancer cells.[4][5]
# Function
The protein encoded by this gene has significant homology to NADH oxidoreductases and the apoptosis-inducing factor PDCD8/AIF. Overexpression of this gene has been shown to induce apoptosis. The expression of this gene is found to be induced by tumor suppressor protein p53 in colon cancer cells.[4]
# Structure
AIFM2 can be found only both in prokaryotes and eukaryotes.[2][3][6][7] Sequence analysis reveals that the AIFM2 gene promoter contains a consensus transcription initiator sequence instead of a TATA box.[7] Though AIFM2 also lacks a recognizable mitochondrial localization sequence and cannot enter the mitochondria, it is found to adhere to the outer mitochondrial membrane (OMM), where it forms a ring-like structure.[2][1][3][7][5] Two deletion mutations at the C-terminal (aa 1–185 and 1–300) result in nuclear localization and failure to effect cell death, suggesting that AIFM2 must be associated with the mitochondria in order to induce apoptosis. Moreover, domain mapping experiments reveal that only the C-terminal 187 aa is required for apoptotic induction.[2] Meanwhile, mutations in the N-terminal putative FAD- and ADP-binding domains, which are responsible for its oxidoreductase function, do not affect its apoptotic function, thus indicating that these two functions operate independently.[3][1] It assembles stoichiometrically and noncovalently with 6-hydroxy-FAD.[3]
The AIFM2 gene contains a putative p53-binding element in intron 5, suggesting that its gene expression can be activated by p53.[1][3][7]
# Function
This protein is a flavoprotein that functions as an NAD(P)H-dependent oxidoreductase and induces caspase- and p53-independent apoptosis.[2][1][3] The exact mechanisms remain unknown, but AIFM2 is found to localize to the cytosol and the OMM. Thus, it may carry out this function by disrupting mitochondrial morphology and releasing proapoptotic factors.[2] Also, under conditions of stress which activate p53-mediated apoptosis, such as hypoxia, AIMF2 may stabilize p53 by inhibiting its degradation and accelerate the apoptotic process. Under normal conditions (i.e., undetectable p53 expression), the AIMF2 gene is highly expressed in the heart, followed by liver and skeletal muscle, with low levels detected in the placenta, lung, kidney, and pancreas and the lowest in the brain. However, in organs such as the heart, there may be additional regulatory mechanisms to suppress its proapoptotic function.[1] For instance, AIFM2 may be able to directly bind nuclear DNA and effect chromatin condensation, as with AIF.[3] Furthermore, AIMF2 expressed at low levels may function as an oxidoreductase involved in metabolism.[1] Hence, under normal cellular conditions, AIFM2 may promote cell survival rather than death by metabolic processes such as generating reactive oxygen species (ROS) to maintain survival signaling.[5]
# Clinical significance
AIFM2 has been implicated in tumorigenesis as a p53-inducible gene.[7] AIFM2 mRNA levels are observed to be downregulated in many human cancer tissues, though a previous study reported that AIFM2 mRNA transcripts were only detected in colon cancer and B-cell lymphoma cell lines.[2][3] Furthermore, its DNA-binding ability contributes to its involvement in the apoptosis-inducing response to viral and bacterial infections, possibly through its role in ROS regulation.[7]
# Evolution
The phylogenetic studies indicates that the divergence of the AIFM1 and other AIFs occurred before the divergence of eukaryotes.[6]
# Interactions
AIFM2 is shown to interact with p53.[1]
AIFM2 is not inhibited by Bcl-2.[1]
AIFM2 can also bind the following coenzymes:
- 6-hydroxy-FAD,[3]
- Flavin adenine dinucleotide (FAD),[3]
- NADPH/NADP+,[3]
- NADH/NAD+,[3] and
- pyridine nucleotide coenzyme.[3] | https://www.wikidoc.org/index.php/AIFM2 | |
d6d3d4280911901315e363152b9611a57664f964 | wikidoc | AKAP4 | AKAP4
A-kinase anchor protein 4 is a scaffold protein that in humans is encoded by the AKAP4 gene. It involves in the intracellular signalling of protein kinase -A. AKAP4 is called as cancer /testis antigen (CTA), it belongs to a class of tumour linked antigens categories by high expression in germ cells and cancer than normal tissues. AKAP4 is not normally expressed in mRNA and protein level in MM cell line.
# Function
The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is localized to the sperm flagellum and may be involved in the regulation of sperm motility. Alternative splicing of this gene results in two transcript variants encoding different isoforms.
AKAP 4 protein belongs to the family of scaffold proteins and is involved in controlled mechanism of flagellar function. In mice, AKAP4 is required for sperm development and male mice that lack AKAP4 are infertiel The fibrous sheath was not formed, flagellum become short and often some proteins associated with the fibrous sheath in this case they were very few or absent. Surprisingly, another component of flagellum was developed as normal. In the conclusion, they state that AKAP4 plays a pivotal role in the fibrous sheath and effect on the motility of sperm, in the absence of AKAP4 these activities affected due to a failure of signal transduction and glycolytic enzymes because they were not able to attach with the fibrous sheath.
# Clinical significance
AKAP4 is a potential biomarker for early diagnosis and immunotherapy of colon cancer. AKAP4 may be implicated as a biomarker and immunotherapeutic target for cervical cancer. AKAP4 is also a circulating biomarker for non-small cell lung cancer. To detect the early stage breast cancer and diagnosis, AKAP4 is used as serum. Investigation was undertaken about AKAP4 with various clinical parameters which could be use as early detector biomarker to treat cancer by developing a tissue or serum.
AKAP4 is associated with diseases such as multiple myeloma, lung cancer, breast cancer and prostate cancer.
AKAP4 is over expressed in multiple myeloma (MM)
# Interactions
AKAP4 has been shown to interact with:
- AKAP3, and
- PRKAR1A. | AKAP4
A-kinase anchor protein 4 is a scaffold protein that in humans is encoded by the AKAP4 gene.[1][2][3] It involves in the intracellular signalling of protein kinase -A.[4] AKAP4 is called as cancer /testis antigen (CTA), it belongs to a class of tumour linked antigens categories by high expression in germ cells and cancer than normal tissues.[5] AKAP4 is not normally expressed in mRNA and protein level in MM cell line.[6]
# Function
The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is localized to the sperm flagellum and may be involved in the regulation of sperm motility. Alternative splicing of this gene results in two transcript variants encoding different isoforms.[3]
AKAP 4 protein belongs to the family of scaffold proteins and is involved in controlled mechanism of flagellar function.[7] In mice, AKAP4 is required for sperm development and male mice that lack AKAP4 are infertiel The fibrous sheath was not formed, flagellum become short and often some proteins associated with the fibrous sheath in this case they were very few or absent. Surprisingly, another component of flagellum was developed as normal. In the conclusion, they state that AKAP4 plays a pivotal role in the fibrous sheath and effect on the motility of sperm, in the absence of AKAP4 these activities affected due to a failure of signal transduction and glycolytic enzymes because they were not able to attach with the fibrous sheath.[7]
# Clinical significance
AKAP4 is a potential biomarker for early diagnosis and immunotherapy of colon cancer.[8] AKAP4 may be implicated as a biomarker and immunotherapeutic target for cervical cancer.[9] AKAP4 is also a circulating biomarker for non-small cell lung cancer.[10] To detect the early stage breast cancer and diagnosis, AKAP4 is used as serum. Investigation was undertaken about AKAP4 with various clinical parameters which could be use as early detector biomarker to treat cancer by developing a tissue or serum.
AKAP4 is associated with diseases such as multiple myeloma, lung cancer, breast cancer and prostate cancer.[11]
AKAP4 is over expressed in multiple myeloma (MM)[12]
# Interactions
AKAP4 has been shown to interact with:
- AKAP3,[13] and
- PRKAR1A.[13][14] | https://www.wikidoc.org/index.php/AKAP4 | |
5be74977c93a981a430c8ed88a089c720435dadf | wikidoc | AKAP6 | AKAP6
A-kinase anchor protein 6 is an enzyme that in humans is encoded by the AKAP6 gene.
The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is highly expressed in various brain regions and cardiac and skeletal muscle. It is specifically localized to the sarcoplasmic reticulum and nuclear membrane, and is involved in anchoring PKA to the nuclear membrane or sarcoplasmic reticulum.
# Interactions
AKAP6 has been shown to interact with Ryanodine receptor 2 and PDE4D3. | AKAP6
A-kinase anchor protein 6 is an enzyme that in humans is encoded by the AKAP6 gene.[1][2][3]
The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is highly expressed in various brain regions and cardiac and skeletal muscle. It is specifically localized to the sarcoplasmic reticulum and nuclear membrane, and is involved in anchoring PKA to the nuclear membrane or sarcoplasmic reticulum.[3]
# Interactions
AKAP6 has been shown to interact with Ryanodine receptor 2[4][5] and PDE4D3.[6] | https://www.wikidoc.org/index.php/AKAP6 | |
64fa07626fbc5fc405e07ba4c0650978c2c2303c | wikidoc | AKAP9 | AKAP9
A-kinase anchor protein 9 is a protein that in humans is encoded by the AKAP9 gene. AKAP9 is also known as Centrosome- and Golgi-localized protein kinase N-associated protein (CG-NAP) or AKAP350 or AKAP450
# Function
The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternate splicing of this gene results in many isoforms that localize to the centrosome and the Golgi apparatus, and interact with numerous signaling proteins from multiple signal transduction pathways. These signaling proteins include type II protein kinase A, serine/threonine kinase protein kinase N, protein phosphatase 1, protein phosphatase 2a, protein kinase C-epsilon and phosphodiesterase 4D3.
# Model organisms
Model organisms have been used in the study of AKAP9 function. A conditional knockout mouse line, called Akap9tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and eight significant abnormalities were observed. Fewer than expected homozygous mutant mice survived until weaning. The remaining tests were carried out on both homozygous and heterozygous mutant adult mice. Animals of both sex displayed decreased body fat and body weight, hematopoietic abnormalities and an atypical plasma chemistry panel. Female homozygotes also displayed abnormal tooth morphology while males heterozygous animals displayed an abnormal pelvic girdle bone morphology.
# Interactions
AKAP9 has been shown to interact with:
- CALM2,
- CALM1,
- FNBP1,
- KvLQT1
- PRKAR2A,
- PKN1, and
- TRIP10. | AKAP9
A-kinase anchor protein 9 is a protein that in humans is encoded by the AKAP9 gene.[1][2][3] AKAP9 is also known as Centrosome- and Golgi-localized protein kinase N-associated protein (CG-NAP) or AKAP350 or AKAP450 [4]
# Function
The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. Alternate splicing of this gene results in many isoforms that localize to the centrosome and the Golgi apparatus, and interact with numerous signaling proteins from multiple signal transduction pathways. These signaling proteins include type II protein kinase A, serine/threonine kinase protein kinase N, protein phosphatase 1, protein phosphatase 2a, protein kinase C-epsilon and phosphodiesterase 4D3.[3]
# Model organisms
Model organisms have been used in the study of AKAP9 function. A conditional knockout mouse line, called Akap9tm1a(KOMP)Wtsi[15][16] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[17][18][19]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[14][20] Twenty six tests were carried out on mutant mice and eight significant abnormalities were observed.[14] Fewer than expected homozygous mutant mice survived until weaning. The remaining tests were carried out on both homozygous and heterozygous mutant adult mice. Animals of both sex displayed decreased body fat and body weight, hematopoietic abnormalities and an atypical plasma chemistry panel. Female homozygotes also displayed abnormal tooth morphology while males heterozygous animals displayed an abnormal pelvic girdle bone morphology.[14]
# Interactions
AKAP9 has been shown to interact with:
- CALM2,[21]
- CALM1,[21]
- FNBP1,[22]
- KvLQT1[23]
- PRKAR2A,[24][25]
- PKN1,[24] and
- TRIP10.[22] | https://www.wikidoc.org/index.php/AKAP9 | |
5f0db789f2cd7d21016cf84729581f1e9b72a23d | wikidoc | AKTIP | AKTIP
AKT-interacting protein is a protein that in humans is encoded by the AKTIP gene.
The mouse homolog of this gene produces fused toes and thymic hyperplasia in heterozygous mutant animals while homozygous mutants die in early development. This gene may play a role in apoptosis as these morphological abnormalities are caused by altered patterns of programmed cell death. The protein encoded by this gene is similar to the ubiquitin ligase domain of other ubiquitin-conjugating enzymes but lacks the conserved cysteine residue that enables those enzymes to conjugate ubiquitin to the target protein. This protein interacts directly with serine/threonine kinase protein kinase B (PKB)/Akt and modulates PKB activity by enhancing the phosphorylation of PKB's regulatory sites. Alternative splicing results in two transcript variants encoding the same protein.
# Interactions
AKTIP has been shown to interact with AKT1.
# Molecular genetics
The association between the AKTIP gene variants in a sample of 273 bipolar patients using 3 single-nucleotide polymorphisms has been investigated. No association between suicidal behavior and AKTIP variants nor any interaction between AKTIP and AKT1 polymorphisms was observed. | AKTIP
AKT-interacting protein is a protein that in humans is encoded by the AKTIP gene.[1][2][3]
The mouse homolog of this gene produces fused toes and thymic hyperplasia in heterozygous mutant animals while homozygous mutants die in early development. This gene may play a role in apoptosis as these morphological abnormalities are caused by altered patterns of programmed cell death. The protein encoded by this gene is similar to the ubiquitin ligase domain of other ubiquitin-conjugating enzymes but lacks the conserved cysteine residue that enables those enzymes to conjugate ubiquitin to the target protein. This protein interacts directly with serine/threonine kinase protein kinase B (PKB)/Akt and modulates PKB activity by enhancing the phosphorylation of PKB's regulatory sites. Alternative splicing results in two transcript variants encoding the same protein.[3]
# Interactions
AKTIP has been shown to interact with AKT1.[4]
# Molecular genetics
The association between the AKTIP gene variants in a sample of 273 bipolar patients using 3 single-nucleotide polymorphisms has been investigated. No association between suicidal behavior and AKTIP variants nor any interaction between AKTIP and AKT1 polymorphisms was observed.[5] | https://www.wikidoc.org/index.php/AKTIP | |
ce59a684caaba95f08594b74c0b3d11c1a8c99cd | wikidoc | ALARA | ALARA
See also: radiation protection
# Overview
ALARA is an acronym for an important principle in radiation protection and stands for "As Low As Reasonably Achievable". The aim is to minimize the risk of radioactive exposure or amount of dose while keeping in mind that some exposure may be acceptable in order to further the task at hand.
This compromise is well illustrated in radiology. The application of radiation can aid the patient by providing doctors with a medical diagnosis, but the exposure should be reasonably low enough to keep the statistical probability of cancers or sarcomas (stochastic effects) below an acceptable level, and to eliminate deterministic effects (eg. skin reddening or cataracts). An acceptable level of incidence of stochastic effects is considered to be equal for a worker to the risk in another work generally considered to be safe.
This policy is based on the principle that any amount of radiation exposure, no matter how small, can increase the chance of negative biological effects such as cancer, though perhaps by a negligible amount. It is also based on the principle that the probability of the occurrence of negative effects of radiation exposure increases with cumulative lifetime dose. These ideas are combined to form the linear no-threshold model. At the same time, radiology and other practices that involve use of radiations bring benefits to population, so reducing radiation exposure can reduce the efficacy of a medical practice. The economic cost, for example of adding a barrier against radiation, must also be considered when applying the ALARA principle.
There are four major ways to reduce radiation exposure to workers or to population:
- Shielding. Use proper barriers to block or reduce ionizing radiation.
- Time. Spend less time in radiation fields.
- Distance. Increase distance between radioactive sources and workers or population.
- Amount. Reduce the quantity of radioactive material for a practice. | ALARA
See also: radiation protection
# Overview
ALARA is an acronym for an important principle in radiation protection and stands for "As Low As Reasonably Achievable". The aim is to minimize the risk of radioactive exposure or amount of dose while keeping in mind that some exposure may be acceptable in order to further the task at hand.
This compromise is well illustrated in radiology. The application of radiation can aid the patient by providing doctors with a medical diagnosis, but the exposure should be reasonably low enough to keep the statistical probability of cancers or sarcomas (stochastic effects) below an acceptable level, and to eliminate deterministic effects (eg. skin reddening or cataracts). An acceptable level of incidence of stochastic effects is considered to be equal for a worker to the risk in another work generally considered to be safe.
This policy is based on the principle that any amount of radiation exposure, no matter how small, can increase the chance of negative biological effects such as cancer, though perhaps by a negligible amount. It is also based on the principle that the probability of the occurrence of negative effects of radiation exposure increases with cumulative lifetime dose. These ideas are combined to form the linear no-threshold model. At the same time, radiology and other practices that involve use of radiations bring benefits to population, so reducing radiation exposure can reduce the efficacy of a medical practice. The economic cost, for example of adding a barrier against radiation, must also be considered when applying the ALARA principle.
There are four major ways to reduce radiation exposure to workers or to population:
- Shielding. Use proper barriers to block or reduce ionizing radiation.
- Time. Spend less time in radiation fields.
- Distance. Increase distance between radioactive sources and workers or population.
- Amount. Reduce the quantity of radioactive material for a practice. | https://www.wikidoc.org/index.php/ALARA | |
6f40b9fd5ce4b775835e896d8b6f5be51a17ed9b | wikidoc | ALAS2 | ALAS2
Delta-aminolevulinate synthase 2 also known as ALAS2 is a protein that in humans is encoded by the ALAS2 gene. ALAS2 is an aminolevulinic acid synthase.
The product of this gene specifies an erythroid-specific mitochondrially located enzyme. The encoded protein catalyzes the first step in the heme biosynthetic pathway. Defects in this gene cause X-linked pyridoxine-responsive sideroblastic anemia. Alternatively spliced transcript variants encoding different isoforms have been identified.
Its gene contains an IRE in its 5'-UTR region on which an IRP binds if the iron level is too low, thus inhibiting its translation. | ALAS2
Delta-aminolevulinate synthase 2 also known as ALAS2 is a protein that in humans is encoded by the ALAS2 gene.[1][2][3] ALAS2 is an aminolevulinic acid synthase.
The product of this gene specifies an erythroid-specific mitochondrially located enzyme. The encoded protein catalyzes the first step in the heme biosynthetic pathway. Defects in this gene cause X-linked pyridoxine-responsive sideroblastic anemia. Alternatively spliced transcript variants encoding different isoforms have been identified.[3]
Its gene contains an IRE in its 5'-UTR region on which an IRP binds if the iron level is too low, thus inhibiting its translation. | https://www.wikidoc.org/index.php/ALAS2 | |
52b7db9c6f685bb9bdc38a07417446890ececd4e | wikidoc | ALCAM | ALCAM
CD166 antigen is a 100-105 kD typeI transmembrane glycoprotein that is a member of the immunoglobulin superfamily of proteins. In humans it is encoded by the ALCAM gene. It is also called CD166 (cluster of differentiation 166), MEMD, SC-1/DM-GRASP/BEN in the chicken, and KG-CAM in the rat.
Some literature sources have also cited it as the CD6 ligand (CD6L). It is expressed on activated T cells, activated monocytes, epithelial cells, fibroblasts, neurons, melanoma cells, and also in sweat and sebaceous glands. CD166 protein expression is reported to be upregulated in a cell line deriving from a metastasizing melanoma. CD166 plays an important role in mediating adhesion interactions between thymic epithelial cells and CD6+ cells during intrathymic T cell development.
Recently, CD166 has also been used as a potential cancer stem cell marker. | ALCAM
CD166 antigen is a 100-105 kD typeI transmembrane glycoprotein that is a member of the immunoglobulin superfamily of proteins. In humans it is encoded by the ALCAM gene.[1][2] It is also called CD166 (cluster of differentiation 166), MEMD,[3] SC-1/DM-GRASP/BEN in the chicken, and KG-CAM in the rat.
Some literature sources have also cited it as the CD6 ligand (CD6L). It is expressed on activated T cells, activated monocytes, epithelial cells, fibroblasts, neurons, melanoma cells, and also in sweat and sebaceous glands.[citation needed] CD166 protein expression is reported to be upregulated in a cell line deriving from a metastasizing melanoma.[3] CD166 plays an important role in mediating adhesion interactions between thymic epithelial cells and CD6+ cells during intrathymic T cell development.[citation needed]
Recently, CD166 has also been used as a potential cancer stem cell marker.[citation needed] | https://www.wikidoc.org/index.php/ALCAM | |
dbbc87c629fedc8ded03ecf6b36ebbbca1df7c9a | wikidoc | ALDH2 | ALDH2
Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12. This protein belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Two major liver isoforms of aldehyde dehydrogenase, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations.
Most caucasians have two major isozymes, while approximately 50% of East Asians have the cytosolic isozyme but not the mitochondrial isozyme. A remarkably higher frequency of acute alcohol intoxication among East Asians than among Caucasians could be related to the absence of a catalytically active form of the mitochondrial isozyme. The increased exposure to acetaldehyde in individuals with the catalytically inactive form may also confer greater susceptibility to many types of cancer.
# Gene
The ALDH2 gene is about 44 kbp in length and contains at least 13 exons which encode 517 amino acid residues. Except for the signal NH2-terminal peptide, which is absent in the mature enzyme, the amino acid sequence deduced from the exons coincided with the reported primary structure of human liver ALDH2. Several introns contain Alu repetitive sequences. A TATA-like sequence (TTATAAAA) and a CAAT-like sequence (GTCATCAT) are located 473 and 515 bp, respectively, upstream from the translation initiation codon.
# Enzyme structure
The enzyme encoded by the human ALDH2 gene is a tetrameric enzyme that contains three domains; two dinucleotide-binding domains and a three-stranded beta-sheet domain. The active site of ALDH2 is divided into two halves by the nicotinamide ring of NAD+. Adjacent to the A-side (Pro-R) of the nicotinamide ring is a cluster of three cysteines (Cys301, Cys302 and Cys303) and adjacent to the B-side (Pro-S) are Thr244, Glu268, Glu476 and an ordered water molecule bound to Thr244 and Glu476. Although there is a recognizable Rossmann fold, the coenzyme-binding region of ALDH2 binds NAD+ in a manner not seen in other NAD+-binding enzymes. The positions of the residues near the nicotinamide ring of NAD+ suggest a chemical mechanism whereby Glu268 functions as a general base through a bound water molecule. The sidechain amide nitrogen of Asn169 and the peptide nitrogen of Cys302 are in position to stabilize the oxyanion present in the tetrahedral transition state prior to hydride transfer. The functional importance of residue Glu487 now appears to be due to indirect interactions of this residue with the substrate-binding site via Arg264 and Arg475.
# Isoforms
Two major liver isoforms of this enzyme, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations. The ALDH2 gene encodes a mitochondrial isoform, which has a low Km for acetaldehydes, and is localized in mitochondrial matrix; in contrast the ALDH1 gene codes for the cytosolic isoform.
# Function
Mitochondrial aldehyde dehydrogenase belongs to the aldehyde dehydrogenase family of enzymes that catalyze the chemical transformation from acetaldehyde to acetic acid. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Additionally, ALDH2 functions as a protector against oxidative stress.
- Acetaldehyde
- Acetic acid
- Error creating thumbnail: File missing
Chemical structure of the ALDH2 activator Alda-1.
