title: Crystal structure of the carboxyltransferase domain of acetyl-coenzyme A carboxylase.
abstract: Acetyl-coenzyme A carboxylases (ACCs) are required for the biosynthesis and oxidation of long-chain fatty acids. They are targets for therapeutics against obesity and diabetes, and several herbicides function by inhibiting their carboxyltransferase (CT) domain. We determined the crystal structure of the free enzyme and the coenzyme A complex of yeast CT at 2.7 angstrom resolution and found that it comprises two domains, both belonging to the crotonase/ClpP superfamily. The active site is at the interface of a dimer. Mutagenesis and kinetic studies reveal the functional roles of conserved residues here. The herbicides target the active site of CT, providing a lead for inhibitor development against human ACCs.
authors.affiliation: Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
authors.forename: Hailong
authors.initials: H
authors.lastname: Zhang
authors.forename: Zhiru
authors.initials: Z
authors.lastname: Yang
authors.forename: Yang
authors.initials: Y
authors.lastname: Shen
authors.forename: Liang
authors.initials: L
authors.lastname: Tong
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D000595:Amino Acid Sequence; D001665:Binding Sites; D001710:Biotin / Q000737:chemistry / Q000378:metabolism; D002384:Catalysis; D003065:Coenzyme A / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D019281:Dimerization; D004791:Enzyme Inhibitors / Q000378:metabolism / Q000494:pharmacology; D006860:Hydrogen Bonding; D007700:Kinetics; D008969:Molecular Sequence Data; D016296:Mutagenesis; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology; D012441:Saccharomyces cerevisiae / Q000201:enzymology*
chemical_list: D004791:Enzyme Inhibitors; D011725:Pyridines; C054176:haloxyfop; D001710:Biotin; D000103:Acetyl-CoA Carboxylase; D003065:Coenzyme A