Malonate—CoA ligase

In enzymology, a malonate—CoA ligase (EC 6.2.1.76), also known as malonyl-CoA synthetase or malonate:CoA ligase (AMP-forming), is an enzyme that catalyzes the chemical reaction:

ATP + malonate + CoA ${\displaystyle \rightleftharpoons }$ AMP + diphosphate + malonyl-CoA

Malonate—CoA ligase
Identifiers
EC no.	6.2.1.76
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Search PMC articles PubMed articles NCBI proteins

The 3 substrates of this enzyme are ATP, malonate, and CoA, whereas its 3 products are AMP, diphosphate, and malonyl-CoA.

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. This enzyme participates in mitochondrial fatty acid synthesis metabolism.

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 has a high specificity for malonate and methylmalonate.^[1] 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, which is a component of citric acid cycle and is complex II of the respiratory chain.^[2][3] The resulting malonyl-CoA (besides being generated by a mitochondrial isoform of acetyl-CoA carboxylase 1) is considered one of the sources of mitochondrial malonyl-CoA, which is required as a precursor for mitochondrial fatty acid synthesis.^[4] Furthermore, ACSF3 is required for the malonylation of mitochondrial proteins.^[2]

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).^[5] Malonyl-CoA is required as a substrate in acylation and condensation reactions.^[6] 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.^[6] In contrast, the mitochondrial isoform is essential for plant growth.^[6]

Clinical relevance

In the inborn error of metabolism combined malonic and methylmalonic aciduria (CMAMMA), the malonyl-CoA synthetase, ACSF3, is impaired, which leads to an accumulation of the metabolites malonate and methylmalonate.^[7]