# Clinical significance
Most Caucasians have two major isozymes, while approximately 50% of East Asians have one normal copy of the ALDH2 gene and one variant copy that encodes an inactive mitochondrial isoenzyme. In native Japanese, this variant ALDH2 gene encodes lysine instead of glutamic acid at amino acid 487 and therefore encodes a product protein that is completely inactive in metabolizing acetaldehyde to acetic acid. In the overall Japanese population, about 57% of individuals are homozygous for the normal gene, 40% are heterozygous for the variant gene, and 3% are homozygous for the variant gene. Since ALDH2 assembles and functions as a tetramer and requires all four of its components to be active in order to metabolize acetaldehyde, heterozygotes have very little ALDH2 activity. Accordingly, individuals heterozygous or homozygous for the abnormal gene metabolize ethanol to acetaldehyde normally but metabolize acetaldehyde poorly and are thereby susceptible to certain adverse effects of alcoholic (i.e. ethanol-containing) beverages; these effects include the transient accumulation of acetaldehyde in blood and tissues; facial flushing (i.e. the "oriental flushing syndrome"), urticaria, systemic dermatitis, and alcohol-induced respiratory reactions such as rhinitis and the exacerbation of asthma bronchoconstriction. The cited allergic reaction-like symptoms: a) do not appear due to classical IgE or T cell-related allergen-induced reactions but rather to the actions of acetaldehyde in stimulating the release of histamine, a probable mediating cause of these symptoms; b) typically occur within 30–60 minutes of ingesting alcoholic beverages; and c) occur in other Asian as well as non-Asian individuals that are either seriously defective in metabolizing ingested ethanol past acetaldehyde to acetic acid or, alternatively, that metabolize ethanol too rapidly for ALDH2 processing.
A remarkably higher frequency of acute alcohol intoxication among East Asians than among Caucasians has been repeatedly shown to be related to the very much reduced activity of the variant ALDH2-2 isoenzyme. During the 80's there has been a steady increase in the number of Japanese alcoholics who manage to overcome their genetically determined aversion to alcoholism from the dominant effects of an ALDH2-2 mutation. This trend demonstrates that, even among those least likely to succumb to alcoholism, there are social pressures to drink.
An activator of ALDH2 enzymatic activity, Alda-1 (N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide), has been shown to reduce ischemia-induced cardiac damage caused by myocardial infarction.
# Interactions
ALDH2 has been shown to interact with GroEL. | ALDH2
Aldehyde dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ALDH2 gene located on chromosome 12.[1][2] This protein belongs to the aldehyde dehydrogenase family of enzymes. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Two major liver isoforms of aldehyde dehydrogenase, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations.[3]
Most caucasians have two major isozymes, while approximately 50% of East Asians have the cytosolic isozyme but not the mitochondrial isozyme. A remarkably higher frequency of acute alcohol intoxication among East Asians than among Caucasians could be related to the absence of a catalytically active form of the mitochondrial isozyme. The increased exposure to acetaldehyde in individuals with the catalytically inactive form may also confer greater susceptibility to many types of cancer.[4]
# Gene
The ALDH2 gene is about 44 kbp in length and contains at least 13 exons which encode 517 amino acid residues. Except for the signal NH2-terminal peptide, which is absent in the mature enzyme, the amino acid sequence deduced from the exons coincided with the reported primary structure of human liver ALDH2. Several introns contain Alu repetitive sequences. A TATA-like sequence (TTATAAAA) and a CAAT-like sequence (GTCATCAT) are located 473 and 515 bp, respectively, upstream from the translation initiation codon.[5]
# Enzyme structure
The enzyme encoded by the human ALDH2 gene is a tetrameric enzyme that contains three domains; two dinucleotide-binding domains and a three-stranded beta-sheet domain. The active site of ALDH2 is divided into two halves by the nicotinamide ring of NAD+. Adjacent to the A-side (Pro-R) of the nicotinamide ring is a cluster of three cysteines (Cys301, Cys302 and Cys303) and adjacent to the B-side (Pro-S) are Thr244, Glu268, Glu476 and an ordered water molecule bound to Thr244 and Glu476.[6] Although there is a recognizable Rossmann fold, the coenzyme-binding region of ALDH2 binds NAD+ in a manner not seen in other NAD+-binding enzymes. The positions of the residues near the nicotinamide ring of NAD+ suggest a chemical mechanism whereby Glu268 functions as a general base through a bound water molecule. The sidechain amide nitrogen of Asn169 and the peptide nitrogen of Cys302 are in position to stabilize the oxyanion present in the tetrahedral transition state prior to hydride transfer. The functional importance of residue Glu487 now appears to be due to indirect interactions of this residue with the substrate-binding site via Arg264 and Arg475.[7]
# Isoforms
Two major liver isoforms of this enzyme, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations. The ALDH2 gene encodes a mitochondrial isoform, which has a low Km for acetaldehydes, and is localized in mitochondrial matrix; in contrast the ALDH1 gene codes for the cytosolic isoform.[3]
# Function
Mitochondrial aldehyde dehydrogenase belongs to the aldehyde dehydrogenase family of enzymes that catalyze the chemical transformation from acetaldehyde to acetic acid. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Additionally, ALDH2 functions as a protector against oxidative stress.[8]
- Acetaldehyde
- Acetic acid
- Error creating thumbnail: File missing
Chemical structure of the ALDH2 activator Alda-1.
# Clinical significance
Most Caucasians have two major isozymes, while approximately 50% of East Asians have one normal copy of the ALDH2 gene and one variant copy that encodes an inactive mitochondrial isoenzyme. In native Japanese, this variant ALDH2 gene encodes lysine instead of glutamic acid at amino acid 487 and therefore encodes a product protein that is completely inactive in metabolizing acetaldehyde to acetic acid.[9] In the overall Japanese population, about 57% of individuals are homozygous for the normal gene, 40% are heterozygous for the variant gene, and 3% are homozygous for the variant gene.[9] Since ALDH2 assembles and functions as a tetramer and requires all four of its components to be active in order to metabolize acetaldehyde, heterozygotes have very little ALDH2 activity.[10] Accordingly, individuals heterozygous or homozygous for the abnormal gene metabolize ethanol to acetaldehyde normally but metabolize acetaldehyde poorly and are thereby susceptible to certain adverse effects of alcoholic (i.e. ethanol-containing) beverages; these effects include the transient accumulation of acetaldehyde in blood and tissues; facial flushing (i.e. the "oriental flushing syndrome"), urticaria, systemic dermatitis, and alcohol-induced respiratory reactions such as rhinitis and the exacerbation of asthma bronchoconstriction.[11] The cited allergic reaction-like symptoms: a) do not appear due to classical IgE or T cell-related allergen-induced reactions but rather to the actions of acetaldehyde in stimulating the release of histamine, a probable mediating cause of these symptoms; b) typically occur within 30–60 minutes of ingesting alcoholic beverages; and c) occur in other Asian as well as non-Asian individuals that are either seriously defective in metabolizing ingested ethanol past acetaldehyde to acetic acid or, alternatively, that metabolize ethanol too rapidly for ALDH2 processing.[11][12]
A remarkably higher frequency of acute alcohol intoxication among East Asians than among Caucasians has been repeatedly shown to be related to the very much reduced activity of the variant ALDH2-2 isoenzyme.[3] During the 80's there has been a steady increase in the number of Japanese alcoholics who manage to overcome their genetically determined aversion to alcoholism from the dominant effects of an ALDH2-2 mutation.[13] This trend demonstrates that, even among those least likely to succumb to alcoholism, there are social pressures to drink.[13]
An activator of ALDH2 enzymatic activity, Alda-1 (N-(1,3-benzodioxol-5-ylmethyl)-2,6-dichlorobenzamide), has been shown to reduce ischemia-induced cardiac damage caused by myocardial infarction.[14]
# Interactions
ALDH2 has been shown to interact with GroEL.[15] | https://www.wikidoc.org/index.php/ALDH2 | |
cb90994b3ad40554c268aab56b192c2ffe3e86ee | wikidoc | ALMS1 | ALMS1
Alstrom syndrome 1 also known as ALMS1 is a protein which in humans is encoded by the ALMS1 gene.
# Molecular biology
The gene is located on the short arm of chromosome 2 (2p13.2) on the plus (Watson) strand. It is 224,161 bases in length organised into 23 exons. The encoded protein has 4,167 amino acids and molecular weight of 460,937 Da. Three isofoms are known. The protein itself has a large tandem-repeat domain comprising 34 imperfect repetitions of 47 amino acids. Mutations associated with disease are usually found in exons 8, 10 and 16.
The gene is expressed in fetal tissues including the aorta, brain, eye, kidney, liver, lung, olfactory bulb, pancreas, skeletal muscle, spleen and testis. The protein is found in the cytoplasm, centrosome, cell projections and cilium basal body. During mitosis it localizes to both spindle poles.
# Function
Knockdown of Alms1 by short interfering RNA in mouse inner medullary collecting duct cells caused defective ciliogenesis. Cilia were stunted and treated cells lacked the ability to increase calcium influx in response to mechanical stimuli.
# Disease association
Mutations in the ALMS1 gene have been found to be causative for Alström syndrome with a total of 81 disease-causing mutations.
Multiple mutations are known: the current (2007) total is 79. These include both nonsense and frameshift mutations. Most of the mutations have been found in exons 8,10 and 16.
# Discovery
The Jackson Laboratory in Bar Harbor, Maine, USA with the University of Southampton, UK isolated ALMS1 as the single gene responsible for Alström syndrome. | ALMS1
Alstrom syndrome 1 also known as ALMS1 is a protein which in humans is encoded by the ALMS1 gene.[1][2]
# Molecular biology
The gene is located on the short arm of chromosome 2 (2p13.2) on the plus (Watson) strand. It is 224,161 bases in length organised into 23 exons. The encoded protein has 4,167 amino acids and molecular weight of 460,937 Da. Three isofoms are known. The protein itself has a large tandem-repeat domain comprising 34 imperfect repetitions of 47 amino acids. Mutations associated with disease are usually found in exons 8, 10 and 16.
The gene is expressed in fetal tissues including the aorta, brain, eye, kidney, liver, lung, olfactory bulb, pancreas, skeletal muscle, spleen and testis. The protein is found in the cytoplasm, centrosome, cell projections and cilium basal body. During mitosis it localizes to both spindle poles.
# Function
Knockdown of Alms1 by short interfering RNA in mouse inner medullary collecting duct cells caused defective ciliogenesis. Cilia were stunted and treated cells lacked the ability to increase calcium influx in response to mechanical stimuli.[3]
# Disease association
Mutations in the ALMS1 gene have been found to be causative for Alström syndrome with a total of 81 disease-causing mutations.[4]
Multiple mutations are known: the current (2007) total is 79. These include both nonsense and frameshift mutations. Most of the mutations have been found in exons 8,10 and 16.
# Discovery
The Jackson Laboratory in Bar Harbor, Maine, USA with the University of Southampton, UK isolated ALMS1 as the single gene responsible for Alström syndrome.[1] | https://www.wikidoc.org/index.php/ALMS1 | |
20e90ac84f8c4514711e1f6a5cddf538e5d252bd | wikidoc | AMELX | AMELX
Amelogenin, X isoform is a protein that in humans is encoded by the AMELX (amelogenin, X isoform) gene.
The protein Amelogenin, X isoform is an isoform of amelogenin that comes from the X chromosome. The protein Amelogenin is a type of extracellular matrix protein, and is involved in the process of amelogenesis, the formation of enamel on teeth. Amelogenin X is a member of the amelogenin family of extracellular matrix proteins. When alternative splicing occurs, it results in multiple transcript variants encoding different isoforms, which in humans results in amelogenin genes on both the X and Y chromosomes.
# Function
AMELX is involved in biomineralization during tooth enamel development. The AMELX gene encodes for the structural modeling protein, amelogenin, which works with other amelogenesis-related proteins to direct the mineralisation of enamel. This process involves the organization of enamel rods, the basic unit of tooth enamel, as well as the inclusion and growth of hydroxyapatite crystals.
# Clinical significance
Mutations in the AMELX gene can result in amelogenesis imperfecta, which refers to the collection of enamel defects resulting from either genetic or environmental causes. It has been shown that mice with a knocked-out AMELX gene will present disorganized and hypoplastic enamel. | AMELX
Amelogenin, X isoform is a protein that in humans is encoded by the AMELX (amelogenin, X isoform) gene.[1]
The protein Amelogenin, X isoform is an isoform of amelogenin that comes from the X chromosome.[2][3] The protein Amelogenin is a type of extracellular matrix protein, and is involved in the process of amelogenesis, the formation of enamel on teeth. Amelogenin X is a member of the amelogenin family of extracellular matrix proteins. When alternative splicing occurs, it results in multiple transcript variants encoding different isoforms, which in humans results in amelogenin genes on both the X and Y chromosomes.[2][3]
# Function
AMELX is involved in biomineralization during tooth enamel development.[4] The AMELX gene encodes for the structural modeling protein, amelogenin, which works with other amelogenesis-related proteins to direct the mineralisation of enamel. This process involves the organization of enamel rods, the basic unit of tooth enamel, as well as the inclusion and growth of hydroxyapatite crystals.
# Clinical significance
Mutations in the AMELX gene can result in amelogenesis imperfecta, which refers to the collection of enamel defects resulting from either genetic or environmental causes.[5] It has been shown that mice with a knocked-out AMELX gene will present disorganized and hypoplastic enamel.[6] | https://www.wikidoc.org/index.php/AMELX | |
f0b6069a768a0f9a7035bedbeb050e62c3ecc01f | wikidoc | AMPD3 | AMPD3
AMP deaminase 3 is an enzyme that in humans is encoded by the AMPD3 gene.
This gene encodes a member of the AMP deaminase gene family. The encoded protein is a highly regulated enzyme that catalyzes the hydrolytic deamination of adenosine monophosphate to inosine monophosphate, a branch point in the adenylate catabolic pathway. This gene encodes the erythrocyte (E) isoforms, whereas other family members encode isoforms that predominate in muscle (M) and liver (L) cells. Mutations in this gene lead to the clinically asymptomatic, autosomal recessive condition erythrocyte AMP deaminase deficiency. Alternatively spliced transcript variants encoding different isoforms of this gene have been described.
# Model organisms
Model organisms have been used in the study of AMPD3 function. A conditional knockout mouse line, called Ampd3tm2a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty eight tests were carried out on mutant mice and four significant abnormalities were observed. Mutant animals had increased IgG1 levels, increased trabecular bone thickness, decreased B cell numbers / increased granulocyte number and unusual brain histopathology (the thickness of the stratum radiatum was reduced and the dorsal 3rd ventricle area was increased). | AMPD3
AMP deaminase 3 is an enzyme that in humans is encoded by the AMPD3 gene.[1][2]
This gene encodes a member of the AMP deaminase gene family. The encoded protein is a highly regulated enzyme that catalyzes the hydrolytic deamination of adenosine monophosphate to inosine monophosphate, a branch point in the adenylate catabolic pathway. This gene encodes the erythrocyte (E) isoforms, whereas other family members encode isoforms that predominate in muscle (M) and liver (L) cells. Mutations in this gene lead to the clinically asymptomatic, autosomal recessive condition erythrocyte AMP deaminase deficiency. Alternatively spliced transcript variants encoding different isoforms of this gene have been described.[2]
# Model organisms
Model organisms have been used in the study of AMPD3 function. A conditional knockout mouse line, called Ampd3tm2a(KOMP)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty eight tests were carried out on mutant mice and four significant abnormalities were observed.[6] Mutant animals had increased IgG1 levels, increased trabecular bone thickness, decreased B cell numbers / increased granulocyte number and unusual brain histopathology (the thickness of the stratum radiatum was reduced and the dorsal 3rd ventricle area was increased).[6] | https://www.wikidoc.org/index.php/AMPD3 | |
0cccd89db3b20e94857ab59ad5ce707d2e3c029f | wikidoc | ANKK1 | ANKK1
Ankyrin repeat and kinase domain containing 1 (ANKK1) also known as protein kinase PKK2 or sugen kinase 288 (SgK288) is an enzyme that in humans is encoded by the ANKK1 gene. The ANKK1 is a member of an extensive family of the Ser/Thr protein kinase family, and protein kinase superfamily involved in signal transduction pathways.
# Clinical significance
This gene contains a single nucleotide polymorphism that causes an amino acid substitution within the 11th of 12 ankyrin repeats of ANKK1 (Glu713Lys of 765 residues). This polymorphism, which is commonly referred to Taq1A, was previously believed to be located in the promoter region of the DRD2 gene, since the polymorphism is proximal to the DRD2 gene and can influence DRD2 receptor expression. It is now known to be located in the coding region of the ANKK1 gene which controls the synthesis of dopamine in the brain. The A1 allele is associated with increased activity of striatal L-amino acid decarboxylase.
## A1+ allele
- Hepatitis C infection
- Antisocial personality disorder
- Borderline personality traits
- Schizoid/avoidant behavior
Given that the A1+ allele is associated with antisocial personality disorder, one may infer that the allele is also associated with narcissistic personality disorder and histrionic personality disorder. However, these predictions have not yet been empirically verified.
## A1+ genotype frequencies
European population estimates for A1+ genotype frequencies range from 20.8 to 43.4% (National Center of Biotechnology Information (NCBI), identification number rs1800497).
## Addictive behaviors
The ANKK1 gene is closely linked to dopamine receptor D2 (DRD2) on chromosome band 11q23.1. The A1 allele of the Taq1A polymorphism (rs1800497T), is located ≈10kb downstream of the dopamine receptor DRD2 gene. Dopamine (DA) is a neurotransmitter in the brain, which controls feelings of wellbeing. This sensation results from the interaction of dopamine and other neurotransmitters such as serotonin, the opioids, and other brain chemicals. Dopamine increases the motivation for food cravings and appetite mediation.
The Reward Deficiency Syndrome (RDS) involves the pleasures or reward mechanisms that rely on dopamine. The result of this deficiency is based on the genetic makeup; this helps explain how certain simple genetic anomalies can give rise to complex aberrant behaviours as the ones mentioned previously. The A1 allelic prevalence has been reported to be significantly higher in obese individuals than in lean subjects, moreover, individuals with increased body mass index (BMI) (BMI >30 kg/m²) have fewer DRD2 dopamine receptors. Investigators have also suggested that hormonal mechanism may underline a gender difference in the ability to suppress hunger in relation to this SNP, which may contribute to the greater incidence of obesity in women compared to men. However, authors have pointed out that A1 carriers have difficulty in learning from negative feedback in a reinforcement-learning task and are less efficient at learning to avoid actions that have negative consequences. | ANKK1
Ankyrin repeat and kinase domain containing 1 (ANKK1) also known as protein kinase PKK2 or sugen kinase 288 (SgK288) is an enzyme that in humans is encoded by the ANKK1 gene. The ANKK1 is a member of an extensive family of the Ser/Thr protein kinase family, and protein kinase superfamily involved in signal transduction pathways.
# Clinical significance
This gene contains a single nucleotide polymorphism that causes an amino acid substitution within the 11th of 12 ankyrin repeats of ANKK1 (Glu713Lys of 765 residues). This polymorphism, which is commonly referred to Taq1A, was previously believed to be located in the promoter region of the DRD2 gene, since the polymorphism is proximal to the DRD2 gene and can influence DRD2 receptor expression.[1] It is now known to be located in the coding region of the ANKK1 gene which controls the synthesis of dopamine in the brain.[2] The A1 allele is associated with increased activity of striatal L-amino acid decarboxylase.[3]
## A1+ allele
- Hepatitis C infection[4]
- Antisocial personality disorder[5][6]
- Borderline personality traits[citation needed]
- Schizoid/avoidant behavior[7]
Given that the A1+ allele is associated with antisocial personality disorder, one may infer that the allele is also associated with narcissistic personality disorder and histrionic personality disorder. However, these predictions have not yet been empirically verified.
## A1+ genotype frequencies
European population estimates for A1+ genotype frequencies range from 20.8 to 43.4% (National Center of Biotechnology Information (NCBI), identification number rs1800497).[8]
## Addictive behaviors
The ANKK1 gene is closely linked to dopamine receptor D2 (DRD2) on chromosome band 11q23.1.[9] The A1 allele of the Taq1A polymorphism (rs1800497T), is located ≈10kb downstream of the dopamine receptor DRD2 gene. Dopamine (DA) is a neurotransmitter in the brain, which controls feelings of wellbeing. This sensation results from the interaction of dopamine and other neurotransmitters such as serotonin, the opioids, and other brain chemicals. Dopamine increases the motivation for food cravings and appetite mediation.[10]
The Reward Deficiency Syndrome (RDS) involves the pleasures or reward mechanisms that rely on dopamine. The result of this deficiency is based on the genetic makeup; this helps explain how certain simple genetic anomalies can give rise to complex aberrant behaviours as the ones mentioned previously. The A1 allelic prevalence has been reported to be significantly higher in obese individuals than in lean subjects,[11] moreover, individuals with increased body mass index (BMI) (BMI >30 kg/m²) have fewer DRD2 dopamine receptors. Investigators have also suggested that hormonal mechanism may underline a gender difference in the ability to suppress hunger in relation to this SNP, which may contribute to the greater incidence of obesity in women compared to men.[12] However, authors have pointed out that A1 carriers have difficulty in learning from negative feedback in a reinforcement-learning task and are less efficient at learning to avoid actions that have negative consequences. | https://www.wikidoc.org/index.php/ANKK1 | |
0d27ccaa03298c0c9834085823053ee949083589 | wikidoc | Aorta | Aorta
The aorta (generally pronounced eɪˈɔːtə or "ay-orta") is the largest artery in the human body, originating from the left ventricle of the heart and bringing oxygenated blood to all parts of the body in the systemic circulation.
# The course of the aorta
The aorta is usually divided into five segments/sections
- Ascending aorta — the section between the heart and the arch of aorta
- Arch of aorta — the peak part that looks somewhat like an inverted "U"
- Descending aorta — the section from the arch of aorta to the point where it divides into the common iliac arteries
Thoracic aorta — the half of the descending aorta above the diaphragm
Abdominal aorta — the half of the descending aorta below the diaphragm
- Thoracic aorta — the half of the descending aorta above the diaphragm
- Abdominal aorta — the half of the descending aorta below the diaphragm
# Features
The aorta is an elastic artery, and as such is quite distensible. When the left ventricle contracts to force blood into the aorta, the aorta expands. This stretching gives the potential energy that will help maintain blood pressure during diastole, as during this time the aorta contracts passively.
# Diseases/pathology
- Aneurysm of sinus of Valsalva
- Aortic aneurysm - myotic, bacterial (e.g. syphilis), senile, genetic, associated with valvular heart disease
Dissecting aortic aneurysm
- Dissecting aortic aneurysm
- Aortic coarctation - pre-ductal, post-ductal
- Atherosclerosis
- Marfan syndrome
- Trauma, such as traumatic aortic rupture, most often thoracic and distal to the left subclavian artery and frequently quickly fatal
- Aorta (Image courtesy of radiopaedia.org) | Aorta
Template:Infobox Artery
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2]
The aorta (generally pronounced eɪˈɔːtə or "ay-orta") is the largest artery in the human body, originating from the left ventricle of the heart and bringing oxygenated blood to all parts of the body in the systemic circulation.
