Malonyl-CoA

 ( Metabolism ) 

Malonyl-CoA is a coenzyme A derivative of malonic acid.

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Biosynthesis Malonyl-CoA cannot cross membranes and there is no known malonyl-CoA import mechanism. The biosynthesis therefore takes place locally:

• cytosol: Malonyl-CoA is formed by Carboxylation acetyl-CoA using the highly regulated enzyme ACACA (ACC1). One molecule of acetyl-CoA joins with a molecule of bicarbonate, requiring energy rendered from ATP.
• Mitochondrial outer membrane: Malonyl-CoA is formed by carboxylating acetyl-CoA using the highly regulated enzyme ACACB (ACC2). The reaction is the same as with ACC1.
• mitochondrial matrix: Malonyl-CoA is formed in coordinated fashion by mtACC1, a mitochondrial isoform of ACC1, and acyl-CoA synthetase family member 3 (ACSF3), a mitochondrial malonyl-CoA synthetase. MtACC1, like cytosolic ACC1 catalyses the carboxylation of acetyl-CoA, while ACSF3 catalyses the thioesterification of Malonic acid to coenzyme A. The latter serves for the clearance of mitochondrial malonate, since malonate is a potent inhibitor of mitochondrial respiration as it competitively inhibits succinate dehydrogenase. However, the source of malonyl-CoA in the Mitochondrion is still up for debate.

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Functions It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis.

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Cytosolic malonyl-CoA Malonyl-CoA provides 2-carbon units to fatty acids and commits them to fatty acid chain synthesis.

Malonyl-CoA is utilised in fatty acid biosynthesis by the enzyme (MCAT). MCAT serves to transfer malonate from malonyl-CoA to the terminal thiol of holo-acyl carrier protein (ACP).

Malonyl-CoA is a highly regulated molecule in fatty acid synthesis; as such, it inhibits the rate-limiting step in beta-oxidation of fatty acids. Malonyl-CoA inhibits fatty acids from associating with carnitine by regulating the enzyme carnitine palmitoyltransferase, thereby preventing them from entering the mitochondria, where fatty acid oxidation and degradation occur.

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Polyketide biosynthesis MCAT is also involved in bacterial polyketide biosynthesis. The enzyme MCAT together with an acyl carrier protein (ACP), and a polyketide synthase (PKS) and chain-length factor heterodimer, constitutes the minimal PKS of type II polyketides.

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Clinical relevance Malonyl-CoA plays a special role in the mitochondrial clearance of toxic malonic acid in the metabolic disorders combined malonic and methylmalonic aciduria (CMAMMA) and malonic aciduria. In CMAMMA, malonyl-CoA synthetase, ACSF3 is impaired, which generates mitochondrial malonyl-CoA from malonic acid, which can then be converted to acetyl-CoA by malonyl-CoA decarboxylase. In contrast, in malonic aciduria, malonyl-CoA decarboxylase is decreased, which converts malonyl-CoA to acetyl-CoA.

$\backslash mathrm\{Malonic\backslash \; acid\; +\; CoA\; +\; ATP\backslash \; \backslash xrightarrowACSF3\{Malonyl\{-\}CoA\backslash \; Synthetase\}\; \backslash \; Malonyl\{-\}CoA\; \backslash \; \backslash xrightarrowMLYCD\{Malonyl-CoA\backslash \; Decarboxylase\}\; \backslash \; Acetyl\{-\}CoA\; \}$

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See also

• MCAT (gene)

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External links

• Hope for new way to beat obesity

Categories: Metabolism, Thioesters Of Coenzyme A

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