期刊
BIOCHEMISTRY
卷 49, 期 12, 页码 2672-2679出版社
AMER CHEMICAL SOC
DOI: 10.1021/bi901432d
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资金
- NSERC
- Saskatchewan Health Research Fund Team
MenD is a thiamin diphosphate-dependent enzyme catalyzing the First unique step in menaquinone biosynthesis in bacteria. We have synthesized acylphosphonate ester analogues of alpha-ketoglutarate, a substrate of MenD. These compounds are competitive inhibitors of MenD, with K-i values its low its 700 nM. Observed structure-activity relationships are in notable contrast to those reported previously for succinylphosphonate inhibition of the alpha-ketoglutarate dehydrogenase complex, despite the apparent homology of these enzymes, and the identical decarboxylation reactions catalyzed. Inhibiting menaquinone biosynthesis is it proposed approach to inhibiting Mycobacterium tuberculosis growth. These inhibitors showed no significant. inhibition of M. tuberculosis growth in vitro under aerobic and hypoxic conditions but give new information about the binding characteristics of the MenD active site. Site-directed Mutation of Ser391 to alanine had only it minor effect on catalysis, but even the conservative mutation of Arg395 to lysine had it significant effect on the catalytic processing of isochorismate.
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