# The course of the aorta
The aorta is usually divided into five segments/sections [1] [2] [3]
[4] :
- Ascending aorta — the section between the heart and the arch of aorta
- Arch of aorta — the peak part that looks somewhat like an inverted "U"
- Descending aorta — the section from the arch of aorta to the point where it divides into the common iliac arteries
Thoracic aorta — the half of the descending aorta above the diaphragm
Abdominal aorta — the half of the descending aorta below the diaphragm
- Thoracic aorta — the half of the descending aorta above the diaphragm
- Abdominal aorta — the half of the descending aorta below the diaphragm
# Features
The aorta is an elastic artery, and as such is quite distensible. When the left ventricle contracts to force blood into the aorta, the aorta expands. This stretching gives the potential energy that will help maintain blood pressure during diastole, as during this time the aorta contracts passively.
# Diseases/pathology
- Aneurysm of sinus of Valsalva
- Aortic aneurysm - myotic, bacterial (e.g. syphilis), senile, genetic, associated with valvular heart disease
Dissecting aortic aneurysm
- Dissecting aortic aneurysm
- Aortic coarctation - pre-ductal, post-ductal
- Atherosclerosis
- Marfan syndrome
- Trauma, such as traumatic aortic rupture, most often thoracic and distal to the left subclavian artery[5] and frequently quickly fatal[6]
- Aorta (Image courtesy of radiopaedia.org) | https://www.wikidoc.org/index.php/AO | |
6ebe1c7d534e531e98412ca96c40c49a7382fb25 | wikidoc | AP1S1 | AP1S1
AP-1 complex subunit sigma-1A is a protein that in humans is encoded by the AP1S1 gene.
# Function
The protein encoded by this gene is part of the clathrin coat assembly complex which links clathrin to receptors in coated vesicles. These vesicles are involved in endocytosis and Golgi processing. This protein, as well as beta-prime-adaptin, gamma-adaptin, and the medium (mu) chain AP47, form the AP-1 assembly protein complex located at the Golgi vesicle. Two alternatively spliced transcript variants of this gene, which encode distinct isoforms, have been reported.
A mutation in the AP1S1 causes the rare familial MEDNIK syndrome described in 2008.
# Interactions
AP1S1 has been shown to interact with AP1G1 and RAB10. | AP1S1
AP-1 complex subunit sigma-1A is a protein that in humans is encoded by the AP1S1 gene.[1][2][3]
# Function
The protein encoded by this gene is part of the clathrin coat assembly complex which links clathrin to receptors in coated vesicles. These vesicles are involved in endocytosis and Golgi processing. This protein, as well as beta-prime-adaptin, gamma-adaptin, and the medium (mu) chain AP47, form the AP-1 assembly protein complex located at the Golgi vesicle. Two alternatively spliced transcript variants of this gene, which encode distinct isoforms, have been reported.[3]
A mutation in the AP1S1 causes the rare familial MEDNIK syndrome described in 2008.[4]
# Interactions
AP1S1 has been shown to interact with AP1G1[2][5][6] and RAB10.[7] | https://www.wikidoc.org/index.php/AP1S1 | |
ba9f0c4641f0bc73fe3fa327279bc59dbaf2b1ab | wikidoc | AP2M1 | AP2M1
AP-2 complex subunit mu is a protein that in humans is encoded by the AP2M1 gene.
# Function
This gene encodes a subunit of the heterotetrameric coat assembly protein complex 2 (AP2), which belongs to the adaptor complexes medium subunits family. The encoded protein is required for the activity of a vacuolar ATPase, which is responsible for proton pumping occurring in the acidification of endosomes and lysosomes. The encoded protein may also play an important role in regulating the intracellular trafficking and function of CTLA-4 protein. Two transcript variants encoding different isoforms have been found for this gene.
# Interactions
AP2M1 has been shown to interact with CTLA-4 and Alpha-1B adrenergic receptor. | AP2M1
AP-2 complex subunit mu is a protein that in humans is encoded by the AP2M1 gene.[1]
# Function
This gene encodes a subunit of the heterotetrameric coat assembly protein complex 2 (AP2), which belongs to the adaptor complexes medium subunits family. The encoded protein is required for the activity of a vacuolar ATPase, which is responsible for proton pumping occurring in the acidification of endosomes and lysosomes. The encoded protein may also play an important role in regulating the intracellular trafficking and function of CTLA-4 protein. Two transcript variants encoding different isoforms have been found for this gene.[2]
# Interactions
AP2M1 has been shown to interact with CTLA-4[3][4] and Alpha-1B adrenergic receptor.[5] | https://www.wikidoc.org/index.php/AP2M1 | |
ebc4683b3a2d225f1a0689654a6047c60d3c0998 | wikidoc | AP4B1 | AP4B1
AP-4 complex subunit beta-1 is a protein that in humans is encoded by the AP4B1 gene.
# Function
The heterotetrameric adaptor protein (AP) complexes sort integral membrane proteins at various stages of the endocytic and secretory pathways. AP4 is composed of 2 large chains, beta-4 (AP4B1, this protein) and epsilon-4 (AP4E1), a medium chain, mu-4 (AP4M1), and a small chain, sigma-4 (AP4S1)
# Interactions
AP4B1 has been shown to interact with AP4M1.
# Clinical relevance
AP4-complex-mediated trafficking plays a crucial role in brain development and functioning. | AP4B1
AP-4 complex subunit beta-1 is a protein that in humans is encoded by the AP4B1 gene.[1][2]
# Function
The heterotetrameric adaptor protein (AP) complexes sort integral membrane proteins at various stages of the endocytic and secretory pathways. AP4 is composed of 2 large chains, beta-4 (AP4B1, this protein) and epsilon-4 (AP4E1), a medium chain, mu-4 (AP4M1), and a small chain, sigma-4 (AP4S1)[2]
# Interactions
AP4B1 has been shown to interact with AP4M1.[3]
# Clinical relevance
AP4-complex-mediated trafficking plays a crucial role in brain development and functioning.[4][5] | https://www.wikidoc.org/index.php/AP4B1 | |
da619021ba1993593e4b7a3fc6d2651983ff5814 | wikidoc | AP4E1 | AP4E1
AP-4 complex subunit epsilon-1 is a protein that in humans is encoded by the AP4E1 gene.
# Function
The heterotetrameric adaptor protein (AP) complexes sort integral membrane proteins at various stages of the endocytic and secretory pathways. AP4 is composed of 2 large chains, beta-4 (AP4B1) and epsilon-4 (AP4E1; this gene), a medium chain, mu-4 (AP4M1), and a small chain, sigma-4 (AP4S1).
# Clinical relevance
It is currently hypothesized that AP4-complex-mediated trafficking plays a crucial role in brain development and functioning.
# Model organisms
Model organisms have been used in the study of AP4E1 function. A conditional knockout mouse line, called Ap4e1tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty four tests were carried out on homozygous mutant mice and four significant abnormalities were observed. Females displayed decreased vertical activity in an open field test, had an abnormal complete blood count, hypoferremia, and a decreased corpus callosum size and enlarged lateral ventricles. | AP4E1
AP-4 complex subunit epsilon-1 is a protein that in humans is encoded by the AP4E1 gene.[1]
# Function
The heterotetrameric adaptor protein (AP) complexes sort integral membrane proteins at various stages of the endocytic and secretory pathways. AP4 is composed of 2 large chains, beta-4 (AP4B1) and epsilon-4 (AP4E1; this gene), a medium chain, mu-4 (AP4M1), and a small chain, sigma-4 (AP4S1).[1]
# Clinical relevance
It is currently hypothesized that AP4-complex-mediated trafficking plays a crucial role in brain development and functioning.[2]
# Model organisms
Model organisms have been used in the study of AP4E1 function. A conditional knockout mouse line, called Ap4e1tm1a(KOMP)Wtsi[10][11] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[12][13][14]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[8][15] Twenty four tests were carried out on homozygous mutant mice and four significant abnormalities were observed.[8] Females displayed decreased vertical activity in an open field test, had an abnormal complete blood count, hypoferremia, and a decreased corpus callosum size and enlarged lateral ventricles.[8] | https://www.wikidoc.org/index.php/AP4E1 | |
f7b7f2b98ebc47996a104db3cd609f467bbe40bd | wikidoc | AP4M1 | AP4M1
AP-4 complex subunit mu-1 is a protein that in humans is encoded by the AP4M1 gene.
# Function
This gene encodes a subunit of the heterotetrameric AP-4 complex. The encoded protein belongs to the adaptor complexes medium subunits family. This AP-4 complex is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system.
# Interactions
AP4M1 has been shown to interact with AP4B1.
# Clinical relevance
The AP4-complex-mediated trafficking plays a crucial role in brain development and functioning. | AP4M1
AP-4 complex subunit mu-1 is a protein that in humans is encoded by the AP4M1 gene.[1][2][3]
# Function
This gene encodes a subunit of the heterotetrameric AP-4 complex. The encoded protein belongs to the adaptor complexes medium subunits family. This AP-4 complex is involved in the recognition and sorting of cargo proteins with tyrosine-based motifs from the trans-golgi network to the endosomal-lysosomal system.[3]
# Interactions
AP4M1 has been shown to interact with AP4B1.[4]
# Clinical relevance
The AP4-complex-mediated trafficking plays a crucial role in brain development and functioning.[5] | https://www.wikidoc.org/index.php/AP4M1 | |
c3491476d52901086f075cde81d50a3255217485 | wikidoc | AP4S1 | AP4S1
AP-4 complex subunit sigma-1 is a protein that in humans is encoded by the AP4S1 gene.
# Function
The heterotetrameric adaptor protein (AP) complexes sort integral membrane proteins at various stages of the endocytic and secretory pathways. AP4 is composed of 2 large chains, beta-4 (AP4B1) and epsilon-4 (AP4E1), a medium chain, mu-4 (AP4M1), and a small chain, sigma-4 (AP4S1, this gene).
# Clinical relevance
It is currently hypothesized that AP4-complex-mediated trafficking plays a crucial role in brain development and functioning. | AP4S1
AP-4 complex subunit sigma-1 is a protein that in humans is encoded by the AP4S1 gene.[1]
# Function
The heterotetrameric adaptor protein (AP) complexes sort integral membrane proteins at various stages of the endocytic and secretory pathways. AP4 is composed of 2 large chains, beta-4 (AP4B1) and epsilon-4 (AP4E1), a medium chain, mu-4 (AP4M1), and a small chain, sigma-4 (AP4S1, this gene).[1]
# Clinical relevance
It is currently hypothesized that AP4-complex-mediated trafficking plays a crucial role in brain development and functioning.[2] | https://www.wikidoc.org/index.php/AP4S1 | |
f1a610bf3ad9cfb9986c48ac48bae45dede82dd1 | wikidoc | APAF1 | APAF1
Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene.
# Function
This gene encodes a cytoplasmic protein that forms one of the central hubs in the apoptosis regulatory network. This protein contains (from the N terminal) a caspase recruitment domain (CARD), an ATPase domain (NB-ARC), few short helical domains and then several copies of the WD40 repeat domain. Upon binding cytochrome c and dATP, this protein forms an oligomeric apoptosome. The apoptosome binds and cleaves Procaspase-9 protein, releasing its mature, activated form. The precise mechanism for this reaction is still debated though work published by Guy Salvesen suggests that the apoptosome may induce caspase-9 dimerization and subsequent autocatalysis. Activated caspase-9 stimulates the subsequent caspase cascade that commits the cell to apoptosis.
Alternative splicing results in several transcript variants encoding different isoforms.
# Structure
APAF1 contains a CARD domain with a Greek key motif composed of six helices, a Rossman fold nucleotide binding domains, a short helical motif and a winged-helix domain.
# Interactions
APAF1 has been shown to interact with:
- APIP,
- BCL2-like 1
- Caspase-9,
- HSPA4, and
- NLRP1. | APAF1
Apoptotic protease activating factor 1, also known as APAF1, is a human homolog of C. elegans CED-4 gene.[1][2][3]
# Function
This gene encodes a cytoplasmic protein that forms one of the central hubs in the apoptosis regulatory network. This protein contains (from the N terminal) a caspase recruitment domain (CARD), an ATPase domain (NB-ARC), few short helical domains and then several copies of the WD40 repeat domain. Upon binding cytochrome c and dATP, this protein forms an oligomeric apoptosome. The apoptosome binds and cleaves Procaspase-9 protein, releasing its mature, activated form. The precise mechanism for this reaction is still debated though work published by Guy Salvesen suggests that the apoptosome may induce caspase-9 dimerization and subsequent autocatalysis.[4] Activated caspase-9 stimulates the subsequent caspase cascade that commits the cell to apoptosis.
Alternative splicing results in several transcript variants encoding different isoforms.[1]
# Structure
APAF1 contains a CARD domain with a Greek key motif composed of six helices, a Rossman fold nucleotide binding domains, a short helical motif and a winged-helix domain.[5]
# Interactions
APAF1 has been shown to interact with:
- APIP,[6]
- BCL2-like 1[7][8]
- Caspase-9,[9][6][10][7][8]
- HSPA4,[11] and
- NLRP1.[9] | https://www.wikidoc.org/index.php/APAF1 | |
8072302a93b6286009eec176733c04a7ec081e5e | wikidoc | APBA1 | APBA1
Amyloid beta A4 precursor protein-binding family A member 1 is a protein that in humans is encoded by the APBA1 gene.
# Function
The protein encoded by this gene is a member of the X11 protein family. It is a neuronal adaptor protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). It stabilises APP and inhibits production of proteolytic APP fragments including the A beta peptide that is deposited in the brains of Alzheimer's disease patients. This gene product is believed to be involved in signal transduction processes. It is also regarded as a putative vesicular trafficking protein in the brain that can form a complex with the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion.
# Interactions
APBA1 has been shown to interact with KCNJ12, CCS, CASK and Amyloid precursor protein. | APBA1
Amyloid beta A4 precursor protein-binding family A member 1 is a protein that in humans is encoded by the APBA1 gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the X11 protein family. It is a neuronal adaptor protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). It stabilises APP and inhibits production of proteolytic APP fragments including the A beta peptide that is deposited in the brains of Alzheimer's disease patients. This gene product is believed to be involved in signal transduction processes. It is also regarded as a putative vesicular trafficking protein in the brain that can form a complex with the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion.[3]
# Interactions
APBA1 has been shown to interact with KCNJ12,[4][5] CCS,[6] CASK[7][8] and Amyloid precursor protein.[9][10] | https://www.wikidoc.org/index.php/APBA1 | |
1fa7154648f7884e230cd3b6f477bc15ed3e03d4 | wikidoc | APBA2 | APBA2
Amyloid beta A4 precursor protein-binding family A member 2 is a protein that in humans is encoded by the APBA2 gene.
# Function
The protein encoded by this gene is a member of the X11 protein family. It is a neuronal adaptor protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). It stabilises APP and inhibits production of proteolytic APP fragments including the A beta peptide that is deposited in the brains of Alzheimer's disease patients. This gene product is believed to be involved in signal transduction processes. It is also regarded as a putative vesicular trafficking protein in the brain that can form a complex with the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion.
# Interactions
APBA2 has been shown to interact with CLSTN1, RELA and Amyloid precursor protein. | APBA2
Amyloid beta A4 precursor protein-binding family A member 2 is a protein that in humans is encoded by the APBA2 gene.[1][2]
# Function
The protein encoded by this gene is a member of the X11 protein family. It is a neuronal adaptor protein that interacts with the Alzheimer's disease amyloid precursor protein (APP). It stabilises APP and inhibits production of proteolytic APP fragments including the A beta peptide that is deposited in the brains of Alzheimer's disease patients. This gene product is believed to be involved in signal transduction processes. It is also regarded as a putative vesicular trafficking protein in the brain that can form a complex with the potential to couple synaptic vesicle exocytosis to neuronal cell adhesion.[2]
# Interactions
APBA2 has been shown to interact with CLSTN1,[3][4] RELA[5] and Amyloid precursor protein.[3][6][7] | https://www.wikidoc.org/index.php/APBA2 | |
d7a4ef6d4f33af386b765743ac13103c278ac0b4 | wikidoc | APBB1 | APBB1
Amyloid beta A4 precursor protein-binding family B member 1 is a protein that in humans is encoded by the APBB1 gene.
# Function
The protein encoded by this gene is a member of the Fe65 protein family. It is an adaptor protein localized in the nucleus. It interacts with the Alzheimer's disease amyloid precursor protein (APP), transcription factor CP2/LSF/LBP1 and the low-density lipoprotein receptor-related protein. APP functions as a cytosolic anchoring site that can prevent the gene product's nuclear translocation. This encoded protein could play an important role in the pathogenesis of Alzheimer's disease. It is thought to regulate transcription. Also it is observed to block cell cycle progression by downregulating thymidylate synthase expression. Multiple alternatively spliced transcript variants have been described for this gene but some of their full length sequence is not known.
# Interactions
APBB1 has been shown to interact with APLP2, TFCP2, LRP1 and Amyloid precursor protein. | APBB1
Amyloid beta A4 precursor protein-binding family B member 1 is a protein that in humans is encoded by the APBB1 gene.[1][2][3]
# Function
The protein encoded by this gene is a member of the Fe65 protein family. It is an adaptor protein localized in the nucleus. It interacts with the Alzheimer's disease amyloid precursor protein (APP), transcription factor CP2/LSF/LBP1 and the low-density lipoprotein receptor-related protein. APP functions as a cytosolic anchoring site that can prevent the gene product's nuclear translocation. This encoded protein could play an important role in the pathogenesis of Alzheimer's disease. It is thought to regulate transcription. Also it is observed to block cell cycle progression by downregulating thymidylate synthase expression. Multiple alternatively spliced transcript variants have been described for this gene but some of their full length sequence is not known.[3]
# Interactions
APBB1 has been shown to interact with APLP2,[4][5] TFCP2,[6] LRP1[7] and Amyloid precursor protein.[4][5][7][8][9] | https://www.wikidoc.org/index.php/APBB1 | |
745fae0441078c2e3de67e15736b2df4e40d02a2 | wikidoc | APEX1 | APEX1
DNA-(apurinic or apyrimidinic site) lyase is an enzyme that in humans is encoded by the APEX1 gene.
Apurinic/apyrimidinic (AP) sites (also called "abasic sites") occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. AP sites are pre-mutagenic lesions that can prevent normal DNA replication. All cells, from simple prokaryotes to humans, have evolved systems to identify and repair such sites. Class II AP endonucleases cleave the phosphodiester backbone 5' to the AP site, thereby initiating a process known as base excision repair (BER). The APEX gene (alternatively named APE1, HAP1, APEN) encodes the major AP endonuclease in human cells. Splice variants have been found for this gene; all encode the same protein.
# Interactions
APEX1 has been shown to interact with MUTYH, Flap structure-specific endonuclease 1 and XRCC1. | APEX1
DNA-(apurinic or apyrimidinic site) lyase is an enzyme that in humans is encoded by the APEX1 gene.
Apurinic/apyrimidinic (AP) sites (also called "abasic sites") occur frequently in DNA molecules by spontaneous hydrolysis, by DNA damaging agents or by DNA glycosylases that remove specific abnormal bases. AP sites are pre-mutagenic lesions that can prevent normal DNA replication. All cells, from simple prokaryotes to humans, have evolved systems to identify and repair such sites. Class II AP endonucleases cleave the phosphodiester backbone 5' to the AP site, thereby initiating a process known as base excision repair (BER). The APEX gene (alternatively named APE1, HAP1, APEN) encodes the major AP endonuclease in human cells. Splice variants have been found for this gene; all encode the same protein.[1]
# Interactions
APEX1 has been shown to interact with MUTYH,[2] Flap structure-specific endonuclease 1[3] and XRCC1.[4] | https://www.wikidoc.org/index.php/APEX1 | |
89387e3ef551ed6d68f6dd5f16fd1ac97221bbac | wikidoc | APLP1 | APLP1
Amyloid-like protein 1, also known as APLP1, is a protein that in humans is encoded by the APLP1 gene. APLP1 along with APLP2 are important modulators of glucose and insulin homeostasis.
# Function
This gene encodes a member of the highly conserved amyloid precursor protein gene family. The encoded protein is a membrane-associated glycoprotein that is cleaved by secretases in a manner similar to amyloid beta A4 precursor protein cleavage. This cleavage liberates an intracellular cytoplasmic fragment that may act as a transcriptional activator. The encoded protein may also play a role in synaptic maturation during cortical development. Alternatively spliced transcript variants encoding different isoforms have been described.
APLP1 and APLP2 double knockout mice display hypoglycemia and hyperinsulinemia indicating that these two proteins are important modulators of glucose and insulin homeostasis. | APLP1
Amyloid-like protein 1, also known as APLP1, is a protein that in humans is encoded by the APLP1 gene.[1][2] APLP1 along with APLP2 are important modulators of glucose and insulin homeostasis.[3]
# Function
This gene encodes a member of the highly conserved amyloid precursor protein gene family. The encoded protein is a membrane-associated glycoprotein that is cleaved by secretases in a manner similar to amyloid beta A4 precursor protein cleavage. This cleavage liberates an intracellular cytoplasmic fragment that may act as a transcriptional activator. The encoded protein may also play a role in synaptic maturation during cortical development. Alternatively spliced transcript variants encoding different isoforms have been described.[1]
APLP1 and APLP2 double knockout mice display hypoglycemia and hyperinsulinemia indicating that these two proteins are important modulators of glucose and insulin homeostasis.[3] | https://www.wikidoc.org/index.php/APLP1 | |
d674b8c6bb7644dd51885557c32581353a712e99 | wikidoc | APLP2 | APLP2
Amyloid-like protein 2, also known as APLP2, is a protein that in humans is encoded by the APLP2 gene. APLP2 along with APLP1 are important modulators of glucose and insulin homeostasis.
# Gene location
The human APLP2 gene is located on the long (q) arm of chromosome 11 at region 2 band 4, from base pair 130, 069, 821 to base pair 130, 144, 811 (GRCh38.p7).
# Protein structure
APLP2 consists of 763 amino acids, with 31 amino acids making up the signal peptide and 732 amino acids making up the chain of the protein.
## Extracellular domain
The extracellular domain (residues 32-692) contains the E1 domain, E2 domain, and BPTI/Kunitz inhibitor domain. The E1 domain contains two independent folding units, the growth factor-like domain (GFLD) and the copper-binding domain (CuBD). GFLD has a highly charged basic surface and a highly flexible region consisting of an N-terminal loop formed by a disulphide bridge. CuBD consists of an alpha-helix that is tightly packed on a triple-stranded beta-sheet.
The E2 domain is the largest subdomain of APLP2 and consists of six alpha-helixes. The N-terminal double stranded coiled coil structure of the first monomer of E2 packs against the C-terminal triple stranded coiled coil structure of the second monomer.
The BPTI/Kunitz inhibitor domain (residues 306-364) is ‘Cys-rich’ and is capable of inhibiting several proteases.
The ectodomain of APLP2 is dimeric and contains multiple binding sites for metal ions and components of the extracellular matrix. These bindings site can bind copper, zinc, collagen and heparan sulfate.
## Transmembrane region
The transmembrane region of APLP2 (residues 693-716) is helical in structure.
