Structural Insights into the Mechanism and Inhibition of the [beta]-Hydroxydecanoyl-Acyl Carrier Protein Dehydratase from Pseudomonas aeruginosa

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...

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Bibliographic Details
Published in:Journal of molecular biology 2013-01, Vol.425 (2), p.365-377
Main Authors: 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
Format: Article
Language:English
Subjects:
Acyl carrier protein
Enzymes
Fatty acids
Gram-negative bacteria
Isomerization
Metabolism
Prokaryotes
Pseudomonas aeruginosa
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Summary: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.
ISSN:0022-2836