Acyl-CoA synthetase family member 3 (ACSF3) (ACSF3)

Acyl-CoA synthetase family member 3 (ACSF3), also commonly known as Malonyl-CoA synthetase, is a mitochondrial enzyme that catalyzes the ATP-dependent ligation of malonate and methylmalonate to Coenzyme A (UniProt: Q4G176). This enzymatic activity is a critical step in mitochondrial fatty acid synthesis (mtFAS), providing the malonyl-CoA necessary for chain elongation within the mitochondria, which is distinct from the more common cytosolic fatty acid synthesis pathway (Witkowski et al., 2014). ACSF3 serves a protective metabolic role by preventing the accumulation of malonate, a potent competitive inhibitor of succinate dehydrogenase in the electron transport chain (Sloan et al., 2011). Mutations in the ACSF3 gene are the primary cause of combined malonic and methylmalonic aciduria (CMAMMA), an autosomal recessive metabolic disorder characterized by elevated levels of these organic acids in body fluids (Alfares et al., 2011). Although no clinical drugs currently target ACSF3, it is a significant focus of research in the context of mitochondrial metabolism, metabolic screening, and the development of therapies for organic acidemias (Levy et al., 2011).

Other names

Malonyl-CoA synthetaseMalonyl-CoA ligaseMethylmalonyl-CoA synthetaseAcyl-CoA synthetase family member 3, mitochondrial

The enzyme catalyzes the conversion of malonate and methylmalonate to malonyl-CoA and methylmalonyl-CoA via an ATP-dependent ligation reaction with Coenzyme A. While no pharmacological drugs currently target this enzyme, its activity is essential for supplying substrates for mitochondrial fatty acid synthesis.