## Cytoplasmic domain
The cytoplasmic domain (resides 717-763) contains a YENPTY sequence suggesting a duel function of the domain. The NPxY motif can function as a signal for endocytosis or the sequence can function to mediate binding of various interactive partners.
# Function
APLP2 associates with antigen presentation molecules like MHC class I molecules and regulates their surface expression by enhancing endocytosis.
APLP1 and APLP2 double knockout mice display hypoglycemia and hyperinsulinemia indicating that these two proteins are important modulators of glucose and insulin homeostasis. APLP2 has also been shown to regulate development of the brain by regulating migration and differentiation of neural stem cells.
Double mice knock outs of APLP2 and its homologues, APP and APLP1 have shown a strong indication that APLP2 has the key physiological role among the family members. APLP2/APP double knock out mice and APLP2/APLP1 double knock out mice each show a lethal phenotype (postnatal day 1), whereas APLP1/APP double knock out mice are apparently normal, demonstrating the importance of the APLP2 protein.
APLP2 plays a role in synaptic plasticity, functioning to promote neurite outgrowth, neural cell migration and copper homeostasis. Analysing the neurons and networks of APP/APLP2 double knock out mice using stem cell-derived neurons and slice cultures, shows deficient excitatory synaptic transmission in this genotype. Moreover, APLP2 together with APP has been demonstrated to exhibit presynaptic and postsynaptic functions in synaptogenesis and maintenance of synapses.
APLP2 has shown to act as a cargo receptor in axonal transport for intact proteins.
# Clinical significance
APLP2 is part of a family of mammalian membrane proteins along with APLP1 and amyloid precursor protein (APP). Since APP plays a key role in the molecular pathology of Alzheimer’s disease (AD), it has been hypothesized that APLP2 also plays a role in AD pathogenesis. The amyloid β peptide (Aβ) that is present on APP has been shown to cause neurotoxic effects leading to AD. Although the Aβ sequence is not present on APLP2, it has been suggested that APLP2 and APP share a functional redundancy whereby both proteins interplay with one another to exhibit physiological functions to do with synapse formation.
# Interactions
APLP2 has been shown to interact with APBB1. | APLP2
Amyloid-like protein 2, also known as APLP2, is a protein that in humans is encoded by the APLP2 gene.[1][2] APLP2 along with APLP1 are important modulators of glucose and insulin homeostasis.[3]
# Gene location
The human APLP2 gene is located on the long (q) arm of chromosome 11 at region 2 band 4, from base pair 130, 069, 821 to base pair 130, 144, 811 (GRCh38.p7).[1]
# Protein structure
APLP2 consists of 763 amino acids, with 31 amino acids making up the signal peptide and 732 amino acids making up the chain of the protein.[4]
## Extracellular domain
The extracellular domain (residues 32-692) contains the E1 domain, E2 domain, and BPTI/Kunitz inhibitor domain.[4][5] The E1 domain contains two independent folding units, the growth factor-like domain (GFLD) and the copper-binding domain (CuBD).[5] GFLD has a highly charged basic surface and a highly flexible region consisting of an N-terminal loop formed by a disulphide bridge.[5] CuBD consists of an alpha-helix that is tightly packed on a triple-stranded beta-sheet.[5]
The E2 domain is the largest subdomain of APLP2 and consists of six alpha-helixes.[5] The N-terminal double stranded coiled coil structure of the first monomer of E2 packs against the C-terminal triple stranded coiled coil structure of the second monomer.[5]
The BPTI/Kunitz inhibitor domain (residues 306-364)[4] is ‘Cys-rich’ and is capable of inhibiting several proteases.[6]
The ectodomain of APLP2 is dimeric and contains multiple binding sites for metal ions and components of the extracellular matrix.[5] These bindings site can bind copper, zinc, collagen and heparan sulfate.[5]
## Transmembrane region
The transmembrane region of APLP2 (residues 693-716) is helical in structure.[4]
## Cytoplasmic domain
The cytoplasmic domain (resides 717-763)[4] contains a YENPTY sequence suggesting a duel function of the domain.[5] The NPxY motif can function as a signal for endocytosis or the sequence can function to mediate binding of various interactive partners.[5]
# Function
APLP2 associates with antigen presentation molecules like MHC class I molecules and regulates their surface expression by enhancing endocytosis.[7][8]
APLP1 and APLP2 double knockout mice display hypoglycemia and hyperinsulinemia indicating that these two proteins are important modulators of glucose and insulin homeostasis.[3] APLP2 has also been shown to regulate development of the brain by regulating migration and differentiation of neural stem cells.[9]
Double mice knock outs of APLP2 and its homologues, APP and APLP1 have shown a strong indication that APLP2 has the key physiological role among the family members.[10] APLP2/APP double knock out mice and APLP2/APLP1 double knock out mice each show a lethal phenotype (postnatal day 1), whereas APLP1/APP double knock out mice are apparently normal, demonstrating the importance of the APLP2 protein.[10]
APLP2 plays a role in synaptic plasticity, functioning to promote neurite outgrowth, neural cell migration and copper homeostasis.[10] Analysing the neurons and networks of APP/APLP2 double knock out mice using stem cell-derived neurons and slice cultures, shows deficient excitatory synaptic transmission in this genotype.[11] Moreover, APLP2 together with APP has been demonstrated to exhibit presynaptic and postsynaptic functions in synaptogenesis and maintenance of synapses.[12]
APLP2 has shown to act as a cargo receptor in axonal transport for intact proteins.[13]
# Clinical significance
APLP2 is part of a family of mammalian membrane proteins along with APLP1 and amyloid precursor protein (APP).[14] Since APP plays a key role in the molecular pathology of Alzheimer’s disease (AD), it has been hypothesized that APLP2 also plays a role in AD pathogenesis.[15] The amyloid β peptide (Aβ) that is present on APP has been shown to cause neurotoxic effects leading to AD.[16] Although the Aβ sequence is not present on APLP2, it has been suggested that APLP2 and APP share a functional redundancy whereby both proteins interplay with one another to exhibit physiological functions to do with synapse formation.[15]
# Interactions
APLP2 has been shown to interact with APBB1.[17][18] | https://www.wikidoc.org/index.php/APLP2 | |
98a6685cff9798175ebcaadf815e49d9d447227b | wikidoc | APOA2 | APOA2
Apolipoprotein A-II is a protein that in humans is encoded by the APOA2 gene.
# Function
This gene encodes apolipoprotein (apo-) A-II, which is the second most abundant protein of the high density lipoprotein particles. The protein is found in plasma as a monomer, homodimer, or heterodimer with apolipoprotein D. Defects in this gene may result in apolipoprotein A-II deficiency or hypercholesterolemia.
# Interactions
APOA2 has been shown to interact with PLTP.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | APOA2
Apolipoprotein A-II is a protein that in humans is encoded by the APOA2 gene.[1]
# Function
This gene encodes apolipoprotein (apo-) A-II, which is the second most abundant protein of the high density lipoprotein particles. The protein is found in plasma as a monomer, homodimer, or heterodimer with apolipoprotein D. Defects in this gene may result in apolipoprotein A-II deficiency or hypercholesterolemia.[2]
# Interactions
APOA2 has been shown to interact with PLTP.[3]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/APOA2 | |
656cf6deb89b3c1480e45ef8c95f3e26629aef9e | wikidoc | APOA4 | APOA4
Apolipoprotein A-IV (also known as apoA-IV, apoAIV, or apoA4) is plasma protein that is the product of the human gene APOA4.
# Gene
APOA4 resides on chromosome 11 in close linkage to APOA1 and APOC3. APOA4 contains 3 exons separated by two introns, and is polymorphic, although most of the reported sequence polymorphisms occur in exon 3. The best validated and studied non-synonymous SNPs are a glutamine → histidine substitution at codon 360 and a threonine → serine substitution at codon 347; a sequence polymorphism has also been identified in the 3'UTR of the third exon. Intra-species comparative gene sequence analysis suggests that the APOA4 gene arose from APOA1 by gene duplication approximately 270 MYA.
# Function
The primary translation product of the APOA4 gene is a 396-residue preprotein, which undergoes proteolytic processing to yield apo A-IV, a 376-residue mature O-linked glycoprotein. In most mammals, including humans, apo A-IV synthesis is confined to the intestine; however in mice and rats hepatic synthesis also occurs. Apo A-IV is secreted into circulation on the surface of newly synthesized chylomicron particles. Intestinal fat absorption dramatically increases the synthesis and secretion of apo A-IV. Although its primary function in human lipid metabolism has not been established, apo A-IV has been found to:
- activate lecithin-cholesterol acyltransferase and cholesterylester transfer protein in vitro;
- play a role in the regulation of appetite and satiety in rodent models;
- display anti-oxidant and anti-atherogenic properties in vitro and in rodent models;
- modulate the efficiency of enterocyte and hepatic transcellular lipid transport in vitro.
Human apo A-IV deficiency has not been reported.
# Interactions
APOA4 has been shown to interact with GPLD1.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | APOA4
Apolipoprotein A-IV (also known as apoA-IV, apoAIV, or apoA4) is plasma protein that is the product of the human gene APOA4.[1][2]
# Gene
APOA4 resides on chromosome 11 in close linkage to APOA1 and APOC3. APOA4 contains 3 exons separated by two introns, and is polymorphic, although most of the reported sequence polymorphisms occur in exon 3. The best validated and studied non-synonymous SNPs are a glutamine → histidine substitution at codon 360 and a threonine → serine substitution at codon 347; a sequence polymorphism has also been identified in the 3'UTR of the third exon.[3] Intra-species comparative gene sequence analysis suggests that the APOA4 gene arose from APOA1 by gene duplication approximately 270 MYA.[4]
# Function
The primary translation product of the APOA4 gene is a 396-residue preprotein, which undergoes proteolytic processing to yield apo A-IV, a 376-residue mature O-linked glycoprotein. In most mammals, including humans, apo A-IV synthesis is confined to the intestine; however in mice and rats hepatic synthesis also occurs. Apo A-IV is secreted into circulation on the surface of newly synthesized chylomicron particles. Intestinal fat absorption dramatically increases the synthesis and secretion of apo A-IV. Although its primary function in human lipid metabolism has not been established, apo A-IV has been found to:
- activate lecithin-cholesterol acyltransferase and cholesterylester transfer protein in vitro;
- play a role in the regulation of appetite and satiety in rodent models;
- display anti-oxidant and anti-atherogenic properties in vitro and in rodent models;
- modulate the efficiency of enterocyte and hepatic transcellular lipid transport in vitro.[3]
Human apo A-IV deficiency has not been reported.
# Interactions
APOA4 has been shown to interact with GPLD1.[5]
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/APOA4 | |
e61e1a91b0844bcabf9fec165e59a4958220f476 | wikidoc | APOA5 | APOA5
Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11. It is significantly expressed in liver. The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors. Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome. The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
# Discovery
The gene for apolipoprotein A5 (APOA5, gene ID 116519, OMIM accession number – 606368) was originally found by comparative sequencing of human and mice DNA as a last member of the gene cluster of apolipoproteins APOA1/APOC3/APOA4/APOA5, located on human chromosome 11 at position 11q23. The creation of two mice models (APOA5 transgenic and APOA5 knock-out) confirmed the important role of this gene in plasma triglyceride determination. The transgenic mice had lower and the knock-out mice higher levels of plasma triglycerides, while plasma cholesterol levels remained unchanged in both animal models. A Dutch group simultaneously described an identical gene as apolipoprotein which it is associated with the early phase of liver regeneration, but failed to recognise its important role in the determination of plasma triglyceride levels.
# Structure
## Gene
The APOA5 gene resides on chromosome 11 at the band 11q23 and contains 4 exons and 3 introns. This gene uses alternate polyadenylation sites and is located proximal to the apolipoprotein gene cluster on chromosome 11q23.
## Protein
This protein belongs to the apolipoprotein A1/A4/E family and contains 2 coiled coil domains. Overall, APOA5 is predicted to have approximately 60% a-helical content. The mature APOA5 protein spans a length of 366 amino acid residues, of which 23 amino acids code for the signal peptide. The molecular mass of the precursor was calculated to be 41 kDa, while the mature APOA5 protein was calculated to be 39 kDa.
# Tissue distribution
In humans, APOA5 is expressed almost exclusively in the liver tissue; some minor expressions have also been detected in the small intestine. Nothing is known about the existence of the potential alternative splicing variants of this gene. In comparison with other apolipoproteins, plasma concentration of APOA5 is very low (less than 1 μg/mL). This suggests that it has more catalytic than structural functions, since there is less than one APOA5 molecule per one lipoprotein particle. APOA5 is associated predominantly with TG-rich lipoproteins (chylomicrons and VLDL) and has also been detected on HDL particles.
# Function
APOA5 mainly functions to influence plasma triglyceride levels. The first suggested mechanism supposes that APOA5 functions as an activator of lipoprotein lipase (which is a key enzyme in triglyceride catabolism) and, through this process, enhances the metabolism of TG-rich particles. The second is the possible effect of APOA5 on the secretion of VLDL particles, since APOA5 reduces hepatic production by inhibiting VLDL-particle production and assembly by binding to cellular membranes and lipids. Finally, the third possibility relates to the acceleration of the hepatic uptake of lipoprotein remnants and it has been shown that APOA5 binds to different members of the low-density lipoprotein receptor family. In addition to its TG-lowering effect, APOA5 also plays a significant role in modulating HDL maturation and cholesterol metabolism. Increased APOA5 levels were associated with skewed cholesterol distribution from VLDL to large HDL particles. APOA5 mRNA is upregulated during liver regeneration and this suggests that APOA5 serves a function in hepatocyte proliferation. It’s also reported that APOA5 could enhance insulin secretion in beta-cells and the cell surface midkine could be involved in APOA5 endocytosis.
# Gene variability
Within the APOA5 gene, a couple of important SNPs with a widely confirmed effect on plasma TG levels as well as rare mutations have been described. In Caucasians, the common variants are inherited mostly in three haplotypes, which are characterised by two SNPs, namely rs662799 (T-1131˃C; in almost complete LD with A-3˃G, where the minor allele is associated with about 50% lower gene expression) and rs3135506 (Ser19˃Trp; C56˃G; alters the signal peptide and influences APOA5 secretion into plasma). There are also a further three common variants (A-3˃G, IVS+476 G˃A and T1259˃C) which are not necessary for haplotype characterisation.
Population frequencies of common APOA5 alleles exhibit large interethnic differences. For example, there are about 15% of carriers of the -1131C allele among Caucasians, but the frequency could reach even between 40% and 50% among Asians. In contrast, the Trp19 allele is very rare in the Asian population (less than 1% of carriers) but is common in Caucasians (about 15% of carriers). Vice versa, important SNP (rs2075291, G553T, Gly185˃Cys) with a population frequency of about 5% has been detected among Asians, but it is extremely rare among Caucasians. Sporadic publications refer to some other common polymorphisms, e.g. Val153˃Met (rs3135507, G457A) and also suggest significant sex-dependent associations with plasma lipids. Rare variants within the APOA5 gene have been described in a couple of different populations. Among the “common mutations/rare SNPs”, one of the most characterised on a population level is the Ala315˃Val exchange. Originally detected in patients with extreme TG levels over 10 mmo/L, it was also found in about 0.7% of the general population (mostly in individuals with normal TG values), which suggests a low penetrance of this variant. More than twenty other rare variants (mutations) have been described within the human APOA5 gene. They cover a wide spectrum that includes preliminary stop codons, amino acid changes as well as insertions and deletions. These mutations are generally associated with hypertriglyceridaemia, but penetration is usually not 100%. Individual mutations have been found mostly in one pedigree only.
But not all the SNPs have a detrimental effect on TG levels. A recent report, showed that, in Sardinian population, the missense mutation Arg282Ser in APOA5 gene, correlates with a decrease in TG levels. The authors believe that this point mutation is a mayor modulatory of TG values in this population.
# Clinical significance
In humans, plasma triglycerides such as triacylglycerols have been long debated as an important risk factor for not only cardiovascular disease but also for other relevant morbidities, such as cancer, renal disease, suicide, and all-cause mortality. The APOA5 gene was found by comparative sequencing of ~200 kbp of human and mice DNA as the last member of the gene cluster of apolipoproteins located on human chromosome 11 at 11q23. Two mouse transgenic mouse models (APOA5 transgenic and APOA5 knockout) confirmed the important role of this gene in plasma triglyceride levels of plasma triglycerides. Obesity and metabolic syndrome are both closely related to plasma triglyceride levels and APOA5. Recent meta-analyses suggest that the effect on metabolic syndrome development is more profound for rs662799 in Asian population and for rs3135506 for Europeans. Moreover, meta-analysis that focused on rs662799 and the risk of type 2 diabetes mellitus has suggested a significant association in Asian populations, but not in European populations.
## As a risk factor
Even though plasma concentration of APOA5 is very low, some studies have focused on the analysis of the potential association of this biochemical parameter with cardiovascular disease (CVD). This relationship remains controversial, as higher plasma levels of APOA5 in individuals with CVD disease have been found in some, but not in all studies.
## Plasma lipids and cardiovascular disease
The major effect of the apolipoprotein A5 gene (and its variants) is on plasma triglyceride levels. Minor alleles (C1131 and Trp19) are primarily associated with the elevation of plasma triglyceride levels. The most extensive information available has been drawn from Caucasian populations, particularly in relation to the rs662799 SNP. Here, one minor allele is associated with an approximate 0,25 mmol/L increase of plasma TG levels. A similar effect is associated with the Trp19 allele, even though it has not been confirmed by a huge number of studies. Original studies have further described that the strongest effect of APOA5 polymorphisms on plasma TG levels is observed among Hispanics, with only minor effects detected among Africans. Among Asians, the effect on plasma TG levels is similar that found among Caucasians. Generally, studies have suggested significant interethnic differences and in some cases sex-dependent associations as well.
Sporadic publications have also mentioned a weak but nonetheless significant effect of APOA5 variants on plasma HDL-cholesterol and non-HDL cholesterol levels.
## Myocardial infarction
A large meta-analysis of 101 studies confirmed a risk associated with the presence of the minor APOA5 allele -1131C and coronary heart disease. The odds ratio was 1.18 for every C allele. There are far fewer studies on the second common APOA5 polymorphism, Ser19>Trp, even though available studies have detected that its effect on plasma triglycerides is similar to C-1131>T. Nevertheless, the minor Trp allele is also associated with increased risk of CVD, and it seems that especially homozygotes and carriers of more minor alleles (both -1131C and 19Trp) are at higher risk of CVD.
## Clinical Marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the APOA5 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).
## BMI, metabolic syndrome
Obesity and metabolic syndrome are both closely related to plasma triglyceride levels. Therefore, the focus on an association between APOA5 and BMI or metabolic syndrome is understandable. Available studies show that minor APOA5 alleles could be associated with an enhanced risk of obesity or metabolic syndrome development. However, genome wide studies have failed to prove that APOA5 is a gene associated with BMI values and/or obesity, so the effect could be far from clinically significant or at least significantly context-dependent.
## Nutri-, acti- and pharmacogenetic associations
Several studies have focused on changes of anthropometrical (body weight, BMI, WHR,…) or biochemical parameters (mostly plasma lipid levels) as a result of the interactions between common APOA5 variants and dietary habits (polyunsaturated fatty acid intake, n-3 and n-6 fatty acid intake, total fat and total energy intake, alcohol intake), dietary (lowering the energy intake) and/or physical activity interventions or dyslipidaemic (using statins or fenofibrate) treatment. Due to the high heterogeneity of the examined populations, differences in protocol and/or interventions used, the studies are difficult to directly compare and draw definitive conclusions. However, with caution, it could be concluded that carriers of the minor C-1131, Trp19, or T553 alleles are in some cases less prone to the positive effects of environmental and/or pharmacological interventions. Some papers suggest the importance of the interactions between APOA5 and other genes, especially with common APOE (OMIM acc. No. 107741) three allelic (E2, E3, and E4) polymorphism, in the modulation of plasma lipids. In these cases, the interaction between minor alleles of both genes seems to be of importance. In the general population, APOE4 seems to have the potential to diminish the effect of minor APOA5 rs662799 and rs3135506 alleles, especially in females. Interaction between APOE and APOA5 Ser19˃Trp has been suggested to play some role in the development of type III hyperlipidaemia. Further studies, in which interaction with APOA5 has been described, have included, for example, variants within FTO, lipoprotein lipase, USF-1 and FEN-1. They have also focused not only on plasma lipids, but on BMI values or hypertension as well.
## Other roles
Some other possible roles of APOA5 variants have been discussed, but generally these reports comprise only one or two papers – and first original papers with positive findings are usually not confirmed in second publications. These papers focus on the possible effect of different APOA5 variants on maternal height, longer foetal birth length, putative associations with plasma levels of C-reactive protein, LDL particle size and haemostatic markers. Despite the very low plasma concentration, variants within apolipoprotein A5 are potent determinants of plasma triglyceride levels. Minor alleles of three SNPs (rs662799, rs3135506, rs3135507) are associated with the higher risk of cardiovascular disease.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | APOA5
Apolipoprotein A-V is a protein that in humans is encoded by the APOA5 gene on chromosome 11.[1][2][3] It is significantly expressed in liver.[4] The protein encoded by this gene is an apolipoprotein and an important determinant of plasma triglyceride levels, a major risk factor for coronary artery disease. It is a component of several lipoprotein fractions including VLDL, HDL, chylomicrons. It is believed that apoA-V affects lipoprotein metabolism by interacting with LDL-R gene family receptors.[5] Considering its association with lipoprotein levels, APOA5 is implicated in metabolic syndrome.[6] The APOA5 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.[7]
# Discovery
The gene for apolipoprotein A5 (APOA5, gene ID 116519, OMIM accession number – 606368) was originally found by comparative sequencing of human and mice DNA as a last member of the gene cluster of apolipoproteins APOA1/APOC3/APOA4/APOA5, located on human chromosome 11 at position 11q23.[1] The creation of two mice models (APOA5 transgenic and APOA5 knock-out) confirmed the important role of this gene in plasma triglyceride determination. The transgenic mice had lower and the knock-out mice higher levels of plasma triglycerides, while plasma cholesterol levels remained unchanged in both animal models. A Dutch group simultaneously described an identical gene as apolipoprotein which it is associated with the early phase of liver regeneration, but failed to recognise its important role in the determination of plasma triglyceride levels.[2]
# Structure
## Gene
The APOA5 gene resides on chromosome 11 at the band 11q23 and contains 4 exons and 3 introns.[3][8] This gene uses alternate polyadenylation sites and is located proximal to the apolipoprotein gene cluster on chromosome 11q23.[3]
## Protein
This protein belongs to the apolipoprotein A1/A4/E family and contains 2 coiled coil domains.[3] Overall, APOA5 is predicted to have approximately 60% a-helical content.[9] The mature APOA5 protein spans a length of 366 amino acid residues, of which 23 amino acids code for the signal peptide.[10] The molecular mass of the precursor was calculated to be 41 kDa, while the mature APOA5 protein was calculated to be 39 kDa.[9]
# Tissue distribution
In humans, APOA5 is expressed almost exclusively in the liver tissue;[1] some minor expressions have also been detected in the small intestine.[11] Nothing is known about the existence of the potential alternative splicing variants of this gene. In comparison with other apolipoproteins, plasma concentration of APOA5 is very low (less than 1 μg/mL).[12] This suggests that it has more catalytic than structural functions, since there is less than one APOA5 molecule per one lipoprotein particle. APOA5 is associated predominantly with TG-rich lipoproteins (chylomicrons and VLDL) and has also been detected on HDL particles.
