Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery

Abstract

Acetyl-coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in most living organisms. Mice deficient in ACC2 have continuous fatty acid oxidation and reduced body fat and body weight, validating this enzyme as a target for drug development against obesity, diabetes and other symptoms of the metabolic syndrome. ACC is a biotin-dependent enzyme and catalyzes the carboxylation of acetyl-CoA to produce malonyl-CoA through its two catalytic activities, biotin carboxylase (BC) and carboxyltransferase (CT). ACC is a multi-subunit enzyme in most prokaryotes, whereas it is a large, multi-domain enzyme in most eukaryotes. The activity of the enzyme can be controlled at the transcriptional level as well as by small molecule modulators and covalent modification. This review will summarize the structural information that is now available for both the BC and CT enzymes, as well as the molecular mechanism of action of potent ACC inhibitors. The current intense research on these enzymes could lead to the development of novel therapies against metabolic syndrome and other diseases.

The cyclic keto-enol insecticide spirotetramat inhibits insect and spider mite acetyl-CoA carboxylases by interfering with the carboxyltransferase partial reaction

“…Furthermore, kinetic analysis showed that haloxyfop inhibited malonyl-CoA binding competitively Tong, 2005).…”

“…In prokaryotes, these half-reactions are performed by distinct protein subunits, whereas eukaryotic ACCs are large, multidomain enzymes with molecular weights of 265 -280 kDa. In humans, two genes code for two ACC isoforms, ACC1 and ACC2, with distinct cellular and tissue-specific localization (Tong, 2005). MalonylCoA produced by the cytosolic ACC1 is mainly used for fatty acid biosynthesis in lipogenic tissues.…”

“…Carboxybiotin transfers the carboxyl group to the acceptor substrate, acetyl-CoA (Tong, 2005;Waldrop et al, 2012).…”

“…Allosteric activation by citrate is also well established, although the precise mechanism of citrate activation is not fully understood. Published data suggest that a polymeric state of up to 10 -20 protomers is induced by citrate (Beaty and Lane, 1982;Tong, 2005) and this supramolecular state is probably essential for full catalytic activity.…”

“…In the pharmaceutical area, ACC has been suggested as a therapeutic target for treatment of obesity and cancer due to its central role in fatty acid metabolism (Tong, 2005;Harwood, 2004). In the agrochemical field, three classes of herbicides inhibit the multi-domain ACC isoform in the plastids of grasses (Poaceae): the aryloxyphenoxypropionic acids (FOPs), the cyclohexanediones (DIMs) and the phenylpyrazoline compound pinoxaden.…”