Acetyl-coenzyme A carboxylases: versatile targets for drug discovery

Abstract

Acetyl‐coenzyme A carboxylases (ACCs) have crucial roles in fatty acid metabolism in humans and most other living organisms. They are attractive targets for drug discovery against a variety of human diseases, including diabetes, obesity, cancer, and microbial infections. In addition, ACCs from grasses are the targets of herbicides that have been in commercial use for more than 20 years. Significant progresses in both basic research and in drug discovery have been made over the past few years in the studies on these enzymes. At the basic research level, the crystal structures of the biotin carboxylase (BC) and the carboxyltransferase (CT) components of ACC have been determined, and the molecular basis for ACC inhibition by small molecules are beginning to be understood. At the drug discovery level, a large number of nanomolar inhibitors of mammalian ACCs have been reported and the extent of their therapeutic potential is being aggressively explored. This review summarizes these new progresses and also offers some prospects in terms of the future directions for the studies on these important enzymes. J. Cell. Biochem. 99: 1476–1488, 2006. © 2006 Wiley‐Liss, Inc.