Journal of Biological Chemistry
Volume 274, Issue 51, 17 December 1999, Pages 36465-36471
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PROTEIN CHEMISTRY AND STRUCTURE
Crystal Structure of β-Ketoacyl-Acyl Carrier Protein Synthase III: A KEY CONDENSING ENZYME IN BACTERIAL FATTY ACID BIOSYNTHESIS*

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β-Ketoacyl-acyl carrier protein synthase III (FabH), the most divergent member of the family of condensing enzymes, is a key catalyst in bacterial fatty acid biosynthesis and a promising target for novel antibiotics. We report here the crystal structures of FabH determined in the presence and absence of acetyl-CoA. These structures display a fold that is common for condensing enzymes. The observed acetylation of Cys112 proves its catalytic role and clearly defines the primer binding pocket. Modeling based on a bound CoA molecule suggests catalytic roles for His244 and Asn274. The structures provide the molecular basis for FabH substrate specificity and reaction mechanism and are important for structure-based design of novel antibiotics.

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The atomic coordinates and the structure factors (code 1D9B) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).