Abstract
The success of Mycobacterium tuberculosis (Mtb) as a pathogen depends on the redundant and complex mechanisms it has evolved for resisting nitrosative and oxidative stresses inflicted by host immunity. Improving our understanding of these defense pathways can reveal vulnerable points in Mtb pathogenesis. In this study, we combined genetic, structural, computational, biochemical, and biophysical approaches to identify a novel enzyme class represented by Rv2466c. We show that Rv2466c is a mycothiol-dependent nitroreductase of Mtb and can reduce the nitro group of a novel mycobactericidal compound using mycothiol as a cofactor. In addition to its function as a nitroreductase, Rv2466c confers partial protection to menadione stress.
Keywords:
Mycobacterium tuberculosis; Rv2466c; menadione; mrx-2; mycothiol; nitrofuranylcalanolide; nitroreductase; oxidoreductase.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bacterial Proteins / chemistry
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Bacterial Proteins / metabolism
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Binding Sites
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Cysteine / chemistry
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Cysteine / metabolism*
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Disease Models, Animal
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Enzyme Activation
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Female
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Glycopeptides / chemistry
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Glycopeptides / metabolism*
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Inositol / chemistry
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Inositol / metabolism*
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Mice
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Models, Molecular
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Mutation
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Mycobacterium tuberculosis / classification
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Mycobacterium tuberculosis / drug effects
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Mycobacterium tuberculosis / enzymology*
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Mycobacterium tuberculosis / genetics
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Nitroreductases / chemistry
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Nitroreductases / genetics*
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Nitroreductases / metabolism*
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Oxidation-Reduction
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Oxidative Stress
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Phylogeny
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Protein Binding
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Protein Conformation
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Structure-Activity Relationship
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Tuberculosis / microbiology
Substances
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Bacterial Proteins
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Glycopeptides
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mycothiol
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Inositol
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Nitroreductases
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Cysteine