The Acetyl-CoA Carboxylase (ACC) Project

Updated Jan. 2018

Acetyl-CoA carboxylase (ACC) catalyzes the biotin-dependent carboxylation of acetyl-CoA to produce malonyl-CoA. This is the first and the committed step in the biosynthesis of long-chain fatty acids. At the same time, a second isoform of ACC, ACC2, is associated with the mitochondrial membrane and produces malonyl-CoA that regulates fatty acid oxidation by potently inhibiting the carnitine palmitoyltransferases (CPT-Is).

Mice that are deficient in ACC2 have elevated fatty acid oxidation and reduced body fat content and body weight, despite consuming more food. Therefore, inhibitors against ACCs might be efficacious for the treatment of obesity and diabetes (metabolic syndrome).

ACCs are multi-subunit enzymes in prokaryotes, whereas most eukaryotic ACCs are multi-domain enzymes. The biotin carboxylase (BC) domain catalyzes the first step of the reaction: the carboxylation of the biotin prosthetic group that is covalently linked to the biotin carboxyl carrier protein (BCCP) domain. In the second step of the reaction, the carboxyltransferase (CT) domain catalyzes the transfer of the carboxyl group from (carboxy)biotin to acetyl-CoA.

Some commercial herbicides (exemplified by haloxyfop, tepraloxydim, and pinoxaden) kill plants by inhibiting the CT domain of their plastid ACC and thereby shutting down fatty acid biosynthesis. More recently, CP-640186 has been reported by Pfizer as a potent inhibitor of both isoforms of mammalian ACCs. Other potent inhibitors of mammalian ACCs have also been reported, some with significant selectivity between the two isoforms.

Soraphen A, a macrocyclic polyketide natural product, is a nanomolar inhibitor of the BC domain of eukaryotic ACCs, but it has no activity against the bacterial BC subunits.

While structures of the E. coli BC and BCCP subunits had been reported, no structural information was available for the CT domain. The CT domain shares no recognizable amino acid sequence homology to other proteins in the database.

Major findings from this project

Publications from this project

Funding for this project

© copyright 2003-2018, Liang Tong.