CIDeRplusGeneral Information:
| Id: | 3,387 |
| Diseases: |
Carnitine deficiency, systemic primary
- [OMIM]
Diabetes mellitus, type II - [OMIM] Insulin resistance |
| Mammalia | |
| review | |
| Reference: | Vaz FM and Wanders RJ(2002) Carnitine biosynthesis in mammals Biochem. J. Pt: 3 417-429 [PMID: 11802770] |
Interaction Information:
| Comment | Carnitine (l-3-hydroxy-4-N,N,N-trimethylaminobutyrate) has an important role in the transport of activated long-chain fatty acids from the cytosol to the mitochondrial matrix, where beta-oxidation takes place. |
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Formal Description Interaction-ID: 31526 |
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| Comment | Carnitine (l-3-hydroxy-4-N,N,N-trimethylaminobutyrate) has an important role in the transport of activated long-chain fatty acids from the cytosol to the mitochondrial matrix, where beta-oxidation takes place. |
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Formal Description Interaction-ID: 31534 |
drug/chemical compound increases_activity of process |
| Comment | Carnitine (l-3-hydroxy-4-N,N,N-trimethylaminobutyrate) has an important role in the transport of activated long-chain fatty acids from the cytosol to the mitochondrial matrix, where beta-oxidation takes place. |
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Formal Description Interaction-ID: 31535 |
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| Comment | Carnitine is involved in the transfer of the products of peroxisomal beta-oxidation, including acetyl-CoA, to the mitochondria for oxidation to CO2and H2O in the Krebs cycle. |
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Formal Description Interaction-ID: 31536 |
drug/chemical compound increases_activity of process |
| Comment | Carnitine is involved in the transfer of the products of peroxisomal beta-oxidation, including acetyl-CoA, to the mitochondria for oxidation to CO2and H2O in the Krebs cycle. |
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Formal Description Interaction-ID: 31538 |
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| Comment | Carnitine modulates the toxic effects of poorly metabolized acyl groups by excreting them as carnitine esters. |
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Formal Description Interaction-ID: 31539 |
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| Comment | Carnitine is synthesized ultimately from the amino acids lysine and methionine. Lysine provides the carbon backbone of carnitine and the 4-N-methyl groups originate from methionine. |
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Formal Description Interaction-ID: 31541 |
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| Comment | Carnitine is synthesized ultimately from the amino acids lysine and methionine. Lysine provides the carbon backbone of carnitine and the 4-N-methyl groups originate from methionine. |
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Formal Description Interaction-ID: 31542 |
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| Comment | In mammals, certain proteins contain N6-trimethyl-lysine (TML) residues. N-methylation of these lysine residues occurs as a post-translational event in proteins such as calmodulin, myosin, actin, cytochrome c and histones. Lysosomal hydrolysis of these proteins results in the release of TML, which is the first metabolite of carnitine biosynthesis. |
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Formal Description Interaction-ID: 31543 |
drug/chemical compound affects_activity of process |
| Comment | TML is first hydroxylated on the 3-position by TML dioxygenase (TMLD; EC 1.14.11.8) to yield 3-hydroxy-TML (HTML). |
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Formal Description Interaction-ID: 31544 |
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| Drugbank entries | Show/Hide entries for TMLHE |
| Comment | TML is first hydroxylated on the 3-position by TML dioxygenase (TMLD; EC 1.14.11.8) to yield 3-hydroxy-TML (HTML). |
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Formal Description Interaction-ID: 31545 |
gene/protein increases_quantity of drug/chemical compound |
| Drugbank entries | Show/Hide entries for TMLHE |
| Comment | Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.X). |
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Formal Description Interaction-ID: 31546 |
gene/protein HTMLA decreases_quantity of drug/chemical compound |
| Comment | Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.X). |
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Formal Description Interaction-ID: 31589 |
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| Comment | Aldolytic cleavage of HTML yields 4-trimethylaminobutyraldehyde (TMABA) and glycine, a reaction catalysed by HTML aldolase (HTMLA; EC 4.1.2.`X'). |
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Formal Description Interaction-ID: 31590 |
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| Drugbank entries | Show/Hide entries for |
| Comment | Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). |
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Formal Description Interaction-ID: 31591 |
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| Drugbank entries | Show/Hide entries for ALDH9A1 |
| Comment | Dehydrogenation of TMABA by TMABA dehydrogenase (TMABA-DH; EC 1.2.1.47) results in the formation of 4-Ntrimethylaminobutyrate (butyrobetaine). |
