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Chembiochem. 2012 Jan 2;13(1):129-36. doi: 10.1002/cbic.201100585. Epub 2011 Nov 23.

Stable analogues of OSB-AMP: potent inhibitors of MenE, the o-succinylbenzoate-CoA synthetase from bacterial menaquinone biosynthesis.

Author information

1
Molecular Pharmacology and Chemistry Program and Tri-Institutional Research Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.

Abstract

MenE, the o-succinylbenzoate (OSB)-CoA synthetase from bacterial menaquinone biosynthesis, is a promising new antibacterial target. Sulfonyladenosine analogues of the cognate reaction intermediate, OSB-AMP, have been developed as inhibitors of the MenE enzymes from Mycobacterium tuberculosis (mtMenE), Staphylococcus aureus (saMenE) and Escherichia coli (ecMenE). Both a free carboxylate and a ketone moiety on the OSB side chain are required for potent inhibitory activity. OSB-AMS (4) is a competitive inhibitor of mtMenE with respect to ATP (K(i) =5.4±0.1 nM) and a noncompetitive inhibitor with respect to OSB (K(i) =11.2±0.9 nM). These data are consistent with a Bi Uni Uni Bi Ping-Pong kinetic mechanism for these enzymes. In addition, OSB-AMS inhibits saMenE with K(i)(app) =22±8 nM and ecMenE with K(i)(OSB) =128±5 nM. Putative active-site residues, Arg222, which may interact with the OSB aromatic carboxylate, and Ser302, which may bind the OSB ketone oxygen, have been identified through computational docking of OSB-AMP with the unliganded crystal structure of saMenE. A pH-dependent interconversion of the free keto acid and lactol forms of the inhibitors is also described, along with implications for inhibitor design.

PMID:
22109989
PMCID:
PMC3436903
DOI:
10.1002/cbic.201100585
[Indexed for MEDLINE]
Free PMC Article

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