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Review
. 2006 Dec 15;99(6):1476-88.
doi: 10.1002/jcb.21077.

Acetyl-coenzyme A carboxylases: versatile targets for drug discovery

Liang Tong  1 , H James Harwood Jr
Affiliations
Review

Acetyl-coenzyme A carboxylases: versatile targets for drug discovery

Liang Tong et al. J Cell Biochem. .

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.

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Figures

Figure 1
Figure 1
Acetyl coenzyme-A carboxylase (ACC) has critical roles in fatty acid metabolism. (A). The ACC-catalyzed biotin carboxylase (BC) and carboxyltransferase (CT) reactions. (B). Distinct roles of ACC1 and ACC2 in fatty acid metabolism. Both ACC1 and ACC2 convert acetyl-CoA, generated from the catabolism of proteins, carbohydrates and fatty acids, into malonyl-CoA. In the liver, which is both oxidative and lipogenic, the malonyl-CoA formed in the cytoplasm through the actions of ACC1 is utilized for formation of fatty acids that can be stored or converted to triglycerides and phospholipids and secreted as triglyceride-rich lipoproteins (e.g. VLDL) for transport to extrahepatic tissues, whereas the malonyl-CoA formed at the mitochondrial surface through the actions of ACC2 acts as an allosteric inhibitor of CPT-I to prevent entry of fatty acids into the mitochondria for oxidation. In the postprandial state, where excess acetyl-CoA formation from dietary sources leads to increases in both ACC1-mediated and ACC2-mediated malonyl-CoA production, simultaneous increases in fatty acid synthesis and reductions in fatty acid oxidation result in a net storage of energy as fat. In the fasted state and during exercise, where acetyl-CoA availability from dietary sources is limited, reductions in both ACC1-mediated and ACC2-mediated malonyl-CoA production lead to simultaneous reductions in fatty acid synthesis and increases in fatty acid oxidation, resulting in a net utilization of stored fat for energy.
Figure 2
Figure 2
Chemical structures of selected ACC inhibitors.
Figure 3
Figure 3
Structures of biotin carboxylase (BC). (A). Structure of yeast BC domain in complex with soraphen A [Shen et al., 2004]. The domains are given different colors. Soraphen A is shown as a stick model in green for carbon atoms, labeled Sor. The expected position of ATP, as observed in the E. coli BC subunit [Thoden et al., 2000], is shown in gray. (B). Dimer of E. coli BC subunit. The dimer axis is indicated with the magenta oval [Thoden et al., 2000]. (C). A model for the mechanism of action of BC. Residues in the dimer interface can assume two states, conformations I and II. Conformation I is compatible with dimerization and catalysis, while conformation II is not. Soraphen A binds and stabilizes this inactive state of the BC domain. (D). Molecular surface of the yeast BC domain in the soraphen A binding site.
Figure 4
Figure 4
Crystal structure of the carboxyltransferase (CT) domain of yeast ACC. (A). Schematic drawing of the structure of yeast CT domain dimer [Zhang et al., 2004a; Zhang et al., 2004b; Zhang et al., 2003]. The N domains of the two monomers are colored in cyan and magenta, and the C domains are colored in yellow and green. The positions of CoA (gray), haloxyfop (black) and CP-640186 (gold) are shown. (B). Molecular surface of the active site region of yeast CT. The CoA and CP-640186 molecules are shown in gray and gold, respectively. (C). Schematic drawing of the interactions between haloxyfop and the yeast CT domain. The side chains from the two monomers are shown in cyan and green, respectively. Leu1705 and Val1967, equivalent to two sites of herbicide resistance mutations, are shown in red. (D). Schematic drawing of the interactions between CP-640186 and the yeast CT domain. The side chains from the two monomers are shown in yellow and magenta, respectively.
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