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Formal Description Interaction-ID: 31595 |
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| Drugbank entries | Show/Hide entries for ALDH9A1 |
| Comment | In the last step, butyrobetaine is hydroxylated on the 3-position by gamma-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. |
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Formal Description Interaction-ID: 31598 |
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| Drugbank entries | Show/Hide entries for BBOX1 |
| Comment | In the last step, butyrobetaine is hydroxylated on the 3-position by gamma-butyrobetaine dioxygenase (BBD; EC 1.14.11.1) to yield carnitine. |
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Formal Description Interaction-ID: 31599 |
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| Drugbank entries | Show/Hide entries for BBOX1 |
| Comment | HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SHMT catalyses the tetrahydrofolate-dependent interconversion of serine and glycine, a reaction that generates one-carbon units for methionine, thymidylate and purine biosynthesis. SHMT also catalyses the aldol cleavage of other beta-hydroxyamino acids in the absence of tetrahydrofolate, including HTML. Two isoforms of SHMT are present in eukaryotic cells: one localized in the cytoplasm and one localized in mitochondria. In humans, the gene encoding the cytosolic SHMT is located on chromosome 17p11.2, and the gene encoding the mitochondrial isoenzyme is on chromosome 12q13.2. |
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Formal Description Interaction-ID: 31603 |
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| Drugbank entries | Show/Hide entries for SHMT1 |
| Comment | The concentration of TML in plasma is relatively constant in both human and rat, ranging from 0.2 to 1.3 microM. Plasma levels of TML have been shown to correlate with body mass. In man, urinary excretion of TML is proportional to that of creatinine, and TML is not reabsorbed by the kidney. In contrast, the rat is capable of tubular reabsorption of TML. |
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Formal Description Interaction-ID: 31610 |
disease affects_quantity of drug/chemical compound |
| Comment | In humans, the plasma carnitine concentration increases during the first year of life, and remains the same for both sexes until puberty. From puberty to adulthood, plasma carnitine concentrations in males increase and stabilize at a level that is significantly higher than those in females. This suggests that sex hormones have a role in the regulation of carnitine plasma concentrations. |
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Formal Description Interaction-ID: 31613 |
drug/chemical compound Sex hormone affects_quantity of drug/chemical compound |
| Comment | By an unknown mechanism, long-term starvation of rats causes a considerable increase in liver carnitine levels, which parallels the ketogenic capacity of the liver. During fasting, urinary levels of TML fall. Urinary excretion of carnitine and butyrobetaine is also decreased upon fasting to 13% and 33% of the levels in fed animals respectively. The conservation of carnitine precursors could lead to enhanced carnitine biosynthesis, which would explain the higher levels of carnitine in liver. However, this increase might also result from redistribution of carnitine from tissues to the liver. |
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Formal Description Interaction-ID: 31620 |
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| Comment | Clofibrate, a peroxisome proliferator and ligand for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), greatly increased liver carnitine and acylcarnitine concentrations (by 6- and 5-fold respectively). These increases were a result of enhanced hepatic carnitine biosynthesis, and not of redistribution of carnitine among tissues or of a decrease in urinary excretion. |
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Formal Description Interaction-ID: 31622 |
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| Drugbank entries | Show/Hide entries for Clofibrate or PPARA |
| Comment | Clofibrate, a peroxisome proliferator and ligand for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), greatly increased liver carnitine and acylcarnitine concentrations (by 6- and 5-fold respectively). These increases were a result of enhanced hepatic carnitine biosynthesis, and not of redistribution of carnitine among tissues or of a decrease in urinary excretion. |
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Formal Description Interaction-ID: 31624 |
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| Drugbank entries | Show/Hide entries for Clofibrate |
| Comment | Clofibrate, a peroxisome proliferator and ligand for the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), greatly increased liver carnitine and acylcarnitine concentrations (by 6- and 5-fold respectively). These increases were a result of enhanced hepatic carnitine biosynthesis, and not of redistribution of carnitine among tissues or of a decrease in urinary excretion. |
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Formal Description Interaction-ID: 31625 |
drug/chemical compound increases_quantity of drug/chemical compound Fatty acid acylcarnitine |
| Drugbank entries | Show/Hide entries for Clofibrate |
