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Science 28 March 2003:
Vol. 299. no. 5615, pp. 2064 - 2067
DOI: 10.1126/science.1081366
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Reports

Crystal Structure of the Carboxyltransferase Domain of Acetyl-Coenzyme A Carboxylase

Hailong Zhang, Zhiru Yang,* Yang Shen,* Liang Tongdagger

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.

Department of Biological Sciences, Columbia University, New York, NY 10027, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed. E-mail: tong{at}como.bio.columbia.edu

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Science. ISSN 0036-8075 (print), 1095-9203 (online)