Malonyl-CoA is a coenzyme A derivative of malonic acid.
It plays a key role in chain elongation in fatty acid biosynthesis and polyketide biosynthesis.
Malonyl-CoA provides 2-carbon units to fatty acids and commits them to fatty acid chain synthesis.
Malonyl-CoA is formed by carboxylating acetyl-CoA using the enzyme acetyl-CoA carboxylase. One molecule of acetyl-CoA joins with a molecule of bicarbonate,[1] requiring energy rendered from ATP.
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 formed in the first step of mitochondrial fatty acid synthesis (mtFASII) from malonic acid by malonyl-CoA synthetase (ACSF3).[2]
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.
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 acyltransferase, thereby preventing them from entering the mitochondria, where fatty acid oxidation and degradation occur.
Malonyl-CoA plays a special role in the mitochondrial clearance of toxic malonic acid in the metabolic disorder combined malonic and methylmalonic aciduria (CMAMMA).[3] In CMAMMA due to ACSF3, malonyl-CoA synthetase is decreased, which can generate malonyl-CoA from malonic acid, which can then be converted to acetyl-CoA by malonyl-CoA decarboxylase.[4] In contrast, in CMAMMA due to malonyl-CoA decarboxylase deficiency, malonyl-CoA decarboxylase is decreased, which converts malonyl-CoA to acetyl-CoA.
Malonic acid+CoA+ATP \xrightarrow[ACSF3]{Malonyl{-CoA Synthetase} Malonyl{-}CoA \xrightarrow[MLYCD]{Malonyl-CoA Decarboxylase} Acetyl{-}CoA}