| Comment | Thyroxine, a thyroid hormone, has been reported to increase liver carnitine levels too. In liver, both the carnitine concentration and BBD activity were increased 2-fold in thyroxine-treated rats. Serum carnitine concentrations were increased moderately, whereas levels in the heart, skeletal muscle and urine were not affected. Effects of sex hormones, pituitary hormones, insulin and glucagon on carnitine levels have been documented, their direct influence on carnitine biosynthesis, however, has not been investigated. |
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Formal Description Interaction-ID: 31627 |
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| Comment | Thyroxine, a thyroid hormone, has been reported to increase liver carnitine levels too. In liver, both the carnitine concentration and BBD activity were increased 2-fold in thyroxine-treated rats. Serum carnitine concentrations were increased moderately, whereas levels in the heart, skeletal muscle and urine were not affected. Effects of sex hormones, pituitary hormones, insulin and glucagon on carnitine levels have been documented, their direct influence on carnitine biosynthesis, however, has not been investigated. |
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Formal Description Interaction-ID: 31628 |
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| Drugbank entries | Show/Hide entries for BBOX1 |
| Comment | Thyroxine, a thyroid hormone, has been reported to increase liver carnitine levels too. In liver, both the carnitine concentration and BBD activity were increased 2-fold in thyroxine-treated rats. Serum carnitine concentrations were increased moderately, whereas levels in the heart, skeletal muscle and urine were not affected. Effects of sex hormones, pituitary hormones, insulin and glucagon on carnitine levels have been documented, their direct influence on carnitine biosynthesis, however, has not been investigated. |
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Formal Description Interaction-ID: 31629 |
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| Comment | Thyroxine, a thyroid hormone, has been reported to increase liver carnitine levels too. In liver, both the carnitine concentration and BBD activity were increased 2-fold in thyroxine-treated rats. Serum carnitine concentrations were increased moderately, whereas levels in the heart, skeletal muscle and urine were not affected. Effects of sex hormones, pituitary hormones, insulin and glucagon on carnitine levels have been documented, their direct influence on carnitine biosynthesis, however, has not been investigated. |
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Formal Description Interaction-ID: 31630 |
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| Comment | The dependence on carnitine uptake is evident from patients who suffer from primary systemic carnitine deficiency (CDSP). These patients show excessive renal and intestinal wastage of carnitine, resulting in very low plasma and tissue carnitine concentrations. Clinically, CDSP patients usually show symptoms of cardiomyopathy, hepatomegaly, myopathy, recurrent episodes of hypoketotic hypoglycaemia, hyperammonaemia and failure to thrive. Studies of cells of CDSP patients have indicated that this disorder is caused by a defect in the active cellular uptake of carnitine into the cell. The disorder is autosomal recessive. Shortly after the identification of the high-affinity carnitine transporter OCTN2, which is located on chromosome 5q33.1, it was demonstrated that mutations in this gene cause CDSP. |
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Formal Description Interaction-ID: 31631 |
decreases_quantity of drug/chemical compound |
| Comment | The dependence on carnitine uptake is evident from patients who suffer from primary systemic carnitine deficiency (CDSP). These patients show excessive renal and intestinal wastage of carnitine, resulting in very low plasma and tissue carnitine concentrations. Clinically, CDSP patients usually show symptoms of cardiomyopathy, hepatomegaly, myopathy, recurrent episodes of hypoketotic hypoglycaemia, hyperammonaemia and failure to thrive. Studies of cells of CDSP patients have indicated that this disorder is caused by a defect in the active cellular uptake of carnitine into the cell. The disorder is autosomal recessive. Shortly after the identification of the high-affinity carnitine transporter OCTN2, which is located on chromosome 5q33.1, it was demonstrated that mutations in this gene cause CDSP. |
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Formal Description Interaction-ID: 31632 |
gene/protein mutant increases_activity of |
| Comment | The dependence on carnitine uptake is evident from patients who suffer from primary systemic carnitine deficiency (CDSP). These patients show excessive renal and intestinal wastage of carnitine, resulting in very low plasma and tissue carnitine concentrations. Clinically, CDSP patients usually show symptoms of cardiomyopathy, hepatomegaly, myopathy, recurrent episodes of hypoketotic hypoglycaemia, hyperammonaemia and failure to thrive. Studies of cells of CDSP patients have indicated that this disorder is caused by a defect in the active cellular uptake of carnitine into the cell. The disorder is autosomal recessive. Shortly after the identification of the high-affinity carnitine transporter OCTN2, which is located on chromosome 5q33.1, it was demonstrated that mutations in this gene cause CDSP. |
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Formal Description Interaction-ID: 31633 |