# Function
APOA5 mainly functions to influence plasma triglyceride levels.[13] The first suggested mechanism supposes that APOA5 functions as an activator of lipoprotein lipase (which is a key enzyme in triglyceride catabolism) and, through this process, enhances the metabolism of TG-rich particles. The second is the possible effect of APOA5 on the secretion of VLDL particles, since APOA5 reduces hepatic production by inhibiting VLDL-particle production and assembly by binding to cellular membranes and lipids.[14] Finally, the third possibility relates to the acceleration of the hepatic uptake of lipoprotein remnants and it has been shown that APOA5 binds to different members of the low-density lipoprotein receptor family.[15] In addition to its TG-lowering effect, APOA5 also plays a significant role in modulating HDL maturation and cholesterol metabolism. Increased APOA5 levels were associated with skewed cholesterol distribution from VLDL to large HDL particles.[16][17] APOA5 mRNA is upregulated during liver regeneration and this suggests that APOA5 serves a function in hepatocyte proliferation.[9] It’s also reported that APOA5 could enhance insulin secretion in beta-cells and the cell surface midkine could be involved in APOA5 endocytosis.[18]
# Gene variability
Within the APOA5 gene, a couple of important SNPs with a widely confirmed effect on plasma TG levels as well as rare mutations have been described. In Caucasians, the common variants are inherited mostly in three haplotypes, which are characterised by two SNPs, namely rs662799 (T-1131˃C; in almost complete LD with A-3˃G, where the minor allele is associated with about 50% lower gene expression) and rs3135506 (Ser19˃Trp; C56˃G; alters the signal peptide and influences APOA5 secretion into plasma). There are also a further three common variants (A-3˃G, IVS+476 G˃A and T1259˃C) which are not necessary for haplotype characterisation.
Population frequencies of common APOA5 alleles exhibit large interethnic differences. For example, there are about 15% of carriers of the -1131C allele among Caucasians, but the frequency could reach even between 40% and 50% among Asians. In contrast, the Trp19 allele is very rare in the Asian population (less than 1% of carriers) but is common in Caucasians (about 15% of carriers). Vice versa, important SNP (rs2075291, G553T, Gly185˃Cys) with a population frequency of about 5% has been detected among Asians, but it is extremely rare among Caucasians. Sporadic publications refer to some other common polymorphisms, e.g. Val153˃Met (rs3135507, G457A) and also suggest significant sex-dependent associations[19] with plasma lipids. Rare variants within the APOA5 gene have been described in a couple of different populations. Among the “common mutations/rare SNPs”, one of the most characterised on a population level is the Ala315˃Val[20] exchange. Originally detected in patients with extreme TG levels over 10 mmo/L, it was also found in about 0.7% of the general population (mostly in individuals with normal TG values), which suggests a low penetrance of this variant. More than twenty other rare variants (mutations) have been described within the human APOA5 gene. They cover a wide spectrum that includes preliminary stop codons, amino acid changes as well as insertions and deletions. These mutations are generally associated with hypertriglyceridaemia, but penetration is usually not 100%. Individual mutations have been found mostly in one pedigree only.[21]
But not all the SNPs have a detrimental effect on TG levels. A recent report, showed that, in Sardinian population, the missense mutation Arg282Ser in APOA5 gene, correlates with a decrease in TG levels. The authors believe that this point mutation is a mayor modulatory of TG values in this population.[22]
# Clinical significance
In humans, plasma triglycerides such as triacylglycerols have been long debated as an important risk factor for not only cardiovascular disease[23] but also for other relevant morbidities, such as cancer, renal disease, suicide, and all-cause mortality.[24] The APOA5 gene was found by comparative sequencing of ~200 kbp of human and mice DNA as the last member of the gene cluster of apolipoproteins located on human chromosome 11 at 11q23. Two mouse transgenic mouse models (APOA5 transgenic and APOA5 knockout) confirmed the important role of this gene in plasma triglyceride levels of plasma triglycerides. Obesity and metabolic syndrome are both closely related to plasma triglyceride levels and APOA5. Recent meta-analyses suggest that the effect on metabolic syndrome development is more profound for rs662799 in Asian population and for rs3135506 for Europeans.[6][25][26] Moreover, meta-analysis that focused on rs662799 and the risk of type 2 diabetes mellitus has suggested a significant association in Asian populations, but not in European populations.[27][28]
## As a risk factor
Even though plasma concentration of APOA5 is very low, some studies have focused on the analysis of the potential association of this biochemical parameter with cardiovascular disease (CVD). This relationship remains controversial, as higher plasma levels of APOA5 in individuals with CVD disease have been found in some, but not in all studies.[29][30]
## Plasma lipids and cardiovascular disease
The major effect of the apolipoprotein A5 gene (and its variants) is on plasma triglyceride levels. Minor alleles (C1131 and Trp19) are primarily associated with the elevation of plasma triglyceride levels. The most extensive information available has been drawn from Caucasian populations, particularly in relation to the rs662799 SNP. Here, one minor allele is associated with an approximate 0,25 mmol/L increase of plasma TG levels.[31] A similar effect is associated with the Trp19 allele, even though it has not been confirmed by a huge number of studies. Original studies have further described that the strongest effect of APOA5 polymorphisms on plasma TG levels is observed among Hispanics, with only minor effects detected among Africans. Among Asians, the effect on plasma TG levels is similar that found among Caucasians. Generally, studies have suggested significant interethnic differences and in some cases sex-dependent associations as well.[19][32][33]
Sporadic publications have also mentioned a weak but nonetheless significant effect of APOA5 variants on plasma HDL-cholesterol and non-HDL cholesterol levels.
## Myocardial infarction
A large meta-analysis of 101 studies[31] confirmed a risk associated with the presence of the minor APOA5 allele -1131C and coronary heart disease. The odds ratio was 1.18 for every C allele. There are far fewer studies on the second common APOA5 polymorphism, Ser19>Trp, even though available studies have detected that its effect on plasma triglycerides is similar to C-1131>T. Nevertheless, the minor Trp allele is also associated with increased risk of CVD, and it seems that especially homozygotes and carriers of more minor alleles (both -1131C and 19Trp) are at higher risk of CVD.[34]
## Clinical Marker
A multi-locus genetic risk score study based on a combination of 27 loci, including the APOA5 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22).[7]
## BMI, metabolic syndrome
Obesity and metabolic syndrome are both closely related to plasma triglyceride levels. Therefore, the focus on an association between APOA5 and BMI or metabolic syndrome is understandable. Available studies show that minor APOA5 alleles could be associated with an enhanced risk of obesity or metabolic syndrome development. However, genome wide studies have failed to prove that APOA5 is a gene associated with BMI values and/or obesity, so the effect could be far from clinically significant or at least significantly context-dependent.
## Nutri-, acti- and pharmacogenetic associations
Several studies have focused on changes of anthropometrical (body weight, BMI, WHR,…) or biochemical parameters (mostly plasma lipid levels) as a result of the interactions between common APOA5 variants and dietary habits (polyunsaturated fatty acid intake, n-3 and n-6 fatty acid intake, total fat and total energy intake, alcohol intake), dietary (lowering the energy intake) and/or physical activity interventions or dyslipidaemic (using statins or fenofibrate) treatment. Due to the high heterogeneity of the examined populations, differences in protocol and/or interventions used, the studies are difficult to directly compare and draw definitive conclusions.[35][36][37][38][39][40] However, with caution, it could be concluded that carriers of the minor C-1131, Trp19, or T553 alleles are in some cases less prone to the positive effects of environmental and/or pharmacological interventions. Some papers suggest the importance of the interactions between APOA5 and other genes, especially with common APOE (OMIM acc. No. 107741) three allelic (E2, E3, and E4) polymorphism, in the modulation of plasma lipids. In these cases, the interaction between minor alleles of both genes seems to be of importance. In the general population, APOE4 seems to have the potential to diminish the effect of minor APOA5 rs662799 and rs3135506 alleles, especially in females. Interaction between APOE and APOA5 Ser19˃Trp has been suggested to play some role in the development of type III hyperlipidaemia.[41] Further studies, in which interaction with APOA5 has been described, have included, for example, variants within FTO, lipoprotein lipase, USF-1 and FEN-1. They have also focused not only on plasma lipids, but on BMI values or hypertension as well.
## Other roles
Some other possible roles of APOA5 variants have been discussed, but generally these reports comprise only one or two papers – and first original papers with positive findings are usually not confirmed in second publications. These papers focus on the possible effect of different APOA5 variants on maternal height, longer foetal birth length, putative associations with plasma levels of C-reactive protein, LDL particle size and haemostatic markers. Despite the very low plasma concentration, variants within apolipoprotein A5 are potent determinants of plasma triglyceride levels. Minor alleles of three SNPs (rs662799, rs3135506, rs3135507) are associated with the higher risk of cardiovascular disease.
# Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- ↑ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430"..mw-parser-output cite.citation{font-style:inherit}.mw-parser-output q{quotes:"\"""\"""'""'"}.mw-parser-output code.cs1-code{color:inherit;background:inherit;border:inherit;padding:inherit}.mw-parser-output .cs1-lock-free a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/6/65/Lock-green.svg/9px-Lock-green.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-limited a,.mw-parser-output .cs1-lock-registration a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/d/d6/Lock-gray-alt-2.svg/9px-Lock-gray-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-lock-subscription a{background:url("https://upload.wikimedia.org/wikipedia/commons/thumb/a/aa/Lock-red-alt-2.svg/9px-Lock-red-alt-2.svg.png")no-repeat;background-position:right .1em center}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration{color:#555}.mw-parser-output .cs1-subscription span,.mw-parser-output .cs1-registration span{border-bottom:1px dotted;cursor:help}.mw-parser-output .cs1-hidden-error{display:none;font-size:100%}.mw-parser-output .cs1-visible-error{display:none;font-size:100%}.mw-parser-output .cs1-subscription,.mw-parser-output .cs1-registration,.mw-parser-output .cs1-format{font-size:95%}.mw-parser-output .cs1-kern-left,.mw-parser-output .cs1-kern-wl-left{padding-left:0.2em}.mw-parser-output .cs1-kern-right,.mw-parser-output .cs1-kern-wl-right{padding-right:0.2em} | https://www.wikidoc.org/index.php/APOA5 | |
4e460bf1b91d44b0e0cdefc15bc872b07770208f | wikidoc | APOL2 | APOL2
Apolipoprotein L2 is a protein that in humans is encoded by the APOL2 gene.
This gene is a member of the apolipoprotein L gene family and protein in this family are lipid-binding proteins. This gene encodes a 37.1 kDa protein and The protein sequence contains 337bp. Localization of this protein is mainly found in the cytosol, nucleoplasm and additionally, it is also seen in the Nuclear bodies. The involvement of this gene may affect in the movement of lipids and binding of lipids to organelles. Two transcript variants encoding the same protein have been found for this gene.
# Protein Sequence
sp|Q9BQE5|1-337
MNPESSIFIEDYLKYFQDQVSRENLLQLLTDDEAWNGFVAAAELPRDEADELRKALNKLA
SHMVMKDKNRHDKDQQHRQWFLKEFPRLKRELEDHIRKLRALAEEVEQVHRGTTIANVVS
NSVGTTSGILTLLGLGLAPFTEGISFVLLDTGMGLGAAAAVAGITCSVVELVNKLRARAQ
ARNLDQSGTNVAKVMKEFVGGNTPNVLTLVDNWYQVTQGIGRNIRAIRRARANPQLGAYA
PPPHIIGRISAEGGEQVERVVEGPAQAMSRGTMIVGAATGGILLLLDVVSLAYESKHLLE
GAKSESAEELKKRAQELEGKLNFLTKIHEMLQPGQDQ
# Interactions
APOL2 has been shown to interact with:
- IFN-γ,
- CD81,
- TNF-α,
- Bcl-2,
# Splice Variants
ApoL2 has 5 splice variants, ,
- APOL2-001
This transcript has got 6 exons, 12 domains and features are annotated, 263 variations are related this and maps to 35 oligo probes.
- APOL2-002
This transcript has got 5 exons, 12 domains and features are annotated, 263 variations are related with this gene and maps to 37 oligo probes.
- APOL2-006
This transcript has got 6 exons, is annotated with 3 domains and features, 62 variations are related with this gene and maps to 20 oligo probes.
- APOL2-008
This transcript has got 6 exons, 12 domains and features are annotated, 331 variations are related with this gene and maps to 32 oligo probes.
- APOL2-009
This transcript has got 5 exons, 4 domains and features are annotated, 104 variations are related with this gene and maps to 13 oligo probes.
# Functions of the ApoL2
- Acute Inflammation Response
- Cholesterol Metabolic Process
- Lipid Metabolic Process
- Maternal Process Involved in Female Pregnancy
- Lipid binding
- Signalling Receptor Binding | APOL2
Apolipoprotein L2 is a protein that in humans is encoded by the APOL2 gene.[1][2][3]
This gene is a member of the apolipoprotein L gene family and protein in this family are lipid-binding proteins. This gene encodes a 37.1 kDa protein and The protein sequence contains 337bp. Localization of this protein is mainly found in the cytosol, nucleoplasm and additionally, it is also seen in the Nuclear bodies.[4] The involvement of this gene may affect in the movement of lipids and binding of lipids to organelles. Two transcript variants encoding the same protein have been found for this gene.[3]
# Protein Sequence
>sp|Q9BQE5|1-337
MNPESSIFIEDYLKYFQDQVSRENLLQLLTDDEAWNGFVAAAELPRDEADELRKALNKLA
SHMVMKDKNRHDKDQQHRQWFLKEFPRLKRELEDHIRKLRALAEEVEQVHRGTTIANVVS
NSVGTTSGILTLLGLGLAPFTEGISFVLLDTGMGLGAAAAVAGITCSVVELVNKLRARAQ
ARNLDQSGTNVAKVMKEFVGGNTPNVLTLVDNWYQVTQGIGRNIRAIRRARANPQLGAYA
PPPHIIGRISAEGGEQVERVVEGPAQAMSRGTMIVGAATGGILLLLDVVSLAYESKHLLE
GAKSESAEELKKRAQELEGKLNFLTKIHEMLQPGQDQ
# Interactions
APOL2 has been shown to interact with:
- IFN-γ,[5]
- CD81,[6]
- TNF-α,[7]
- Bcl-2,[8]
# Splice Variants
ApoL2 has 5 splice variants,[9] ,
- APOL2-001
This transcript has got 6 exons, 12 domains and features are annotated, 263 variations are related this and maps to 35 oligo probes.
- APOL2-002
This transcript has got 5 exons, 12 domains and features are annotated, 263 variations are related with this gene and maps to 37 oligo probes.
- APOL2-006
This transcript has got 6 exons, is annotated with 3 domains and features, 62 variations are related with this gene and maps to 20 oligo probes.
- APOL2-008
This transcript has got 6 exons, 12 domains and features are annotated, 331 variations are related with this gene and maps to 32 oligo probes.
- APOL2-009
This transcript has got 5 exons, 4 domains and features are annotated, 104 variations are related with this gene and maps to 13 oligo probes.
# Functions of the ApoL2
- Acute Inflammation Response [10][11]
- Cholesterol Metabolic Process[12]
- Lipid Metabolic Process[8]
- Maternal Process Involved in Female Pregnancy[13]
- Lipid binding[14]
- Signalling Receptor Binding[14] | https://www.wikidoc.org/index.php/APOL2 | |
a4378e172d8244338464c28cd686ed0212871bd6 | wikidoc | APPL1 | APPL1
Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1), or DCC-interacting protein 13-alpha (DIP13alpha), is a protein that in humans is encoded by the APPL1 gene. APPL1 contains several key interactory domains: pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain and Bin–Amphiphysin–Rvs (BAR) domain.
# Function
APPL1 is an adaptor protein localized to a subset of Rab5-positive ("early") endosomes, where it recruits other binding partners and regulates vesicle trafficking and endosomal signalling. APPL1 is enriched at very early endosomes which are negative for EEA1, indicating that APPL1 affects the earliest stages of endosomal traffic before EEA1 takes over. This is in line with observations that APPL1 and EEA1 compete for Rab5 binding. APPL1 affects the speed of internalization of key endosomal cargo (eg. EGF receptor) which is dependent on Rab5 activation.
PTB domain of APPL1 regulates many cell signalling events in specific endosomal compartments - sometimes termed the "signalling endosomes". This includes lysophosphatidic acid (LPA)-induced signaling (together with interacting protein GIPC1). Additional roles for APPL1 were pinpointed to the nucleus where APPL1 can localize once dissociated from endosomes.
# Mutant studies
# Interactions
APPL1 has been shown to interact with Deleted in Colorectal Cancer, AKT2, but also Rab5, Rab21, OCRL and almost 30 other proteins. | APPL1
Adaptor protein, phosphotyrosine interacting with PH domain and leucine zipper 1 (APPL1), or DCC-interacting protein 13-alpha (DIP13alpha), is a protein that in humans is encoded by the APPL1 gene.[1][2][3] APPL1 contains several key interactory domains: pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain and Bin–Amphiphysin–Rvs (BAR) domain.[4]
# Function
APPL1 is an adaptor protein localized to a subset of Rab5-positive ("early") endosomes, where it recruits other binding partners and regulates vesicle trafficking and endosomal signalling. APPL1 is enriched at very early endosomes which are negative for EEA1, indicating that APPL1 affects the earliest stages of endosomal traffic before EEA1 takes over. This is in line with observations that APPL1 and EEA1 compete for Rab5 binding. APPL1 affects the speed of internalization of key endosomal cargo (eg. EGF receptor) which is dependent on Rab5 activation.[4]
PTB domain of APPL1 regulates many cell signalling events in specific endosomal compartments - sometimes termed the "signalling endosomes". This includes lysophosphatidic acid (LPA)-induced signaling (together with interacting protein GIPC1). Additional roles for APPL1 were pinpointed to the nucleus where APPL1 can localize once dissociated from endosomes.[4]
# Mutant studies
# Interactions
APPL1 has been shown to interact with Deleted in Colorectal Cancer,[5] AKT2,[1] but also Rab5, Rab21, OCRL and almost 30 other proteins.[4] | https://www.wikidoc.org/index.php/APPL1 | |
e39485878eb113c1d6e7211c9142fbf00745888b | wikidoc | APPL2 | APPL2
DCC-interacting protein 13-beta is a protein that in humans is encoded by the APPL2 gene.
# Model organisms
Model organisms have been used in the study of APPL2 function. A conditional knockout mouse line, called Appl2tm1a(KOMP)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty three tests were carried out on mutant mice, but no significant abnormalities were observed. | APPL2
DCC-interacting protein 13-beta is a protein that in humans is encoded by the APPL2 gene.[1][2][3]
# Model organisms
Model organisms have been used in the study of APPL2 function. A conditional knockout mouse line, called Appl2tm1a(KOMP)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists — at the Wellcome Trust Sanger Institute.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty three tests were carried out on mutant mice, but no significant abnormalities were observed.[6] | https://www.wikidoc.org/index.php/APPL2 | |
606ad5a6888825aad746cbcbbcaf82c5d590d47d | wikidoc | ARID2 | ARID2
AT-rich interactive domain-containing protein 2 (ARID2) is a protein that in humans is encoded by the ARID2 gene.
# Function
ARID2 is a subunit of the PBAF chromatin-remodeling complex, which facilitates ligand-dependent transcriptional
activation by nuclear receptors.
# Structure
The ARID2 protein contains two conserved C-terminal C2H2 zinc fingers motifs, a region rich in the amino acid residues proline and glutamine, a RFX (regulatory factor X)-type winged-helix DNA-binding domain, and a conserved N-terminal AT-rich DNA interaction domain—the last domain for which the protein is named.
# Clinical significance
Mutation studies have revealed ARID2 to be a significant tumor suppressor in many cancer subtypes. ARID2 mutations are prevalent in hepatocellular carcinoma and melanoma. Mutations are present in a smaller but significant fraction in a wide range of other tumors. ARID2 mutations are enriched in hepatitis C virus-associated hepatocellular carcinoma in the US and European patient populations compared with the overall mutation frequency.
# Model organisms
The ARID2 gene, located on chromosome 12q in humans, consists of 21 exons; orthologs are known from mouse, rat, cattle, chicken, and mosquito. Model organisms have been used in the study of ARID2 function. A conditional knockout mouse line, called Arid2tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant adult mice and two significant abnormalities were observed. A recessive lethal study found fewer homozygous mutant embryos during gestation than predicted by Mendelian ratio. In a second study, no homozygous mutant animals survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; these displayed no abnormalities. | ARID2
AT-rich interactive domain-containing protein 2 (ARID2) is a protein that in humans is encoded by the ARID2 gene.[1]
# Function
ARID2 is a subunit of the PBAF chromatin-remodeling complex, which facilitates ligand-dependent transcriptional
activation by nuclear receptors.[1]
# Structure
The ARID2 protein contains two conserved C-terminal C2H2 zinc fingers motifs, a region rich in the amino acid residues proline and glutamine, a RFX (regulatory factor X)-type winged-helix DNA-binding domain, and a conserved N-terminal AT-rich DNA interaction domain—the last domain for which the protein is named.[2]
# Clinical significance
Mutation studies have revealed ARID2 to be a significant tumor suppressor in many cancer subtypes. ARID2 mutations are prevalent in hepatocellular carcinoma[3] and melanoma.[4][5] Mutations are present in a smaller but significant fraction in a wide range of other tumors.[6] ARID2 mutations are enriched in hepatitis C virus-associated hepatocellular carcinoma in the US and European patient populations compared with the overall mutation frequency.[2]
# Model organisms
The ARID2 gene, located on chromosome 12q in humans, consists of 21 exons; orthologs are known from mouse, rat, cattle, chicken, and mosquito.[2] Model organisms have been used in the study of ARID2 function. A conditional knockout mouse line, called Arid2tm1a(EUCOMM)Wtsi[11][12] was generated as part of the International Knockout Mouse Consortium program, a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[13][14][15]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Twenty six tests were carried out on mutant adult mice and two significant abnormalities were observed.[9] A recessive lethal study found fewer homozygous mutant embryos during gestation than predicted by Mendelian ratio. In a second study, no homozygous mutant animals survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; these displayed no abnormalities.[9] | https://www.wikidoc.org/index.php/ARID2 | |
32ceb3c59ae48dcb26ca53aab3424408bff2c915 | wikidoc | ARL4D | ARL4D
ADP-ribosylation factor-like protein 4D is a protein that in humans is encoded by the ARL4D gene.
# Function
ADP-ribosylation factor 4D is a member of the ADP-ribosylation factor family of GTP-binding proteins. ARL4D is closely similar to ARL4A and ARL4C and each has a nuclear localization signal and an unusually high guanine nucleotide exchange rate. This protein may play a role in membrane-associated intracellular trafficking. Mutations in this gene have been associated with Bardet–Biedl syndrome (BBS).
