Mechanism and inhibition of the FabV enoyl-ACP reductase from Burkholderia mallei.

Biochemistry
Hao Lu, Peter J Tonge

Abstract

Enoyl-ACP reductases catalyze the final step in the elongation cycle of the bacterial fatty acid biosynthesis (FAS-II) pathway. At present, four distinct enoyl-ACP reductases have been identified, which are the products of the fabI, fabL, fabK, and fabV genes. The FabV enoyl-ACP reductase is the most recent member of this enzyme class and was originally identified in Vibrio cholerae by Cronan and co-workers [Massengo-Tiasse, R. P., and Cronan, J. E. (2008) Vibrio cholerae FabV defines a new class of enoyl-acyl carrier protein reductase. J. Biol. Chem. 283, 1308-1316]. In this work, a detailed kinetic analysis of the mechanism of the FabV enzyme from Burkholderia mallei (bmFabV) has been undertaken, which reveals that bmFabV catalyzes a sequential bi-bi mechanism with NADH binding first and NAD(+) dissociating last. The enzyme is a member of the short chain dehydrogenase/reductase superfamily in which the catalytic tyrosine (Y235) and lysine (K244) residues are organized in the consensus Tyr-(Xaa)(8)-Lys motif. The role of these active site residues has been investigated using site-directed mutagenesis which has shown that both Y235 and K244 are involved in acid-base chemistry during substrate reduction. Sequence alignment and s...Continue Reading

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Citations

Mar 12, 2011·The Journal of Antimicrobial Chemotherapy·Nina LiuPeter J Tonge
May 29, 2012·Nature Chemical Biology·Jianting ZhengAdrian T Keatinge-Clay
Apr 23, 2014·Drug Metabolism Reviews·Minmin HuangSu Zeng
May 24, 2011·Enzyme Research·Patrícia Soares de Maria de MedeirosLuiz Hildebrando Pereira da Silva
Jun 10, 2011·Expert Opinion on Therapeutic Patents·Xiaoyun LuQidong You
Mar 19, 2013·Progress in Lipid Research·Joshua B Parsons, Charles O Rock
Sep 5, 2020·European Journal of Medicinal Chemistry·Preeti RanaSrinivas Nanduri

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