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| Comment | Cytosolic long-chain fatty acids, which are present as CoA esters, are trans-esterified to L-carnitine in a reaction catalysed by carnitine palmitoyltransferase I (CPT I) at the mitochondrial outer membrane. In this reaction, the acyl moiety of the long-chain fatty acids is transferred from CoA to the hydroxyl group of carnitine. |
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Formal Description Interaction-ID: 31717 |
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| Drugbank entries | Show/Hide entries for CPT1A |
| Comment | Cytosolic long-chain fatty acids, which are present as CoA esters, are trans-esterified to L-carnitine in a reaction catalysed by carnitine palmitoyltransferase I (CPT I) at the mitochondrial outer membrane. In this reaction, the acyl moiety of the long-chain fatty acids is transferred from CoA to the hydroxyl group of carnitine. |
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Formal Description Interaction-ID: 31718 |
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| Drugbank entries | Show/Hide entries for CPT1A |
| Comment | Cytosolic long-chain fatty acids, which are present as CoA esters, are trans-esterified to L-carnitine in a reaction catalysed by carnitine palmitoyltransferase I (CPT I) at the mitochondrial outer membrane. In this reaction, the acyl moiety of the long-chain fatty acids is transferred from CoA to the hydroxyl group of carnitine. |
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Formal Description Interaction-ID: 31719 |
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| Drugbank entries | Show/Hide entries for CPT1A |
| Comment | Cytosolic long-chain fatty acids, which are present as CoA esters, are trans-esterified to L-carnitine in a reaction catalysed by carnitine palmitoyltransferase I (CPT I) at the mitochondrial outer membrane. In this reaction, the acyl moiety of the long-chain fatty acids is transferred from CoA to the hydroxyl group of carnitine. |
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Formal Description Interaction-ID: 31720 |
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| Drugbank entries | Show/Hide entries for CPT1A |
| Comment | The resulting long-chain acylcarnitine esters are transported over the inner mitochondrial membrane via a specific carrier, carnitine-acylcarnitine translocase (CACT). |
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Formal Description Interaction-ID: 31721 |
gene/protein increases_transport of drug/chemical compound Long-chain acylcarnitine |
| Drugbank entries | Show/Hide entries for SLC25A20 |
| Comment | At the matrix side of the mitochondrial membrane, the long-chain fatty acids are transesterified to intramitochondrial CoA, a reaction catalysed by carnitine palmitoyltransferase II (CPT II). |
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Formal Description Interaction-ID: 31722 |
gene/protein decreases_quantity of drug/chemical compound Long-chain acylcarnitine |
| Drugbank entries | Show/Hide entries for CPT2 |
| Comment | At the matrix side of the mitochondrial membrane, the long-chain fatty acids are transesterified to intramitochondrial CoA, a reaction catalysed by carnitine palmitoyltransferase II (CPT II). |
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Formal Description Interaction-ID: 31723 |
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| Drugbank entries | Show/Hide entries for CPT2 |
| Comment | The released carnitine can then leave the mitochondrion via CACT for another round of transport. |
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Formal Description Interaction-ID: 31724 |
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| Drugbank entries | Show/Hide entries for SLC25A20 |
| Comment | At the matrix side of the mitochondrial membrane, the long-chain fatty acids are transesterified to intramitochondrial CoA, a reaction catalysed by carnitine palmitoyltransferase II (CPT II). |
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Formal Description Interaction-ID: 31725 |
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| Drugbank entries | Show/Hide entries for CPT2 |
| Comment | In the mitochondrial matrix, the enzyme carnitine acetyltransferase (CAT) is able to reconvert short- and medium-chain acyl-CoAs into acetylcarnitines using intramitochondrial carnitine. These acetylcarnitines can then leave the mitochondria via CACT. |
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Formal Description Interaction-ID: 31726 |
gene/protein increases_quantity of drug/chemical compound Medium-chain acylcarnitine |
| Drugbank entries | Show/Hide entries for CRAT |
| Comment | Carnitine (l-3-hydroxy-4-N,N,N-trimethylaminobutyrate) has an important role in the transport of activated long-chain fatty acids from the cytosol to the mitochondrial matrix, where beta-oxidation takes place. |
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Formal Description Interaction-ID: 31727 |
process decreases_quantity of drug/chemical compound |
| Comment | In the mitochondrial matrix, the enzyme carnitine acetyltransferase (CAT) is able to reconvert short- and medium-chain acyl-CoAs into acetylcarnitines using intramitochondrial carnitine. These acetylcarnitines can then leave the mitochondria via CACT. |
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Formal Description Interaction-ID: 31728 |