# Model organisms
Model organisms have been used in the study of ARL4D function. A conditional knockout mouse line, called Arl4dtm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and significant abnormalities were observed. Homozygous mutant females had decreased bone mineral content, heart weight, lean body mass and CD8-positive, alpha-beta memory T cell number. Males had abnormal rib morphology with vertebral transformation. Both sexes displayed a reduction in dorsal third ventricle area and hippocampal area. | ARL4D
ADP-ribosylation factor-like protein 4D is a protein that in humans is encoded by the ARL4D gene.[1][2]
# Function
ADP-ribosylation factor 4D is a member of the ADP-ribosylation factor family of GTP-binding proteins. ARL4D is closely similar to ARL4A and ARL4C and each has a nuclear localization signal and an unusually high guanine nucleotide exchange rate. This protein may play a role in membrane-associated intracellular trafficking. Mutations in this gene have been associated with Bardet–Biedl syndrome (BBS).[2]
# Model organisms
Model organisms have been used in the study of ARL4D function. A conditional knockout mouse line, called Arl4dtm1a(EUCOMM)Wtsi[11][12] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[13][14][15]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[9][16] Twenty five tests were carried out on mutant mice and significant abnormalities were observed.[9] Homozygous mutant females had decreased bone mineral content, heart weight, lean body mass and CD8-positive, alpha-beta memory T cell number. Males had abnormal rib morphology with vertebral transformation. Both sexes displayed a reduction in dorsal third ventricle area and hippocampal area.[9] | https://www.wikidoc.org/index.php/ARL4D | |
f7a90ce8b937f98ae8b9e422208fdb4170f690b5 | wikidoc | ARMC6 | ARMC6
The human gene ARMC6 encodes a protein called Armadillo repeat-containing protein 6.
The function of this gene's protein product has not been determined. A related protein in mouse suggests that this protein has a conserved function.
The protein is characterized by the presence of armadillo repeats in its amino acid sequence. Diseases associated with ARMC6 include pancreatic cancer, and pancreatitis. | ARMC6
The human gene ARMC6 encodes a protein called Armadillo repeat-containing protein 6.[1][2]
The function of this gene's protein product has not been determined. A related protein in mouse suggests that this protein has a conserved function.[2]
The protein is characterized by the presence of armadillo repeats in its amino acid sequence. Diseases associated with ARMC6 include pancreatic cancer, and pancreatitis. | https://www.wikidoc.org/index.php/ARMC6 | |
491c229bb839877d427a91c106988f8868547657 | wikidoc | ARPC4 | ARPC4
Actin-related protein 2/3 complex subunit 4 is a protein that in humans is encoded by the ARPC4 gene.
# Function
This gene encodes one of seven subunits of the human Arp2/3 protein complex. The Arp2/3 protein complex has been implicated in the control of actin polymerization in cells and has been conserved through evolution. The exact role of the protein encoded by this gene, the p20 subunit, has yet to be determined. Three transcript variants encoding two distinct isoforms have been found for this gene.
# Model organisms
Model organisms have been used in the study of ARPC4 function. A conditional knockout mouse line, called Arpc4tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty six tests were carried out on mutant mice and two significant abnormalities were observed. No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.
# Interactions
ARPC4 has been shown to interact with ARPC5. | ARPC4
Actin-related protein 2/3 complex subunit 4 is a protein that in humans is encoded by the ARPC4 gene.[1][2][3]
# Function
This gene encodes one of seven subunits of the human Arp2/3 protein complex. The Arp2/3 protein complex has been implicated in the control of actin polymerization in cells and has been conserved through evolution. The exact role of the protein encoded by this gene, the p20 subunit, has yet to be determined. Three transcript variants encoding two distinct isoforms have been found for this gene.[3]
# Model organisms
Model organisms have been used in the study of ARPC4 function. A conditional knockout mouse line, called Arpc4tm1a(EUCOMM)Wtsi[9][10] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[11][12][13]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[7][14] Twenty six tests were carried out on mutant mice and two significant abnormalities were observed.[7] No homozygous mutant embryos were identified during gestation, and therefore none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; no additional significant abnormalities were observed in these animals.[7]
# Interactions
ARPC4 has been shown to interact with ARPC5.[15][16] | https://www.wikidoc.org/index.php/ARPC4 | |
f7bb55095853cfd14a65d2d55217bdef9712e258 | wikidoc | ARVD1 | ARVD1
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 1;
# Overview
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
There is an autosomal dominant pattern of inheritance. This variant is due to a heterozygous mutation in the TGFB3 gene (190230) on chromosome 14q24.
# Epidemiology and Demographics
The incidence of ARVD is about 1/10,000 in the general population in the United States, although some studies have suggested that it may be as common as 1/1,000. It accounts for up to 17% of all sudden cardiac deaths in the young. In Italy, the incidence is 40/10,000, making it the most common cause of sudden cardiac death in the young population. It is more common in Northern Italy.
## Gender
The male to female ratio is 3:1.
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | ARVD1
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 1;
# Overview
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
There is an autosomal dominant pattern of inheritance. This variant is due to a heterozygous mutation in the TGFB3 gene (190230) on chromosome 14q24.[1]
# Epidemiology and Demographics
The incidence of ARVD is about 1/10,000 in the general population in the United States, although some studies have suggested that it may be as common as 1/1,000. It accounts for up to 17% of all sudden cardiac deaths in the young. In Italy, the incidence is 40/10,000, making it the most common cause of sudden cardiac death in the young population. It is more common in Northern Italy.
## Gender
The male to female ratio is 3:1.
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | https://www.wikidoc.org/index.php/ARVD1 | |
4748c76184435cfdc7a7f48bfcd5cca12714a0f8 | wikidoc | ARVD2 | ARVD2
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 2; arrhythmogenic right ventricular cardiomyopathy 2; ARVC2
# Overview
Arrhythmogenic right ventricular dysplasia type 2 is a "concealed form" of ARVD. There is no change in heart size. There are no EKG changes on the resting electrocardiogram, but there may be exercise induced polymorphic ventricular tachycardia This variant is associated with premature death.
# Pathophysiology
Although the heart is normal in size, on pathologic examination, there are large areas of fibro-fatty replacement in the subepicardial layer of the right ventricle.
There are also abnormalities in calcium hemostasis in the myocytes which may contribute to the occurrence of ventricular arrhythmias.
## Genetics
This variant (600996) is associated with a mutation in the RYR2 gene (180902) on chromosome 1q42-q43.
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
This ARVD variant is associated with premature death.
# Diagnosis
## Symptoms
Exercise induced polymorphic VT may be present.
## Electrocardiogram
There are no EKG changes on the resting electrocardiogram, but there may be exercise induced polymorphic ventricular tachycardia. | ARVD2
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 2; arrhythmogenic right ventricular cardiomyopathy 2; ARVC2
# Overview
Arrhythmogenic right ventricular dysplasia type 2 is a "concealed form" of ARVD. There is no change in heart size. There are no EKG changes on the resting electrocardiogram, but there may be exercise induced polymorphic ventricular tachycardia[1] This variant is associated with premature death.
# Pathophysiology
Although the heart is normal in size, on pathologic examination, there are large areas of fibro-fatty replacement in the subepicardial layer of the right ventricle.
There are also abnormalities in calcium hemostasis in the myocytes which may contribute to the occurrence of ventricular arrhythmias.[2]
## Genetics
This variant (600996) is associated with a mutation in the RYR2 gene (180902) on chromosome 1q42-q43.[3]
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
This ARVD variant is associated with premature death.
# Diagnosis
## Symptoms
Exercise induced polymorphic VT may be present.
## Electrocardiogram
There are no EKG changes on the resting electrocardiogram, but there may be exercise induced polymorphic ventricular tachycardia. | https://www.wikidoc.org/index.php/ARVD2 | |
702216162266344bdcf36f2e16e1e87bbcde1982 | wikidoc | ARVD3 | ARVD3
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 3; arrhythmogenic right ventricular cardiomyopathy 3; ARVC3
# Overview
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (602086) is associated with a mutation in the chromosome 14q12-q22 region.
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | ARVD3
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 3; arrhythmogenic right ventricular cardiomyopathy 3; ARVC3
# Overview
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (602086) is associated with a mutation in the chromosome 14q12-q22 region.[1]
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | https://www.wikidoc.org/index.php/ARVD3 | |
f62060e139e3537875c2685b9faa1621b976c786 | wikidoc | ARVD4 | ARVD4
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 4; arrhythmogenic right ventricular cardiomyopathy 4; ARVC4
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle. This variant of ARVD is somewhat unusual as some family members were found to have involvement of the left ventricle and left bundle branch block.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias. This variant of ARVD is somewhat unusual as some family members were found to have involvement of the left ventricle and left bundle branch block.
## Genetics
This variant (602087) is associated with a mutation in the chromosome 2q32.1-q32.3 region.
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
This variant of ARVD is somewhat unusual as some family members were found to have involvement of the left ventricle and left bundle branch block.
## Echocardiogram
## MRI | ARVD4
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 4; arrhythmogenic right ventricular cardiomyopathy 4; ARVC4
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle. This variant of ARVD is somewhat unusual as some family members were found to have involvement of the left ventricle and left bundle branch block.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias. This variant of ARVD is somewhat unusual as some family members were found to have involvement of the left ventricle and left bundle branch block.
## Genetics
This variant (602087) is associated with a mutation in the chromosome 2q32.1-q32.3 region.[1]
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
This variant of ARVD is somewhat unusual as some family members were found to have involvement of the left ventricle and left bundle branch block.
## Echocardiogram
## MRI | https://www.wikidoc.org/index.php/ARVD4 | |
d902137a991586333058cff5e44e3bbae48b115f | wikidoc | ARVD5 | ARVD5
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 5; arrhythmogenic right ventricular cardiomyopathy 5; ARVC5
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (604400) is associated with a mutation in the TMEM43 gene (612048) on chromosome 3p23 region.
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | ARVD5
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 5; arrhythmogenic right ventricular cardiomyopathy 5; ARVC5
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (604400) is associated with a mutation in the TMEM43 gene (612048) on chromosome 3p23 region.[1]
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | https://www.wikidoc.org/index.php/ARVD5 | |
8799bca506727ec3db67332ac982d18325e1cf93 | wikidoc | ARVD6 | ARVD6
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 6; arrhythmogenic right ventricular cardiomyopathy 6; ARVC6
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (604401), is associated with a mutation in the chromosome 10p14-p12 region.
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | ARVD6
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 6; arrhythmogenic right ventricular cardiomyopathy 6; ARVC6
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (604401), is associated with a mutation in the chromosome 10p14-p12 region.[1]
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | https://www.wikidoc.org/index.php/ARVD6 | |
b9072c0114c5e5da7ea305f78f971905edb4243c | wikidoc | ARVD7 | ARVD7
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 7; arrhythmogenic right ventricular cardiomyopathy 7; ARVC7
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (609160) is associated with a mutation in the chromosome 10q22.3 region.
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | ARVD7
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 7; arrhythmogenic right ventricular cardiomyopathy 7; ARVC7
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (609160) is associated with a mutation in the chromosome 10q22.3 region.[1]
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | https://www.wikidoc.org/index.php/ARVD7 | |
8360b4c65a1306f893cccc844b102b2b432fa101 | wikidoc | ARVD8 | ARVD8
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 8; arrhythmogenic right ventricular cardiomyopathy 8; ARVC8
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (607450) is associated with a mutation in the DSP gene (125647) on chromosome 6p24.
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | ARVD8
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 8; arrhythmogenic right ventricular cardiomyopathy 8; ARVC8
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (607450) is associated with a mutation in the DSP gene (125647) on chromosome 6p24.[1]
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | https://www.wikidoc.org/index.php/ARVD8 | |
40cc8486f3b31b782e6ac912714e99dd313941d0 | wikidoc | ARVD9 | ARVD9
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 9; arrhythmogenic right ventricular cardiomyopathy 9; ARVC9
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (609040) is associated with a mutation in the PKP2 gene (602861) on chromosome 12p11.
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | ARVD9
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Synonyms and keywords: Arrhythmogenic right ventricular dysplasia type 9; arrhythmogenic right ventricular cardiomyopathy 9; ARVC9
# Overview
Arrhythmogenic right ventricular dysplasia is a type of nonischemic cardiomyopathy that involves primarily the right ventricle. It is characterized by hypokinetic areas involving the free wall of the right ventricle, with fibrofatty replacement of the right ventricular myocardium, with associated arrhythmias originating in the right ventricle.
# Pathophysiology
The pathogenesis of ARVD involves apoptosis with fatty and fibro-fatty infiltration of the right ventricular free wall leading to heart failure and ventricular arrhythmias.
## Genetics
This variant (609040) is associated with a mutation in the PKP2 gene (602861) on chromosome 12p11.[1]
# Epidemiology and Demographics
# Natural History, Complications, Prognosis
# Diagnosis
## Symptoms
## Electrocardiogram
## Echocardiogram
## MRI | https://www.wikidoc.org/index.php/ARVD9 | |
9f004512ea6e84f2a24c88829c1bafe7c8ce3850 | wikidoc | ASCL1 | ASCL1
Achaete-scute homolog 1 is a protein that in humans is encoded by the ASCL1 gene. Because it was discovered subsequent to studies on its homolog in Drosophila, the Achaete-scute complex, it was originally named MASH-1 for mammalian achaete scute homolog-1.
# Function
This gene encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors. The protein activates transcription by binding to the E box (5'-CANNTG-3'). Dimerization with other BHLH proteins is required for efficient DNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomic neurons. It is highly expressed in medullary thyroid cancer and small cell lung cancer and may be a useful marker for these cancers. The presence of a CAG repeat in the gene suggests that it may also play a role in tumor formation.
# Role in neuronal commitment
Development of the vertebrate nervous system begins when the neural tube forms in the early embryo. The neural tube eventually gives rise to the entire nervous system, but first neuroblasts must differentiate from the neuroepithelium of the tube. The neuroblasts are the cells that undergo mitotic division and produce neurons. Asc is central to the differentiation of the neuroblasts and the lateral inhibition mechanism which inherently creates a safety net in the event of damage or death in these incredibly important cells.
Differentiation of the neuroblast begins when the cells of the neural tube express Asc and thus upregulate the expression of Delta, a protein essential to the lateral inhibition pathway of neuronal commitment. Delta can diffuse to neighboring cells and bind to the Notch receptor, a large transmembrane protein which upon activation undergoes proteolytic cleavage to release the intracellular domain (Notch-ICD). The Notch-ICD is then free to travel to the nucleus and form a complex with Suppressor of Hairless (SuH) and Mastermind. This complex acts as transcription regulator of Asc and accomplishes two important tasks. First, it prevents the expression of factors required for differentiation of the cell into a neuroblast. Secondly, it inhibits the neighboring cell's production of Delta. Therefore, the future neuroblast will be the cell that has the greatest Asc activation in the vicinity and consequently the greatest Delta production that will inhibit the differentiation of neighboring cells. The select group of neuroblasts that then differentiate in the neural tube are thus replaceable because the neuroblast's ability to suppress differentiation of neighboring cells depends on its own ability to produce Asc.
This process of neuroblast differentiation via Asc is common to all animals. Although this mechanism was initially studied in Drosophila, homologs to all proteins in the pathway have been found in vertebrates that have the same bHLH structure.
# Autonomic nervous system development
In addition to its important role in neuroblast formation, Asc also functions to mediate autonomic nervous system (ANS) formation. Asc was initially suspected to play a role in the ANS when ASCL1 was found expressed in cells surrounding the dorsal aorta, the adrenal glands and in the developing sympathetic chain during a specific stage of development. Subsequent studies of mice genetically altered to be MASH-1 deficient revealed defective development of both sympathetic and parasympathetic ganglia, the two constituents of the ANS.
# Interactions
ASCL1 has been shown to interact with Myocyte-specific enhancer factor 2A. | ASCL1
Achaete-scute homolog 1 is a protein that in humans is encoded by the ASCL1 gene.[1][2] Because it was discovered subsequent to studies on its homolog in Drosophila, the Achaete-scute complex, it was originally named MASH-1 for mammalian achaete scute homolog-1.[3]
# Function
This gene encodes a member of the basic helix-loop-helix (BHLH) family of transcription factors. The protein activates transcription by binding to the E box (5'-CANNTG-3'). Dimerization with other BHLH proteins is required for efficient DNA binding. This protein plays a role in the neuronal commitment and differentiation and in the generation of olfactory and autonomic neurons. It is highly expressed in medullary thyroid cancer and small cell lung cancer and may be a useful marker for these cancers. The presence of a CAG repeat in the gene suggests that it may also play a role in tumor formation.[2]
# Role in neuronal commitment
Development of the vertebrate nervous system begins when the neural tube forms in the early embryo. The neural tube eventually gives rise to the entire nervous system, but first neuroblasts must differentiate from the neuroepithelium of the tube. The neuroblasts are the cells that undergo mitotic division and produce neurons.[3] Asc is central to the differentiation of the neuroblasts and the lateral inhibition mechanism which inherently creates a safety net in the event of damage or death in these incredibly important cells.[3]
Differentiation of the neuroblast begins when the cells of the neural tube express Asc and thus upregulate the expression of Delta, a protein essential to the lateral inhibition pathway of neuronal commitment.[3] Delta can diffuse to neighboring cells and bind to the Notch receptor, a large transmembrane protein which upon activation undergoes proteolytic cleavage to release the intracellular domain (Notch-ICD).[3] The Notch-ICD is then free to travel to the nucleus and form a complex with Suppressor of Hairless (SuH) and Mastermind.[3] This complex acts as transcription regulator of Asc and accomplishes two important tasks. First, it prevents the expression of factors required for differentiation of the cell into a neuroblast.[3] Secondly, it inhibits the neighboring cell's production of Delta.[3] Therefore, the future neuroblast will be the cell that has the greatest Asc activation in the vicinity and consequently the greatest Delta production that will inhibit the differentiation of neighboring cells. The select group of neuroblasts that then differentiate in the neural tube are thus replaceable because the neuroblast's ability to suppress differentiation of neighboring cells depends on its own ability to produce Asc.[3]
This process of neuroblast differentiation via Asc is common to all animals.[3] Although this mechanism was initially studied in Drosophila, homologs to all proteins in the pathway have been found in vertebrates that have the same bHLH structure.[3]
# Autonomic nervous system development
In addition to its important role in neuroblast formation, Asc also functions to mediate autonomic nervous system (ANS) formation.[4] Asc was initially suspected to play a role in the ANS when ASCL1 was found expressed in cells surrounding the dorsal aorta, the adrenal glands and in the developing sympathetic chain during a specific stage of development.[4] Subsequent studies of mice genetically altered to be MASH-1 deficient revealed defective development of both sympathetic and parasympathetic ganglia, the two constituents of the ANS.[4]
# Interactions
ASCL1 has been shown to interact with Myocyte-specific enhancer factor 2A.[5] | https://www.wikidoc.org/index.php/ASCL1 | |
4a6e13ac60eb664f5ec56c323fc2b210887ea1a1 | wikidoc | ASF1A | ASF1A
Histone chaperone ASF1A is a protein that in humans is encoded by the ASF1A gene.
# Function
This gene encodes a member of the H3/H4 family of histone chaperone proteins and is similar to the anti-silencing function-1 gene in yeast. The protein is a key component of a histone donor complex that functions in nucleosome assembly. It interacts with histones H3 and H4, and functions together with a chromatin assembly factor during DNA replication and repair.
# Interactions
ASF1A has been shown to interact with TLK1, TLK2, CHAF1B and CHAF1A. | ASF1A
Histone chaperone ASF1A is a protein that in humans is encoded by the ASF1A gene.[1][2][3]
# Function
This gene encodes a member of the H3/H4 family of histone chaperone proteins and is similar to the anti-silencing function-1 gene in yeast. The protein is a key component of a histone donor complex that functions in nucleosome assembly. It interacts with histones H3 and H4, and functions together with a chromatin assembly factor during DNA replication and repair.[3]
# Interactions
ASF1A has been shown to interact with TLK1,[4][5] TLK2,[4] CHAF1B[6] and CHAF1A.[6] | https://www.wikidoc.org/index.php/ASF1A | |
aaea02cc4f41bbf56ff3fee5e6948964706ae1da | wikidoc | ASF1B | ASF1B
Histone chaperone ASF1B is a protein that in humans is encoded by the ASF1B gene.
# Function
This gene encodes a member of the H3/H4 family of histone chaperone proteins and is similar to the anti-silencing function-1 gene in yeast. The encoded protein is the substrate of the tousled-like kinase family of cell cycle-regulated kinases, and may play a key role in modulating the nucleosome structure of chromatin by ensuring a constant supply of histones at sites of nucleosome assembly.
# Interactions
ASF1B has been shown to interact with TLK2, CHAF1B, TLK1 and CHAF1A. | ASF1B
Histone chaperone ASF1B is a protein that in humans is encoded by the ASF1B gene.[1][2][3]
# Function
This gene encodes a member of the H3/H4 family of histone chaperone proteins and is similar to the anti-silencing function-1 gene in yeast. The encoded protein is the substrate of the tousled-like kinase family of cell cycle-regulated kinases, and may play a key role in modulating the nucleosome structure of chromatin by ensuring a constant supply of histones at sites of nucleosome assembly.[3]
# Interactions
ASF1B has been shown to interact with TLK2,[2][4] CHAF1B,[1][4] TLK1[2][4] and CHAF1A.[1][4] | https://www.wikidoc.org/index.php/ASF1B | |
ce8cde148f95fa34787bb493c20c6d82861f8a4f | wikidoc | ASH1L | ASH1L
ASH1L (also called huASH1, ASH1, ASH1L1, ASH1-like, or KMT2H) is a histone-lysine N-methyltransferase enzyme encoded by the ASH1L gene located at chromosomal band 1q22. ASH1L is the human homolog of Drosophila Ash1 (absent, small, or homeotic-like).
# Gene
Ash1 was discovered as a gene causing an imaginal disc mutant phenotype in Drosophila. Ash1 is a member of the trithorax-group (trxG) of proteins, a group of transcriptional activators that are involved in regulating Hox gene expression and body segment identity. Drosophila Ash1 interacts with trithorax to regulate ultrabithorax expression.
The human ASH1L gene spans 227.5 kb on chromosome 1, band q22. This region is rearranged in a variety of human cancers such as leukemia, non-Hodgkin’s lymphoma, and some solid tumors. The gene is expressed in multiple tissues, with highest levels in brain, kidney, and heart, as a 10.5-kb mRNA transcript.
# Structure
Human ASH1L protein is 2969 amino acids long with a molecular weight of 333 kDa. ASH1L has an associated with SET domain (AWS), a SET domain, a post-set domain, a bromodomain, a bromo-adjacent homology domain, and a plant homeodomain finger. Human and Drosophila Ash1 share 66% and 77% similarity in their SET and PHD finger domains, respectively. A bromodomain is not present in Drosophila Ash1.
The SET domain is responsible for ASH1L’s histone methyltransferase (HMTase) activity. Unlike other proteins that contain a SET domain at their C terminus, ASH1L has a SET domain in the middle of the protein. The crystal structure of the human ASH1L catalytic domain, including the AWS, SET, and post-SET domains, has been solved to 2.9 angstrom resolution. The structure shows that the substrate binding pocket is blocked by a loop from the post-SET domain, and because mutation of the loop stimulates ASH1L HMTase activity, it was proposed that this loop serves a regulatory role.
