Acetyl-coenzyme A carboxylase: crucial metabolic enzyme and attractive target for drug discovery.
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.
Tong
L
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Department of Biological Sciences, Columbia University, New York, New York 10027, USA. tong@como.bio.columbia.edu
D000103:Acetyl-CoA Carboxylase / Q000737:chemistry / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002384:Catalysis; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000201:enzymology; D015195:Drug Design; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000378:metabolism*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009765:Obesity / Q000188:drug therapy / Q000201:enzymology; D011485:Protein Binding; D011487:Protein Conformation; D013379:Substrate Specificity
D007527:Isoenzymes; D000103:Acetyl-CoA Carboxylase