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Stable Analogues of OSB‐AMP: Potent Inhibitors of MenE, the o ‐Succinylbenzoate‐CoA Synthetase from Bacterial Menaquinone Biosynthesis
Author(s) -
Lu Xuequan,
Zhou Rong,
Sharma Indrajeet,
Li Xiaokai,
Kumar Gyanendra,
Swaminathan Subramanyam,
Tonge Peter J.,
Tan Derek S.
Publication year - 2012
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201100585
Subject(s) - chemistry , stereochemistry , enzyme , active site , biochemistry , moiety , carboxylate , ketone , organic chemistry
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 n M ) and a noncompetitive inhibitor with respect to OSB ( K i =11.2±0.9 n M ). These data are consistent with a Bi Uni Uni Bi Ping‐Pong kinetic mechanism for these enzymes. In addition, OSB‐AMS inhibits saMenE with ${K{{{\rm app}\hfill \atop {\rm i}\hfill}}}$ =22±8 n M and ecMenE with ${K{{{\rm OSB}\hfill \atop {\rm i}\hfill}}}$ =128±5 n M . 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.