Acetyl coenzyme A (acetyl-CoA) carboxylases (ACCs) and carnitine acyltransferases have crucial roles in the biosynthesis and the metabolism of fatty acids. In humans and other mammals, the ACC 1 isoform catalyzes the ATP-dependent carboxylation of acetyl-CoA to produce malonyl-CoA, the first and the committed step in the biosynthesis of long-chain fatty acids. At the same time, the malonyl-CoA product from the ACC2 isoform is a crucial regulator of fatty acid oxidation by potently inhibiting the carnitine palmitoyltransferase enzyme (CPT-I). CPT-I and CPT-II enable the transport of long-chain fatty acyl-CoAs from the cytosol into the mitochondria for oxidation. Mice that are deficient for ACC2 have reduced body fat content and body weight despite consuming more food, due to elevated fatty acid oxidation. A covalent inhibitor of CPT-I has proven to be effective in treating diabetes in humans and animals, although the clinical use of this compound is severely limited by its toxicity. An agonist of CPT-I can increase fatty acid oxidation and lower body weight. These results demonstrate that ACCs and CPTs are important targets for the development of therapeutic agents against obesity, diabetes, as well as bacterial infections. In addition, inhibitors of the carboxyltransferase domain of plant ACCs are used commercially as herbicides, confirming the therapeutic relevance of ACC as a drug discovery target. ? ? We have recently determined the crystal structures of mouse carnitine acetyltransferase (CRAT) and the carboxyltransferase domain of yeast ACC. These represent the first structural information on any of these enzymes. The initial results set the stage for detailed structural, biochemical, and biological studies of these crucial enzymes, which will be the focus of this proposed research project. ? ?
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