Structural insights into the mechanism and inhibition of the β-hydroxydecanoyl-acyl carrier protein dehydratase from Pseudomonas aeruginosa

J Mol Biol. 2013 Jan 23;425(2):365-77. doi: 10.1016/j.jmb.2012.11.017. Epub 2012 Nov 19.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Crystallography, X-Ray
  • Fatty Acid Synthase, Type II / chemistry*
  • Fatty Acid Synthase, Type II / genetics
  • Fatty Acid Synthase, Type II / metabolism
  • Hydro-Lyases / chemistry*
  • Hydro-Lyases / genetics
  • Hydro-Lyases / metabolism
  • Models, Molecular
  • Protein Conformation
  • Pseudomonas aeruginosa / enzymology*
  • Pseudomonas aeruginosa / metabolism
  • Recombinant Proteins / chemistry*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism

Substances

  • Recombinant Proteins
  • Hydro-Lyases
  • 3-hydroxyacyl-(acyl-carrier-protein) dehydratase
  • Fatty Acid Synthase, Type II