Acetyl-coenzyme A carboxylase 2 (ACC2)

Acetyl-coenzyme A carboxylase 2 (ACC2) is a biotin-dependent enzyme encoded by the ACACB gene and primarily localized at the mitochondrial membrane in oxidative tissues such as skeletal muscle and heart[3][1][2]. ACC2 catalyzes the carboxylation of acetyl-CoA to malonyl-CoA, a key metabolic intermediate. Unlike ACC1, which is involved in lipogenesis, ACC2-generated malonyl-CoA functions as a potent inhibitor of carnitine palmitoyltransferase 1 (CPT1), thus regulating the flux of fatty acids into mitochondria for β-oxidation[1][2][3][5]. Through this mechanism, ACC2 serves as a key regulator of energy homeostasis—its inhibition increases fatty acid oxidation and has been targeted for potential therapies in obesity, diabetes, and other metabolic diseases[2][5]. Drugs that inhibit ACC2 are under investigation, though the physiological effects in preclinical models are complex; for example, genetic knockout of ACC2 in mice does not always lead to reduced body weight[3]. ACC2 is a validated therapeutic target, but metabolic and safety challenges remain in clinical translation.

Other names

ACC-betaACC2ACACBAcetyl-CoA carboxylase 2

Inhibition of ACC2 decreases malonyl-CoA levels at the mitochondrial membrane, which relieves inhibition of carnitine palmitoyltransferase 1 (CPT1), thereby increasing mitochondrial fatty acid β-oxidation[2][5]. Targeted drugs act as allosteric enzyme inhibitors or bind catalytic domains (biotin carboxylase or carboxyl transferase domains), leading to reduced enzymatic production of malonyl-CoA[1][5].