Acetyl-CoA Carboxylase

Acetyl-CoA carboxylase (ACC) is a biotin carboxylase that catalyzes the ATP-dependent condensation of acetyl-CoA and carbonate to form malonyl-CoA. The malonyl-CoA produced by ACC serves two major physiologic functions. It is an essential and rate-limiting substrate for de novo lipogenesis (DNL), and it acts as an allosteric inhibitor of the enzyme carnitine-palmitoyl transferase I (CPT-1). Acetyl-CoA carboxylase (ACC) inhibitors offer significant potential for the treatment of type 2 diabetes mellitus (T2DM), hepatic steatosis, and cancer.

Acetyl-CoA carboxylase (ACC) in mammals is encoded by two related enzymes ACC1 and ACC2, which catalyze the ATP dependent carboxylation of acetyl-CoA to form malonyl-CoA. ACC1 encodes a cytoplasmic isoform that is thought to be the predominant isoform controlling FASyn, whereas ACC2 is tethered to the mitochondrial outer membrane, where localized malonyl-CoA production blocks CPT-1 function to prevent fatty acids from entering the mitochondria to undergo fatty acid oxidation (FAOxn).