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

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MoynieJMolBiol425_2Structural.pdf (1.460Mb)
Date
23/01/2013
Author
Moynie, Lucile
Leckie, Stuart M.
McMahon, Stephen A.
Duthie, Fraser G.
Koehnke, Alessa
Taylor, James W.
Alphey, Magnus S.
Brenk, Ruth
Smith, Andrew D.
Naismith, James H.
Funder
European Commission
Grant ID
HEALTH-F3-2008-223461
Keywords
Design
FABZ
Isomerase
Helicobacter-pylori
Antibacterial drug discovery
Macromolecular crystallography
Fatty-acid biosynthesis
Lead discovery
Crystal-structure characterization
Diffraction data
QH301 Biology
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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.
Citation
Moynie , L , Leckie , S M , McMahon , S A , Duthie , F G , Koehnke , A , Taylor , J W , Alphey , M S , Brenk , R , Smith , A D & Naismith , J H 2013 , ' Structural insights into the mechanism and inhibition of the beta-Hydroxydecanoyl-Acyl carrier protein dehydratase from pseudomonas aeruginosa ' , Journal of Molecular Biology , vol. 425 , no. 2 , pp. 365-377 . https://doi.org/10.1016/j.jmb.2012.11.017
Publication
Journal of Molecular Biology
Status
Peer reviewed
DOI
https://doi.org/10.1016/j.jmb.2012.11.017
ISSN
0022-2836
Type
Journal article
Rights
(c) The authors. This is an open access article, available from http://www.sciencedirect.com
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  • University of St Andrews Research
URI
http://hdl.handle.net/10023/3510

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