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

Research output: Contribution to journalArticlepeer-review

Author(s)

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

School/Research organisations

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.

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Details

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

    Research areas

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

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