# Function
The ASH1L protein is localized to intranuclear speckles and tight junctions, where it was hypothesized to function in adhesion-mediated signaling. ChIP analysis demonstrated that ASH1L binds to the 5’-transcribed region of actively transcribed genes. The chromatin occupancy of ASH1L mirrors that of the TrxG-related H3K4-HMTase MLL1, however ASH1L’s association with chromatin can occur independently of MLL1. While ASH1L binds to the 5’-transcribed region of housekeeping genes, it is distributed across the entire transcribed region of Hox genes. ASH1L is required for maximal expression and H3K4 methylation of HOXA6 and HOXA10.
A Hox promoter reporter construct in HeLa cells requires both MLL1 and ASH1L for activation, whereas MLL1 or ASH1L alone are not sufficient to activate transcription. The methyltransferase activity of ASH1L is not required for Hox gene activation but instead has repressive action. Knockdown of ASH1L in K562 cells causes up-regulation of the ε-globin gene and down-regulation of myelomonocytic markers GPIIb and GPIIIa, and knockdown of ASH1L in lineage marker-negative hematopoietic progenitor cells skews differentiation from myelomonocytic towards lymphoid or erythroid lineages. These results imply that ASH1L, like MLL1, facilitates myelomonocytic differentiation of hematopoietic stem cells.
The in vivo target for ASH1L’s HMTase activity has been a topic of some controversy. Blobel’s group found that in vitro ASH1L methylates H3K4 peptides, and the distribution of ASH1L across transcribed genes resembles that of H3K4 levels. In contrast, two other groups have found that ASH1L’s HMTase activity is directed toward H3K36, using nucleosomes as substrate.
# Role in disease
ASH1L has been implicated in facioscapulohumeral muscular dystrophy, a common autosomal-dominant myopathy in which patients experience progressive muscle wasting in the face, upper arm, and shoulder muscles. At the molecular level, FSHD is associated with a lower-than-normal number of D4Z4 repeats at 4q35. D4Z4 copy number reduction in FSHD patients causes insufficient binding of Polycomb-group repressors, permitting transcription of a long noncoding RNA called DBE-T that is encoded by a sequence within D4Z4 repeats. DBE-T recruits ASH1L to the FSHD locus, resulting in H3K36 dimethylation, chromatin remodeling, and 4q35 gene de-repression. | ASH1L
ASH1L (also called huASH1, ASH1, ASH1L1, ASH1-like, or KMT2H) is a histone-lysine N-methyltransferase enzyme encoded by the ASH1L gene located at chromosomal band 1q22. ASH1L is the human homolog of Drosophila Ash1 (absent, small, or homeotic-like).
# Gene
Ash1 was discovered as a gene causing an imaginal disc mutant phenotype in Drosophila. Ash1 is a member of the trithorax-group (trxG) of proteins, a group of transcriptional activators that are involved in regulating Hox gene expression and body segment identity.[1] Drosophila Ash1 interacts with trithorax to regulate ultrabithorax expression.[2]
The human ASH1L gene spans 227.5 kb on chromosome 1, band q22. This region is rearranged in a variety of human cancers such as leukemia, non-Hodgkin’s lymphoma, and some solid tumors. The gene is expressed in multiple tissues, with highest levels in brain, kidney, and heart, as a 10.5-kb mRNA transcript.[3]
# Structure
Human ASH1L protein is 2969 amino acids long with a molecular weight of 333 kDa.[4] ASH1L has an associated with SET domain (AWS), a SET domain, a post-set domain, a bromodomain, a bromo-adjacent homology domain, and a plant homeodomain finger. Human and Drosophila Ash1 share 66% and 77% similarity in their SET and PHD finger domains, respectively.[3] A bromodomain is not present in Drosophila Ash1.
The SET domain is responsible for ASH1L’s histone methyltransferase (HMTase) activity. Unlike other proteins that contain a SET domain at their C terminus, ASH1L has a SET domain in the middle of the protein. The crystal structure of the human ASH1L catalytic domain, including the AWS, SET, and post-SET domains, has been solved to 2.9 angstrom resolution. The structure shows that the substrate binding pocket is blocked by a loop from the post-SET domain, and because mutation of the loop stimulates ASH1L HMTase activity, it was proposed that this loop serves a regulatory role.[5]
# Function
The ASH1L protein is localized to intranuclear speckles and tight junctions, where it was hypothesized to function in adhesion-mediated signaling.[3] ChIP analysis demonstrated that ASH1L binds to the 5’-transcribed region of actively transcribed genes. The chromatin occupancy of ASH1L mirrors that of the TrxG-related H3K4-HMTase MLL1, however ASH1L’s association with chromatin can occur independently of MLL1. While ASH1L binds to the 5’-transcribed region of housekeeping genes, it is distributed across the entire transcribed region of Hox genes. ASH1L is required for maximal expression and H3K4 methylation of HOXA6 and HOXA10.[6]
A Hox promoter reporter construct in HeLa cells requires both MLL1 and ASH1L for activation, whereas MLL1 or ASH1L alone are not sufficient to activate transcription. The methyltransferase activity of ASH1L is not required for Hox gene activation but instead has repressive action. Knockdown of ASH1L in K562 cells causes up-regulation of the ε-globin gene and down-regulation of myelomonocytic markers GPIIb and GPIIIa, and knockdown of ASH1L in lineage marker-negative hematopoietic progenitor cells skews differentiation from myelomonocytic towards lymphoid or erythroid lineages. These results imply that ASH1L, like MLL1, facilitates myelomonocytic differentiation of hematopoietic stem cells.[1]
The in vivo target for ASH1L’s HMTase activity has been a topic of some controversy. Blobel’s group found that in vitro ASH1L methylates H3K4 peptides, and the distribution of ASH1L across transcribed genes resembles that of H3K4 levels.[6] In contrast, two other groups have found that ASH1L’s HMTase activity is directed toward H3K36, using nucleosomes as substrate.[5][7]
# Role in disease
ASH1L has been implicated in facioscapulohumeral muscular dystrophy, a common autosomal-dominant myopathy in which patients experience progressive muscle wasting in the face, upper arm, and shoulder muscles. At the molecular level, FSHD is associated with a lower-than-normal number of D4Z4 repeats at 4q35. D4Z4 copy number reduction in FSHD patients causes insufficient binding of Polycomb-group repressors, permitting transcription of a long noncoding RNA called DBE-T that is encoded by a sequence within D4Z4 repeats. DBE-T recruits ASH1L to the FSHD locus, resulting in H3K36 dimethylation, chromatin remodeling, and 4q35 gene de-repression.[8] | https://www.wikidoc.org/index.php/ASH1L | |
edc73eb6f6688b4e6efa39e7d3ea132398a0bc81 | wikidoc | ASIC1 | ASIC1
Acid-sensing ion channel 1 (ASIC1) also known as amiloride-sensitive cation channel 2, neuronal (ACCN2) or brain sodium channel 2 (BNaC2) is a protein that in humans is encoded by the ASIC1 gene. The ASIC1 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals. The cDNA of this gene was first cloned in 1996. The ASIC genes have splicing variants that encode different proteins that are called isoforms.
These genes are mainly expressed in the central and peripheral nervous system.
ASICs can form both homotrimeric (meaning composed of three identical subunits) and heterotrimeric channels.
# Structure and function
This gene encodes a member of the ASIC/ENaC superfamily of proteins. The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, 2 hydrophobic transmembrane (TM) regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The TM regions are generally symbolized as TM1 (clone to N-terminus) and TM2 (close to C-terminus).
The pore of the channel through which ions selectively flow from the extracellular side into the cytoplasm is formed by the three TM2 regions of the trimer.
# Interactions
ASIC1 has been shown to interact with PICK1. | ASIC1
Acid-sensing ion channel 1 (ASIC1) also known as amiloride-sensitive cation channel 2, neuronal (ACCN2) or brain sodium channel 2 (BNaC2) is a protein that in humans is encoded by the ASIC1 gene. The ASIC1 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals.[1] The cDNA of this gene was first cloned in 1996.[2] The ASIC genes have splicing variants that encode different proteins that are called isoforms.
These genes are mainly expressed in the central and peripheral nervous system.
ASICs can form both homotrimeric (meaning composed of three identical subunits) and heterotrimeric channels.[3][4]
# Structure and function
This gene encodes a member of the ASIC/ENaC superfamily of proteins.[5] The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, 2 hydrophobic transmembrane (TM) regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The TM regions are generally symbolized as TM1 (clone to N-terminus) and TM2 (close to C-terminus).
The pore of the channel through which ions selectively flow from the extracellular side into the cytoplasm is formed by the three TM2 regions of the trimer.[1]
# Interactions
ASIC1 has been shown to interact with PICK1.[6][7] | https://www.wikidoc.org/index.php/ASIC1 | |
db2d0963af6260ee3a21a56fedce4b5183d23e69 | wikidoc | ASIC2 | ASIC2
Acid-sensing ion channel 2 (ASIC2) also known as amiloride-sensitive cation channel 1, neuronal (ACCN1) or brain sodium channel 1 (BNaC1) is a protein that in humans is encoded by the ASIC2 gene. The ASIC2 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals. The cDNA of this gene was first cloned in 1996. The ASIC genes have splicing variants that encode different proteins that are called isoforms.
These genes are mainly expressed in the central and peripheral nervous system.
ASICs can form both homotrimeric (meaning composed of three identical subunits) and heterotrimeric channels.
# Structure and function
This gene encodes a member of the ASIC/ENaC superfamily of proteins. The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, 2 hydrophobic transmembrane (TM) regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The TM regions are generally symbolized as TM1 (clone to N-terminus) and TM2 (close to C-terminus).
The pore of the channel through which ions selectively flow from the extracellular side into the cytoplasm is formed by the three TM2 regions of the trimer. | ASIC2
Acid-sensing ion channel 2 (ASIC2) also known as amiloride-sensitive cation channel 1, neuronal (ACCN1) or brain sodium channel 1 (BNaC1) is a protein that in humans is encoded by the ASIC2 gene. The ASIC2 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals.[1] The cDNA of this gene was first cloned in 1996.[2][3][4][5] The ASIC genes have splicing variants that encode different proteins that are called isoforms.
These genes are mainly expressed in the central and peripheral nervous system.
ASICs can form both homotrimeric (meaning composed of three identical subunits) and heterotrimeric channels.[6][7]
# Structure and function
This gene encodes a member of the ASIC/ENaC superfamily of proteins.[8] The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, 2 hydrophobic transmembrane (TM) regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The TM regions are generally symbolized as TM1 (clone to N-terminus) and TM2 (close to C-terminus).
The pore of the channel through which ions selectively flow from the extracellular side into the cytoplasm is formed by the three TM2 regions of the trimer.[1] | https://www.wikidoc.org/index.php/ASIC2 | |
f4961b7ba1b42bb85d860e1855c29efafbf6ba96 | wikidoc | ASIC3 | ASIC3
Acid-sensing ion channel 3 (ASIC3) also known as amiloride-sensitive cation channel 3 (ACCN3) or testis sodium channel 1 (TNaC1) is a protein that in humans is encoded by the ASIC3 gene. The ASIC3 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals. The cDNA of this gene was first cloned in 1998. The ASIC genes have splicing variants that encode different proteins that are called isoforms.
These genes are mainly expressed in the central and peripheral nervous system.
ASICs can form both homotrimeric (meaning composed of three identical subunits) and heterotrimeric channels.
# Structure and function
This gene encodes a member of the ASIC/ENaC superfamily of proteins. The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, 2 hydrophobic transmembrane (TM) regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The TM regions are generally symbolized as TM1 (clone to N-terminus) and TM2 (close to C-terminus).
The pore of the channel through which ions selectively flow from the extracellular side into the cytoplasm is formed by the three TM2 regions of the trimer.
# Interactions
ASIC3 has been shown to interact with LIN7B, GOPC and MAGI1. | ASIC3
Acid-sensing ion channel 3 (ASIC3) also known as amiloride-sensitive cation channel 3 (ACCN3) or testis sodium channel 1 (TNaC1) is a protein that in humans is encoded by the ASIC3 gene. The ASIC3 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals.[1] The cDNA of this gene was first cloned in 1998.[2][3] The ASIC genes have splicing variants that encode different proteins that are called isoforms.
These genes are mainly expressed in the central and peripheral nervous system.
ASICs can form both homotrimeric (meaning composed of three identical subunits) and heterotrimeric channels.[4]
# Structure and function
This gene encodes a member of the ASIC/ENaC superfamily of proteins.[5] The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, 2 hydrophobic transmembrane (TM) regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The TM regions are generally symbolized as TM1 (clone to N-terminus) and TM2 (close to C-terminus).
The pore of the channel through which ions selectively flow from the extracellular side into the cytoplasm is formed by the three TM2 regions of the trimer.[1]
# Interactions
ASIC3 has been shown to interact with LIN7B,[6] GOPC[6] and MAGI1.[6] | https://www.wikidoc.org/index.php/ASIC3 | |
d5acc51787dd95dda11c5b4945a8ccb2de136c82 | wikidoc | ASIC4 | ASIC4
Acid-sensing ion channel 4 (ASIC4) also known as amiloride-sensitive cation channel 4 (ACCN4) is a protein that in humans is encoded by the ASIC4 gene. The ASIC4 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals. The cDNA of this gene was first cloned in 2000. The ASIC genes have splicing variants that encode different proteins that are called isoforms.
These genes are mainly expressed in the central and peripheral nervous system.
ASICs can form both homotrimeric (meaning composed of three identical subunits) and heterotrimeric channels.
# Structure and function
This gene encodes a member of the ASIC/ENaC superfamily of proteins. The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, 2 hydrophobic transmembrane (TM) regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The TM regions are generally symbolized as TM1 (clone to N-terminus) and TM2 (close to C-terminus).
The pore of the channel through which ions selectively flow from the extracellular side into the cytoplasm is formed by the three TM2 regions of the trimer. | ASIC4
Acid-sensing ion channel 4 (ASIC4) also known as amiloride-sensitive cation channel 4 (ACCN4) is a protein that in humans is encoded by the ASIC4 gene. The ASIC4 gene is one of the five paralogous genes that encode proteins that form trimeric acid-sensing ion channels (ASICs) in mammals.[1] The cDNA of this gene was first cloned in 2000.[2][3] The ASIC genes have splicing variants that encode different proteins that are called isoforms.
These genes are mainly expressed in the central and peripheral nervous system.
ASICs can form both homotrimeric (meaning composed of three identical subunits) and heterotrimeric channels.[4]
# Structure and function
This gene encodes a member of the ASIC/ENaC superfamily of proteins.[5] The members of this family are amiloride-sensitive sodium channels that contain intracellular N and C termini, 2 hydrophobic transmembrane (TM) regions, and a large extracellular loop, which has many cysteine residues with conserved spacing. The TM regions are generally symbolized as TM1 (clone to N-terminus) and TM2 (close to C-terminus).
The pore of the channel through which ions selectively flow from the extracellular side into the cytoplasm is formed by the three TM2 regions of the trimer. [1] | https://www.wikidoc.org/index.php/ASIC4 | |
321c59487cfe1eca3327c14c7e830f82768c162c | wikidoc | ASK-1 | ASK-1
Apoptosis signal-regulating kinase 1, ASK-1, is part of the mitogen-activated protein kinase (MAPK) cascade. In humans it is also known as "mitogen-activated protein kinase kinase kinase 5", abbreviated as "MAP3K5".
Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. Phosphorylation of ASK-1 protein can lead to apoptosis or other cellular responses depending on the cell type. Northern blot analysis shows that ASK-1 transcript is abundantly expressed in human heart and pancreas. The ASK-1 (MAPKKK5) protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; ASK-1 does not activate MAPK/ERK.
ASK-1 found in the inactive form, bound to reduced thioredoxin. When oxidized by a reactive oxygen species, Trx dissociates from ASK-1. The ASK-1, which is found as a homo-oligodimer, autophosphorylates and becomes an active MAP kinase kinase kinase.
ASK-1 contains 1,374 amino acids with all 11 kinase subdomains. It is located on chromosome 6 at locus 6q22.33. | ASK-1
Apoptosis signal-regulating kinase 1, ASK-1, is part of the mitogen-activated protein kinase (MAPK) cascade. In humans it is also known as "mitogen-activated protein kinase kinase kinase 5", abbreviated as "MAP3K5".
Mitogen-activated protein kinase (MAPK) signaling cascades include MAPK or extracellular signal-regulated kinase (ERK), MAPK kinase (MKK or MEK), and MAPK kinase kinase (MAPKKK or MEKK). MAPKK kinase/MEKK phosphorylates and activates its downstream protein kinase, MAPK kinase/MEK, which in turn activates MAPK. The kinases of these signaling cascades are highly conserved, and homologs exist in yeast, Drosophila, and mammalian cells. Phosphorylation of ASK-1 protein can lead to apoptosis or other cellular responses depending on the cell type. Northern blot analysis shows that ASK-1 transcript is abundantly expressed in human heart and pancreas. The ASK-1 (MAPKKK5) protein phosphorylates and activates MKK4 (aliases SERK1, MAPKK4) in vitro, and activates c-Jun N-terminal kinase (JNK)/stress-activated protein kinase (SAPK) during transient expression in COS and 293 cells; ASK-1 does not activate MAPK/ERK.[1]
ASK-1 found in the inactive form, bound to reduced thioredoxin. When oxidized by a reactive oxygen species, Trx dissociates from ASK-1. The ASK-1, which is found as a homo-oligodimer, autophosphorylates and becomes an active MAP kinase kinase kinase.
ASK-1 contains 1,374 amino acids with all 11 kinase subdomains. It is located on chromosome 6 at locus 6q22.33. | https://www.wikidoc.org/index.php/ASK-1 | |
8c456498786bc38f6a39727da533be6435e7ff58 | wikidoc | ASXL1 | ASXL1
Putative Polycomb group protein ASXL1 is a protein that in humans is encoded by the ASXL1 gene.
In Drosophila, the Additional sex combs (Asx) gene encodes a chromatin-binding protein required for normal determination of segment identity in the developing embryo. The protein is a member of the Polycomb group of proteins, which are necessary for the maintenance of stable repression of homeotic and other loci. The protein is thought to disrupt chromatin in localized areas, enhancing transcription of certain genes while repressing the transcription of other genes. Although the function of the protein encoded by this gene is not known, it does show some sequence similarity to the protein encoded by the Drosophila Asx gene.
# Model organisms
Model organisms have been used in the study of ASXL1 function. A conditional knockout mouse line, called Asxl1tm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty five tests were carried out on mutant mice and four significant abnormalities were observed. Few homozygous mutant embryos were identified during gestation and those that were alive had craniofacial and eye defects, none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; decreased vertebrae number and increased bone strength was observed in these animals. | ASXL1
Putative Polycomb group protein ASXL1 is a protein that in humans is encoded by the ASXL1 gene.[1][2]
In Drosophila, the Additional sex combs (Asx) gene encodes a chromatin-binding protein required for normal determination of segment identity in the developing embryo. The protein is a member of the Polycomb group of proteins, which are necessary for the maintenance of stable repression of homeotic and other loci. The protein is thought to disrupt chromatin in localized areas, enhancing transcription of certain genes while repressing the transcription of other genes. Although the function of the protein encoded by this gene is not known, it does show some sequence similarity to the protein encoded by the Drosophila Asx gene.[2]
# Model organisms
Model organisms have been used in the study of ASXL1 function. A conditional knockout mouse line, called Asxl1tm1a(EUCOMM)Wtsi[8][9] was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists.[10][11][12]
Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion.[6][13] Twenty five tests were carried out on mutant mice and four significant abnormalities were observed.[6] Few homozygous mutant embryos were identified during gestation and those that were alive had craniofacial and eye defects, none survived until weaning. The remaining tests were carried out on heterozygous mutant adult mice; decreased vertebrae number and increased bone strength was observed in these animals.[6] | https://www.wikidoc.org/index.php/ASXL1 | |
71d7916a3231b390c4c30df7b108ab3645755f71 | wikidoc | ATG12 | ATG12
Autophagy-related protein 12 is a protein that in humans is encoded by the ATG12 gene.
Autophagy is a process of bulk protein degradation in which cytoplasmic components, including organelles, are enclosed in double-membrane structures called autophagosomes and delivered to lysosomes or vacuoles for degradation. ATG12 is the human homolog of a yeast protein involved in autophagy (Mizushima et al., 1998).
Autophagy requires the covalent attachment of the protein Atg12 to ATG5 through a ubiquitin-like conjugation system. The Atg12-Atg5 conjugate then promotes the conjugation of ATG8 to the lipid phosphatidylethanolamine.
Atg12 was found to be involved in apoptosis. This protein promotes apoptosis through an interaction with anti-apoptotic members of the Bcl-2 family. | ATG12
Autophagy-related protein 12 is a protein that in humans is encoded by the ATG12 gene.[1][2]
Autophagy is a process of bulk protein degradation in which cytoplasmic components, including organelles, are enclosed in double-membrane structures called autophagosomes and delivered to lysosomes or vacuoles for degradation. ATG12 is the human homolog of a yeast protein involved in autophagy (Mizushima et al., 1998).[supplied by OMIM][2]
Autophagy requires the covalent attachment of the protein Atg12 to ATG5 through a ubiquitin-like conjugation system. The Atg12-Atg5 conjugate then promotes the conjugation of ATG8 to the lipid phosphatidylethanolamine.[3]
Atg12 was found to be involved in apoptosis. This protein promotes apoptosis through an interaction with anti-apoptotic members of the Bcl-2 family.[4] | https://www.wikidoc.org/index.php/ATG12 | |
628e5390be4428d9b02032dc6beefb9a9610c68c | wikidoc | ATG4B | ATG4B
Cysteine protease ATG4B is an enzyme that in humans is encoded by the ATG4B gene.
# Function
Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed. This gene encodes a member of the autophagin protein family. The encoded protein is also designated as a member of the C-54 family of cysteine proteases. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.
One main function of Atg4 is to cleave the pre-protein of Atg8, leading to the non-lipidated soluble (-I) form which can be processed further by Atg3, Atg7, Atg5-12 into the lipidated form (-II) anchored to the autophagic membrane.
# Interactions
ATG4B has been shown to interact with GABARAPL2. | ATG4B
Cysteine protease ATG4B is an enzyme that in humans is encoded by the ATG4B gene.[1][2]
# Function
Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed. This gene encodes a member of the autophagin protein family. The encoded protein is also designated as a member of the C-54 family of cysteine proteases. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.[2]
One main function of Atg4 is to cleave the pre-protein of Atg8, leading to the non-lipidated soluble (-I) form which can be processed further by Atg3, Atg7, Atg5-12 into the lipidated form (-II) anchored to the autophagic membrane.
# Interactions
ATG4B has been shown to interact with GABARAPL2.[3][4] | https://www.wikidoc.org/index.php/ATG4B | |
deee5073aeba1128afe83658d4670ad0c2b91014 | wikidoc | ATG4D | ATG4D
The human ATG4D gene encodes the protein Autophagy related 4D, cysteine peptidase.
# Function
Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed.
