Malonate—CoA ligase
Template:Short description Template:Cs1 config Template:Infobox enzyme In enzymology, a malonate—CoA ligase (Template:EnzExplorer), also known as malonyl-CoA synthetase or malonate:CoA ligase (AMP-forming), is an enzyme that catalyzes the chemical reaction:
This enzyme belongs to the class of ligases, specifically those forming carbon-sulfur bonds as acid-thiol ligases or, more precisely, to the family of acyl-CoA synthetases.
Representatives of the malonate—CoA ligase family are required for malonate detoxification, mitochondrial fatty acid synthesis, lysine malonylation, and acetyl-CoA synthesis.[1][2]
Examples
The following enzymes with malonyl-CoA synthetase activity are known:
Acyl-CoA synthetase family member 3 (ACSF3)
The only known malonyl-CoA synthetase in mammals is the mitochondrial enzyme acyl-CoA synthetase family member 3 (ACSF3), which, in addition to malonate, also accepts methylmalonate as a substrate with approximately 70% efficiency.[3] ACSF3 is required for the clearance of intramitochondrial malonate, as malonate is a potent inhibitor of mitochondrial respiration through the competitive inhibition of succinate dehydrogenase (Complex II), an enzyme that simultaneously functions in the citric acid cycle and the respiratory chain.[1][4] In addition to the mitochondrial isoform of acetyl-CoA carboxylase 1 (mtACC1), which produces malonyl-CoA from acetyl-CoA, ACSF3 hereby contributes to the mitochondrial malonyl-CoA pool required for mitochondrial fatty acid synthesis, lysine malonylation, acetyl-CoA synthesis, and incorporation into cellular lipids.[5][2][1]
Acyl activating enzyme 13 (AAE13)
Also in plants, more precisely in Arabidopsis thaliana, there is a malonyl-CoA synthetase, the acyl activation enzyme 13 (AAE13).[6] Malonyl-CoA is required as a substrate in acylation and condensation reactions.[7] AAE13 is localized both in the cytosol and in the mitochondria, whereby the cytosolic isoform is not essential, as cytosolic malonyl-CoA is sufficiently provided by cytosolic acetyl-CoA carboxylase.[7] In contrast, the mitochondrial isoform is essential for plant growth.[7]
Clinical relevance
In the inborn error of metabolism combined malonic and methylmalonic aciduria (CMAMMA), the malonyl-CoA synthetase ACSF3 is defective, leading to an accumulation of malonate and methylmalonate, and to a deficiency of malonyl-CoA and methylmalonyl-CoA.[8]
References
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