Structural insights into the mechanism and inhibition of the beta-Hydroxydecanoyl-Acyl carrier protein dehydratase from pseudomonas aeruginosa

Lucile Moynie, Stuart M. Leckie, Stephen A. McMahon, Fraser G. Duthie, Alessa Koehnke, James W. Taylor, Magnus S. Alphey, Ruth Brenk, Andrew D. Smith, James H. Naismith*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)
12 Downloads (Pure)

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. (C) 2012 Elsevier Ltd. All rights reserved.

Original languageEnglish
Pages (from-to)365-377
Number of pages13
JournalJournal of Molecular Biology
Volume425
Issue number2
DOIs
Publication statusPublished - 23 Jan 2013

Keywords

  • Design
  • FABZ
  • Isomerase
  • Helicobacter-pylori
  • Antibacterial drug discovery
  • Macromolecular crystallography
  • Fatty-acid biosynthesis
  • Lead discovery
  • Crystal-structure characterization
  • Diffraction data

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