title: Crystal structure of beta-ketoacyl-acyl carrier protein synthase III. A key condensing enzyme in bacterial fatty acid biosynthesis.
abstract: 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 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 Cys(112) proves its catalytic role and clearly defines the primer binding pocket. Modeling based on a bound CoA molecule suggests catalytic roles for His(244) and Asn(274). The structures provide the molecular basis for FabH substrate specificity and reaction mechanism and are important for structure-based design of novel antibiotics.
authors.affiliation: SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA. xiayang_qiu-1@sbphrd.com
authors.forename: X
authors.initials: X
authors.lastname: Qiu
authors.forename: C A
authors.initials: CA
authors.lastname: Janson
authors.forename: A K
authors.initials: AK
authors.lastname: Konstantinidis
authors.forename: S
authors.initials: S
authors.lastname: Nwagwu
authors.forename: C
authors.initials: C
authors.lastname: Silverman
authors.forename: W W
authors.initials: WW
authors.lastname: Smith
authors.forename: S
authors.initials: S
authors.lastname: Khandekar
authors.forename: J
authors.initials: J
authors.lastname: Lonsdale
authors.forename: S S
authors.initials: SS
authors.lastname: Abdel-Meguid
mesh_terms: D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase / Q000737:chemistry* / Q000378:metabolism; D001426:Bacterial Proteins / Q000737:chemistry* / Q000378:metabolism; D004926:Escherichia coli; D005227:Fatty Acids / Q000378:metabolism; D007527:Isoenzymes / Q000737:chemistry* / Q000378:metabolism; D008969:Molecular Sequence Data; D011487:Protein Conformation; D013379:Substrate Specificity
chemical_list: D001426:Bacterial Proteins; D005227:Fatty Acids; D007527:Isoenzymes; C078182:beta-ketoacyl-acyl carrier protein synthase I; D015099:3-Oxoacyl-(Acyl-Carrier-Protein) Synthase