title: Structural insights into the mechanism and inhibition of the β-hydroxydecanoyl-acyl carrier protein dehydratase from Pseudomonas aeruginosa.
abstract: Fatty acid biosynthesis is an essential component of metabolism in both eukaryotes and prokaryotes. The fatty acid biosynthetic pathway of Gram-negative bacteria is an established therapeutic target. Two homologous enzymes FabA and FabZ catalyze a key step in fatty acid biosynthesis; both dehydrate hydroxyacyl fatty acids that are coupled via a phosphopantetheine to an acyl carrier protein (ACP). The resulting trans-2-enoyl-ACP is further polymerized in a processive manner. FabA, however, carries out a second reaction involving isomerization of trans-2-enoyl fatty acid to cis-3-enoyl fatty acid. We have solved the structure of Pseudomonas aeruginosa FabA with a substrate allowing detailed molecular insight into the interactions of the active site. This has allowed a detailed examination of the factors governing the second catalytic step. We have also determined the structure of FabA in complex with small molecules (so-called fragments). These small molecules occupy distinct regions of the active site and form the basis for a rational inhibitor design program.
authors.affiliation: Biomedical Sciences Research Complex, The University, St. Andrews KY16 9ST, UK.
authors.forename: Lucile
authors.initials: L
authors.lastname: Moynié
authors.forename: Stuart M
authors.initials: SM
authors.lastname: Leckie
authors.forename: Stephen A
authors.initials: SA
authors.lastname: McMahon
authors.forename: Fraser G
authors.initials: FG
authors.lastname: Duthie
authors.forename: Alessa
authors.initials: A
authors.lastname: Koehnke
authors.forename: James W
authors.initials: JW
authors.lastname: Taylor
authors.forename: Magnus S
authors.initials: MS
authors.lastname: Alphey
authors.forename: Ruth
authors.initials: R
authors.lastname: Brenk
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Smith
authors.forename: James H
authors.initials: JH
authors.lastname: Naismith
mesh_terms: D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054889:Fatty Acid Synthase, Type II / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D006836:Hydro-Lyases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D008958:Models, Molecular; D011487:Protein Conformation; D011550:Pseudomonas aeruginosa / Q000201:enzymology* / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D011994:Recombinant Proteins; D006836:Hydro-Lyases; C047118:3-hydroxyacyl-(acyl-carrier-protein) dehydratase; D054889:Fatty Acid Synthase, Type II