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Mechanism and Inhibition of the Dihydroxynaphthoyl‐CoA Synthase MenB from Mycobacterium Tuberculosis
Author(s) -
Liu Nina,
Li Xiaokai,
Tonge Peter J
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.463.11
Subject(s) - active site , mycobacterium tuberculosis , biochemistry , cofactor , enzyme , chemistry , bacteria , atp synthase , biology , stereochemistry , tuberculosis , genetics , medicine , pathology
The lipid soluble redox cofactor menaquinone is an essential component of the respiratory chain in many bacteria including the pathogen Mycobacterium tuberculosis. Enzymes involved in menaquinone biosynthesis are thought to be promising drug targets since the pathway is absent in humans and also because compounds that affect respiration may be active against latent populations of M. tuberculosis. Currently we are comparing the mechanism of the M. tuberculosis MenB (mtMenB) with that from Eschericia coli (ecMenB). MenB, which is a member of the crotonase superfamily, catalyzes an intramolecular Claisen condensation leading to the formation of dihydroxynaphthoyl‐CoA from O‐succinylbenzoyl‐CoA. While most active site residues are conserved between mtMenB and ecMenB, mycobacterial MenBs contain an active site aspartate (D185) which is replaced with glycine in MenBs from other organisms. D185 is structurally homologous to E164, a conserved base in the active site of enoyl‐CoA hydratase, the prototypical member of the crotonase superfamily. Kinetic and structural studies suggest a fundamental difference in the catalytic mechanisms of mtMenB and ecMenB due to the presence or absence of D185. Inhibitor discovery efforts are also in progress both as mechanistic probes and also as leads for the development of potent MenB inhibitors