gene/protein increases_quantity of drug/chemical compound Short-chain acylcarnitine |
| Drugbank entries | Show/Hide entries for CRAT |
| Comment | In the mitochondrial matrix, the enzyme carnitine acetyltransferase (CAT) is able to reconvert short- and medium-chain acyl-CoAs into acetylcarnitines using intramitochondrial carnitine. These acetylcarnitines can then leave the mitochondria via CACT. |
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Formal Description Interaction-ID: 31729 |
gene/protein increases_transport of drug/chemical compound Medium-chain acylcarnitine |
| Drugbank entries | Show/Hide entries for SLC25A20 |
| Comment | In the mitochondrial matrix, the enzyme carnitine acetyltransferase (CAT) is able to reconvert short- and medium-chain acyl-CoAs into acetylcarnitines using intramitochondrial carnitine. These acetylcarnitines can then leave the mitochondria via CACT. |
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Formal Description Interaction-ID: 31730 |
gene/protein increases_transport of drug/chemical compound Short-chain acylcarnitine |
| Drugbank entries | Show/Hide entries for SLC25A20 |
| Comment | HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SHMT catalyses the tetrahydrofolate-dependent interconversion of serine and glycine, a reaction that generates one-carbon units for methionine, thymidylate and purine biosynthesis. SHMT also catalyses the aldol cleavage of other beta-hydroxyamino acids in the absence of tetrahydrofolate, including HTML. Two isoforms of SHMT are present in eukaryotic cells: one localized in the cytoplasm and one localized in mitochondria. In humans, the gene encoding the cytosolic SHMT is located on chromosome 17p11.2, and the gene encoding the mitochondrial isoenzyme is on chromosome 12q13.2. |
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Formal Description Interaction-ID: 46095 |
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| Drugbank entries | Show/Hide entries for SHMT2 |
| Comment | HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SHMT catalyses the tetrahydrofolate-dependent interconversion of serine and glycine, a reaction that generates one-carbon units for methionine, thymidylate and purine biosynthesis. SHMT also catalyses the aldol cleavage of other beta-hydroxyamino acids in the absence of tetrahydrofolate, including HTML. Two isoforms of SHMT are present in eukaryotic cells: one localized in the cytoplasm and one localized in mitochondria. In humans, the gene encoding the cytosolic SHMT is located on chromosome 17p11.2, and the gene encoding the mitochondrial isoenzyme is on chromosome 12q13.2. |
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Formal Description Interaction-ID: 46096 |
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| Drugbank entries | Show/Hide entries for SHMT2 |
| Comment | HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SHMT catalyses the tetrahydrofolate-dependent interconversion of serine and glycine, a reaction that generates one-carbon units for methionine, thymidylate and purine biosynthesis. SHMT also catalyses the aldol cleavage of other beta-hydroxyamino acids in the absence of tetrahydrofolate, including HTML. Two isoforms of SHMT are present in eukaryotic cells: one localized in the cytoplasm and one localized in mitochondria. In humans, the gene encoding the cytosolic SHMT is located on chromosome 17p11.2, and the gene encoding the mitochondrial isoenzyme is on chromosome 12q13.2. |
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Formal Description Interaction-ID: 46097 |
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| Drugbank entries | Show/Hide entries for SHMT2 or Glycine |
| Comment | HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SHMT catalyses the tetrahydrofolate-dependent interconversion of serine and glycine, a reaction that generates one-carbon units for methionine, thymidylate and purine biosynthesis. SHMT also catalyses the aldol cleavage of other beta-hydroxyamino acids in the absence of tetrahydrofolate, including HTML. Two isoforms of SHMT are present in eukaryotic cells: one localized in the cytoplasm and one localized in mitochondria. In humans, the gene encoding the cytosolic SHMT is located on chromosome 17p11.2, and the gene encoding the mitochondrial isoenzyme is on chromosome 12q13.2. |
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Formal Description Interaction-ID: 46098 |
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| Drugbank entries | Show/Hide entries for SHMT1 |
| Comment | HTMLA might be identical to serine hydroxymethyltransferase (SHMT; EC 2.1.2.1), since it has been shown that SHMT purified from rabbit liver acts upon HTML, yielding TMABA and glycine. SHMT catalyses the tetrahydrofolate-dependent interconversion of serine and glycine, a reaction that generates one-carbon units for methionine, thymidylate and purine biosynthesis. SHMT also catalyses the aldol cleavage of other beta-hydroxyamino acids in the absence of tetrahydrofolate, including HTML. Two isoforms of SHMT are present in eukaryotic cells: one localized in the cytoplasm and one localized in mitochondria. In humans, the gene encoding the cytosolic SHMT is located on chromosome 17p11.2, and the gene encoding the mitochondrial isoenzyme is on chromosome 12q13.2. |
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Formal Description Interaction-ID: 46099 |
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| Drugbank entries | Show/Hide entries for SHMT1 or Glycine |