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Structural Insights into the Mechanism and Inhibition of the β-Hydroxydecanoyl-Acyl Carrier Protein Dehydratase from Pseudomonasaeruginosa

DOI: 10.1016/j.jmb.2012.11.017 DOI Help
PMID: 23174186 PMID Help

Authors: Lucile Moynie (University of St. Andrews) , Stuart M. Leckie (University of St. Andrews) , Stephen A. Mcmahon (University of St. Andrews) , Fraser G. Duthie (University of St. Andrews) , Alessa Koehnke (University of St. Andrews) , James W. Taylor (University of St. Andrews) , Magnus S. Alphey (University of St. Andrews) , Ruth Brenk (University of Dundee) , Andrew D. Smith (University of St. Andrews) , James H. Naismith (University of St. Andrews)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology , VOL 425 (2) , PAGES 365 - 377

State: Published (Approved)
Published: January 2013
Diamond Proposal Number(s): 8268

Open Access Open Access

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.

Journal Keywords: Crystallography; X-Ray; Fatty; Type; Hydro-Lyases; Models; Molecular; Protein; Pseudomonas; Recombinant Proteins

Subject Areas: Biology and Bio-materials, Chemistry

Instruments: I02-Macromolecular Crystallography , I04-1-Macromolecular Crystallography (fixed wavelength)

Other Facilities: ESRF