Crystal structure of beta-ketoacyl-acyl carrier protein synthase III - A key condensing enzyme in bacterial fatty acid biosynthesis

beta-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 re port here the crystal structures of FabH determined in the presence and abs ence of acetyl-CoA. These structures display a fold that is common for cond ensing enzymes. The observed acetylation of Cys(112) proves its catalytic r ole and clearly defines the primer binding pocket, Modeling based on a boun d CoA molecule suggests catalytic roles for His(244) and Asn(274), The stru ctures provide the molecular basis for FabH substrate specificity and react ion mechanism and are important for structure-based design of novel antibio tics.