This gene belongs to the autophagy-related protein 4 (Atg4) family of C54 endopeptidases. Members of this family encode proteins that play a role in the biogenesis of autophagosomes, which sequester the cytosol and organelles for degradation by lysosomes. Alternative splicing results in multiple transcript variants. . | ATG4D
The human ATG4D gene encodes the protein Autophagy related 4D, cysteine peptidase.[1]
# Function
Autophagy is the process by which endogenous proteins and damaged organelles are destroyed intracellularly. Autophagy is postulated to be essential for cell homeostasis and cell remodeling during differentiation, metamorphosis, non-apoptotic cell death, and aging. Reduced levels of autophagy have been described in some malignant tumors, and a role for autophagy in controlling the unregulated cell growth linked to cancer has been proposed.
This gene belongs to the autophagy-related protein 4 (Atg4) family of C54 endopeptidases. Members of this family encode proteins that play a role in the biogenesis of autophagosomes, which sequester the cytosol and organelles for degradation by lysosomes. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2013]. | https://www.wikidoc.org/index.php/ATG4D | |
20796e0e844682c9d3742ae52cbec398223e8571 | wikidoc | ATOX1 | ATOX1
ATOX1 is a copper metallochaperone protein that is encoded by the ATOX1 gene in humans. In mammals, ATOX1 plays a key role in copper homeostasis as it delivers copper from the cytosol to transporters ATP7A and ATP7B. Homologous proteins are found in a wide variety of eukaryotes, including Saccharomyces cerevisiae as ATX1, and all contain a conserved metal binding domain.
# Function
ATOX1 is an abbreviation of the full name Antioxidant Protein 1. The nomenclature stems from initial characterization that showed that ATOX1 protected cells from reactive oxygen species. Since then, the primary role of ATOX1 has been established as a copper metallochaperone protein found in the cytoplasm of eukaryotes. A metallochaperone is an important protein that has metal trafficking and sequestration roles. As a metal sequestration protein, ATOX1 is capable of binding free metals in vivo, in order to protect cells from generation of reactive oxygen species and mismetallation of metalloproteins. As a metal trafficking protein, ATOX1 is responsible for shuttling copper from the cytosol to ATPase transporters ATP7A and ATP7B that move copper to the trans-Golgi network or secretory vesicles. In Saccharomyces cerevisiae, Atx1 delivers Cu(I) to a homologous transporter, Ccc2. The delivery of copper to ATPase transporters is vital for the subsequent insertion of copper into ceruloplasmin, a ferroxidase required for iron metabolism, within the golgi apparatus.
In addition to the metallochaperone function, recent reports have characterized ATOX1 as a cyclin D1 transcription factor.
# Structure & metal coordination
ATOX1 has a ferrodoxin-like βαββαβ fold and coordinates to Cu(I) via a MXCXXC binding motif located in between the first β-sheet and α-helix. The metal binding motif is largely solvent exposed in Apo-ATOX1 and a conformational change is induced upon coordination to Cu(I). Cu(I) is coordinated in a distorted linear geometry to sulfurs of cystine to form a bond angle of 120°. The overall -1 charge of the primary coordination sphere is stabilized through the secondary coordination sphere that contains a proximal positively charged lysine. ATOX1 also binds Hg(II), Cd(II), Ag(I), and cisplatin via this motif, but a physiological role, if any, is not yet known.
# Metal transfer
ATOX1 transfers Cu(I) to transporters ATP7A and ATP7B. Transfer occurs via a ligand exchange mechanism, where Cu(I) transiently adopts a 3-coordinate geometry with cysteine ligands from ATOX1 and the associated transporter. The ligand exchange mechanism allows for faster exchange than a diffusion mechanism and imparts specificity for both the metal and transporter. Since the ligand exchange accelerates that transfer and the reaction has a shallow thermodynamic gradient, it is said to be under kinetic control rather than thermodynamic control.
# Clinical significance
Although there are presently no known diseases directly associated with ATOX1 malfunction, there is currently active research in a few areas:
- There is a link between ATOX1 levels and sensitivity of cells for Pt-based drugs like cisplatin.
- The mechanism of ammonium tetrathiomolybdate 2MoS4 treatment of Wilson's Disease is under review. Since ATOX1 forms a stable complex tetrathiomolybdate, it is being studied as the potential therapeutic target. | ATOX1
ATOX1 is a copper metallochaperone protein that is encoded by the ATOX1 gene in humans.[1][2] In mammals, ATOX1 plays a key role in copper homeostasis as it delivers copper from the cytosol to transporters ATP7A and ATP7B.[3][4][5] Homologous proteins are found in a wide variety of eukaryotes, including Saccharomyces cerevisiae as ATX1, and all contain a conserved metal binding domain.[3][6]
# Function
ATOX1 is an abbreviation of the full name Antioxidant Protein 1. The nomenclature stems from initial characterization that showed that ATOX1 protected cells from reactive oxygen species. Since then, the primary role of ATOX1 has been established as a copper metallochaperone protein found in the cytoplasm of eukaryotes.[3] A metallochaperone is an important protein that has metal trafficking and sequestration roles. As a metal sequestration protein, ATOX1 is capable of binding free metals in vivo, in order to protect cells from generation of reactive oxygen species and mismetallation of metalloproteins. As a metal trafficking protein, ATOX1 is responsible for shuttling copper from the cytosol to ATPase transporters ATP7A and ATP7B that move copper to the trans-Golgi network or secretory vesicles.[3][4][5] In Saccharomyces cerevisiae, Atx1 delivers Cu(I) to a homologous transporter, Ccc2. The delivery of copper to ATPase transporters is vital for the subsequent insertion of copper into ceruloplasmin, a ferroxidase required for iron metabolism, within the golgi apparatus.[3]
In addition to the metallochaperone function, recent reports have characterized ATOX1 as a cyclin D1 transcription factor.[4]
# Structure & metal coordination
ATOX1 has a ferrodoxin-like βαββαβ fold and coordinates to Cu(I) via a MXCXXC binding motif located in between the first β-sheet and α-helix.[3][5] The metal binding motif is largely solvent exposed in Apo-ATOX1 and a conformational change is induced upon coordination to Cu(I).[5][6] Cu(I) is coordinated in a distorted linear geometry to sulfurs of cystine to form a bond angle of 120°.[5] The overall -1 charge of the primary coordination sphere is stabilized through the secondary coordination sphere that contains a proximal positively charged lysine.[5][6] ATOX1 also binds Hg(II), Cd(II), Ag(I), and cisplatin via this motif, but a physiological role, if any, is not yet known.[5]
# Metal transfer
ATOX1 transfers Cu(I) to transporters ATP7A and ATP7B.[3][4][5] Transfer occurs via a ligand exchange mechanism, where Cu(I) transiently adopts a 3-coordinate geometry with cysteine ligands from ATOX1 and the associated transporter.[5] The ligand exchange mechanism allows for faster exchange than a diffusion mechanism and imparts specificity for both the metal and transporter.[7] Since the ligand exchange accelerates that transfer and the reaction has a shallow thermodynamic gradient, it is said to be under kinetic control rather than thermodynamic control.[5][7]
# Clinical significance
Although there are presently no known diseases directly associated with ATOX1 malfunction, there is currently active research in a few areas:
- There is a link between ATOX1 levels and sensitivity of cells for Pt-based drugs like cisplatin.[5]
- The mechanism of ammonium tetrathiomolybdate [NH4]2MoS4 treatment of Wilson's Disease is under review. Since ATOX1 forms a stable complex tetrathiomolybdate, it is being studied as the potential therapeutic target.[8][9] | https://www.wikidoc.org/index.php/ATOX1 | |
9d07674e9d1fec6e32cc7e02f29ff0a07a7311f2 | wikidoc | ATP5D | ATP5D
ATP synthase subunit delta, mitochondrial, also known as ATP synthase F1 subunit delta or F-ATPase delta subunit is an enzyme that in humans is encoded by the ATP5F1D (formerly ATP5D) gene. This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation.
# Structure
The ATP5F1D gene is located on the p arm of chromosome 19 at position 13.3 and it spans 3,075 base pairs. The ATP5F1D gene produces a 17.5 kDa protein composed of 168 amino acids. The coded protein is a subunit of the mitochondrial ATP synthase (Complex V), which is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel consists of three main subunits (a, b, c). This gene encodes the delta subunit of the catalytic core. Alternatively spliced transcript variants encoding the same isoform have been identified. The structure of the protein has been known to resemble a 'lollipop' structure due to the attachment of the F1 catalytic unit to the mitochondrial inner membrane by the F0 unit.
# Function
This gene encodes a subunit of the mitochondrial ATP synthase (Complex V) of the mitochondrial respiratory chain, which is necessary for the catalysis of ATP synthesis. Utilizing an electrochemical gradient of protons produced by electron transport complexes of the respiratory chain, the synthase converts ADP into ATP across the inner membrane during oxidative phosphorylation. F-type ATPases consist of two structural domains, F1 and F0, that contribute to the catalysis. The F1 domain contains an extramembranous catalytic core and the F0 domain contains the membrane proton channel linked by a central and a peripheral stalk. During catalysis, ATP turnover in the catalytic domain of F1 is coupled by a rotary mechanism of the central stalk subunits to proton transport. The encoded protein is a part of the complex F1 domain and of the central stalk which is part of the complex rotary element. Rotation of the central stalk against the surrounding alpha3beta3 subunits leads to the hydrolysis of ATP in three separate catalytic sites on the beta subunits.
# Clinical significance
Mutations of ATP5F1D have been associated with childhood mitochondrial disorders with phenotypes such as episodic decompensations, lactic acidosis, and hyperammonemia accompanied by ketoacidosis or hypoglycemia. Biallelic mutations of c.245C>T and c.317T>G in ATP5F1D were shown to cause a metabolic disorder with such phenotypes due to mitochondrial dysfunction in two unrelated individuals. Mutations of ATP5F1D with decreased expression of the protein has also been found to result in synaptic dysfunction of the mitochondria that could play an essential role in sALS(Amyotrophic lateral sclerosis) pathogenesis.
# Interactions
Among the two components, CF1 - the catalytic core - and CF0 - the membrane proton channel of the F-type ATPase, ATP5F1D is associated with the catalytic core. The catalytic core is composed of five different subunits including alpha, beta, gamma, delta, and epsilon subunits. The protein has additional interactions with ATP5I, ATP5O, PUS1, NDUFB5, GTPBP6, ATP5L, ATP5J and others. | ATP5D
ATP synthase subunit delta, mitochondrial, also known as ATP synthase F1 subunit delta or F-ATPase delta subunit is an enzyme that in humans is encoded by the ATP5F1D (formerly ATP5D) gene.[1][2][3] This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation.[4]
# Structure
The ATP5F1D gene is located on the p arm of chromosome 19 at position 13.3 and it spans 3,075 base pairs.[4] The ATP5F1D gene produces a 17.5 kDa protein composed of 168 amino acids.[5][6] The coded protein is a subunit of the mitochondrial ATP synthase (Complex V), which is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and a single representative of the other 3. The proton channel consists of three main subunits (a, b, c). This gene encodes the delta subunit of the catalytic core. Alternatively spliced transcript variants encoding the same isoform have been identified.[4] The structure of the protein has been known to resemble a 'lollipop' structure due to the attachment of the F1 catalytic unit to the mitochondrial inner membrane by the F0 unit.[7]
# Function
This gene encodes a subunit of the mitochondrial ATP synthase (Complex V) of the mitochondrial respiratory chain, which is necessary for the catalysis of ATP synthesis. Utilizing an electrochemical gradient of protons produced by electron transport complexes of the respiratory chain, the synthase converts ADP into ATP across the inner membrane during oxidative phosphorylation.[4] F-type ATPases consist of two structural domains, F1 and F0, that contribute to the catalysis. The F1 domain contains an extramembranous catalytic core and the F0 domain contains the membrane proton channel linked by a central and a peripheral stalk. During catalysis, ATP turnover in the catalytic domain of F1 is coupled by a rotary mechanism of the central stalk subunits to proton transport. The encoded protein is a part of the complex F1 domain and of the central stalk which is part of the complex rotary element. Rotation of the central stalk against the surrounding alpha3beta3 subunits leads to the hydrolysis of ATP in three separate catalytic sites on the beta subunits.[1][2]
# Clinical significance
Mutations of ATP5F1D have been associated with childhood mitochondrial disorders with phenotypes such as episodic decompensations, lactic acidosis, and hyperammonemia accompanied by ketoacidosis or hypoglycemia. Biallelic mutations of c.245C>T and c.317T>G in ATP5F1D were shown to cause a metabolic disorder with such phenotypes due to mitochondrial dysfunction in two unrelated individuals.[8] Mutations of ATP5F1D with decreased expression of the protein has also been found to result in synaptic dysfunction of the mitochondria that could play an essential role in sALS(Amyotrophic lateral sclerosis) pathogenesis.[9]
# Interactions
Among the two components, CF1 - the catalytic core - and CF0 - the membrane proton channel of the F-type ATPase, ATP5F1D is associated with the catalytic core. The catalytic core is composed of five different subunits including alpha, beta, gamma, delta, and epsilon subunits. The protein has additional interactions with ATP5I, ATP5O, PUS1, NDUFB5, GTPBP6, ATP5L, ATP5J and others.[10][1][2] | https://www.wikidoc.org/index.php/ATP5D | |
2b9c2d0a93e421cfe7ede4fbf01bd7fbe4d86901 | wikidoc | ATP5E | ATP5E
ATP synthase F1 subunit epsilon, mitochondrial is an enzyme that in humans is encoded by the ATP5F1E gene. The protein encoded by ATP5F1E is a subunit of ATP synthase, also known as Complex V. Variations of this gene have been associated with mitochondrial complex V deficiency, nuclear 3 (MC5DN3) and Papillary Thyroid Cancer.
# Function
This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and one each of gamma, delta and epsilon. The proton channel consists of three main subunits (a, b, c). This gene encodes the epsilon subunit of the catalytic core. Two pseudogenes of this gene are located on chromosomes 4 and 13.
# Structure
The ATP5F1E gene, located on the q arm of chromosome 20 in position 13.32, is made up of 3 exons and is 3,690 base pairs in length. The ATP5F1E protein weighs 5.7 kDa and is composed of 51 amino acids. The protein is a subunit of the F1Fo ATPase, also known as Complex V, which consists of 14 nuclear and 2 mitochondrial -encoded subunits. The nomenclature of the enzyme has a long history. The F1 fraction derives its name from the term "Fraction 1" and Fo (written as a subscript letter "o", not "zero") derives its name from being the binding fraction for oligomycin, a type of naturally-derived antibiotic that is able to inhibit the Fo unit of ATP synthase. The F1 particle is large and can be seen in the transmission electron microscope by negative staining. These are particles of 9 nm diameter that pepper the inner mitochondrial membrane. They were originally called elementary particles and were thought to contain the entire respiratory apparatus of the mitochondrion, but, through a long series of experiments, Efraim Racker and his colleagues (who first isolated the F1 particle in 1961) were able to show that this particle is correlated with ATPase activity in uncoupled mitochondria and with the ATPase activity in submitochondrial particles created by exposing mitochondria to ultrasound. This ATPase activity was further associated with the creation of ATP by a long series of experiments in many laboratories.
# Function
Mitochondrial membrane ATP synthase (F1Fo ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F1 - containing the extramembraneous catalytic core, and Fo - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F1 is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F1 domain and of the central stalk which is part of the complex rotary element. Rotation of the central stalk against the surrounding alpha3beta3 subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits (By similarity).
The epsilon subunit is located in the stalk region of the F1 complex, and acts as an inhibitor of the ATPase catalytic core. The epsilon subunit can assume two conformations, contracted and extended, where the latter inhibits ATP hydrolysis. The conformation of the epsilon subunit is determined by the direction of rotation of the gamma subunit, and possibly by the presence of ADP. The epsilon subunit is thought to become extended in the presence of ADP, thereby acting as a safety lock to prevent wasteful ATP hydrolysis.
# Clinical significance
Mutations in the ATP5F1E gene cause mitochondrial complex V deficiency, nuclear 3 (MC5DN3), a mitochondrial disorder with heterogeneous clinical manifestations including dysmorphic features, psychomotor retardation, hypotonia, growth retardation, cardiomyopathy, enlarged liver, hypoplastic kidneys and elevated lactate levels in urine, plasma and cerebrospinal fluid. Pathogenic variations have included a homozygous Tyr12Cys mutation in the ATP5E gene, which has been linked with neonatal onset complex V deficiency with lactic acidosis, 3-methylglutaconic aciduria, mild mental retardation and developed peripheral neuropathy.
Reduced expression of ATP5F1E is significantly associated with the diagnosis of Papillary Thyroid Cancer and may serve as an early tumor marker of the disease. Papillary Thyroid Cancer is the most common type of thyroid cancer, representing 75 percent to 85 percent of all thyroid cancer cases. It occurs more frequently in women and presents in the 20–55 year age group. It is also the predominant cancer type in children with thyroid cancer, and in patients with thyroid cancer who have had previous radiation to the head and neck.
# Interactions
ATP5F1E has been shown to have 34 binary protein-protein interactions including 28 co-complex interactions. ATP5F1E appears to interact with ATP5F1D, AGTRAP, CYP17A1, UBE2N. | ATP5E
ATP synthase F1 subunit epsilon, mitochondrial is an enzyme that in humans is encoded by the ATP5F1E gene.[1][2] The protein encoded by ATP5F1E is a subunit of ATP synthase, also known as Complex V. Variations of this gene have been associated with mitochondrial complex V deficiency, nuclear 3 (MC5DN3) and Papillary Thyroid Cancer.[3][4]
# Function
This gene encodes a subunit of mitochondrial ATP synthase. Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. ATP synthase is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, Fo, comprising the proton channel. The catalytic portion of mitochondrial ATP synthase consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled with a stoichiometry of 3 alpha, 3 beta, and one each of gamma, delta and epsilon. The proton channel consists of three main subunits (a, b, c). This gene encodes the epsilon subunit of the catalytic core. Two pseudogenes of this gene are located on chromosomes 4 and 13.[2]
# Structure
The ATP5F1E gene, located on the q arm of chromosome 20 in position 13.32, is made up of 3 exons and is 3,690 base pairs in length.[2] The ATP5F1E protein weighs 5.7 kDa and is composed of 51 amino acids.[5][6] The protein is a subunit of the F1Fo ATPase, also known as Complex V, which consists of 14 nuclear and 2 mitochondrial -encoded subunits. The nomenclature of the enzyme has a long history. The F1 fraction derives its name from the term "Fraction 1" and Fo (written as a subscript letter "o", not "zero") derives its name from being the binding fraction for oligomycin, a type of naturally-derived antibiotic that is able to inhibit the Fo unit of ATP synthase.[7][8] The F1 particle is large and can be seen in the transmission electron microscope by negative staining.[9] These are particles of 9 nm diameter that pepper the inner mitochondrial membrane. They were originally called elementary particles and were thought to contain the entire respiratory apparatus of the mitochondrion, but, through a long series of experiments, Efraim Racker and his colleagues (who first isolated the F1 particle in 1961) were able to show that this particle is correlated with ATPase activity in uncoupled mitochondria and with the ATPase activity in submitochondrial particles created by exposing mitochondria to ultrasound. This ATPase activity was further associated with the creation of ATP by a long series of experiments in many laboratories.
# Function
Mitochondrial membrane ATP synthase (F1Fo ATP synthase or Complex V) produces ATP from ADP in the presence of a proton gradient across the membrane which is generated by electron transport complexes of the respiratory chain. F-type ATPases consist of two structural domains, F1 - containing the extramembraneous catalytic core, and Fo - containing the membrane proton channel, linked together by a central stalk and a peripheral stalk. During catalysis, ATP synthesis in the catalytic domain of F1 is coupled via a rotary mechanism of the central stalk subunits to proton translocation. Part of the complex F1 domain and of the central stalk which is part of the complex rotary element. Rotation of the central stalk against the surrounding alpha3beta3 subunits leads to hydrolysis of ATP in three separate catalytic sites on the beta subunits (By similarity).[10]
The epsilon subunit is located in the stalk region of the F1 complex, and acts as an inhibitor of the ATPase catalytic core. The epsilon subunit can assume two conformations, contracted and extended, where the latter inhibits ATP hydrolysis. The conformation of the epsilon subunit is determined by the direction of rotation of the gamma subunit, and possibly by the presence of ADP. The epsilon subunit is thought to become extended in the presence of ADP, thereby acting as a safety lock to prevent wasteful ATP hydrolysis.[11]
# Clinical significance
Mutations in the ATP5F1E gene cause mitochondrial complex V deficiency, nuclear 3 (MC5DN3), a mitochondrial disorder with heterogeneous clinical manifestations including dysmorphic features, psychomotor retardation, hypotonia, growth retardation, cardiomyopathy, enlarged liver, hypoplastic kidneys and elevated lactate levels in urine, plasma and cerebrospinal fluid.[3] Pathogenic variations have included a homozygous Tyr12Cys mutation in the ATP5E gene, which has been linked with neonatal onset complex V deficiency with lactic acidosis, 3-methylglutaconic aciduria, mild mental retardation and developed peripheral neuropathy.[12]
Reduced expression of ATP5F1E is significantly associated with the diagnosis of Papillary Thyroid Cancer and may serve as an early tumor marker of the disease.[4] Papillary Thyroid Cancer is the most common type of thyroid cancer,[13] representing 75 percent to 85 percent of all thyroid cancer cases.[14] It occurs more frequently in women and presents in the 20–55 year age group. It is also the predominant cancer type in children with thyroid cancer, and in patients with thyroid cancer who have had previous radiation to the head and neck.[15]
# Interactions
ATP5F1E has been shown to have 34 binary protein-protein interactions including 28 co-complex interactions. ATP5F1E appears to interact with ATP5F1D, AGTRAP, CYP17A1, UBE2N.[16] | https://www.wikidoc.org/index.php/ATP5E | |
36f0e442da9a4348e626080d0b65ac11f2c7c816 | wikidoc | ATP5H | ATP5H
The human gene ATP5PD encodes subunit d of the peripheral stalk part of the enzyme mitochondrial ATP synthase.
Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. It is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, F0, which comprises the proton channel. The F1 complex consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled in a ratio of 3 alpha, 3 beta, and a single representative of the other 3. The Fo seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene encodes the d subunit of the Fo complex.
Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. In addition, three pseudogenes are located on chromosomes 9, 12 and 15. | ATP5H
The human gene ATP5PD encodes subunit d of the peripheral stalk part of the enzyme mitochondrial ATP synthase.[1][2]
Mitochondrial ATP synthase catalyzes ATP synthesis, utilizing an electrochemical gradient of protons across the inner membrane during oxidative phosphorylation. It is composed of two linked multi-subunit complexes: the soluble catalytic core, F1, and the membrane-spanning component, F0, which comprises the proton channel. The F1 complex consists of 5 different subunits (alpha, beta, gamma, delta, and epsilon) assembled in a ratio of 3 alpha, 3 beta, and a single representative of the other 3. The Fo seems to have nine subunits (a, b, c, d, e, f, g, F6 and 8). This gene encodes the d subunit of the Fo complex.
Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. In addition, three pseudogenes are located on chromosomes 9, 12 and 15.[2] | https://www.wikidoc.org/index.php/ATP5H |
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