Mycoredoxin-1 is one of the missing links in the oxidative stress defence mechanism of Mycobacteria.

TitleMycoredoxin-1 is one of the missing links in the oxidative stress defence mechanism of Mycobacteria.
Publication TypeJournal Article
Year of Publication2012
AuthorsVan Laer, K., L. Buts, N. Foloppe, D. Vertommen, K. Van Belle, K. Wahni, G. Roos, L. Nilsson, L. M. Mateos, M. Rawat, N. A. J. van Nuland, and J. Messens
JournalMol Microbiol
Volume86
Issue4
Pagination787-804
Date Published2012 Nov
Type of Articleredox
ISSN1365-2958
KeywordsCysteine, Disulfides, Gene Deletion, Glycopeptides, Inositol, Magnetic Resonance Spectroscopy, Models, Molecular, Mycobacterium smegmatis, Oxidation-Reduction, Oxidative Stress, Oxidoreductases, Protein Conformation
Abstract

To survive hostile conditions, the bacterial pathogen Mycobacterium tuberculosis produces millimolar concentrations of mycothiol as a redox buffer against oxidative stress. The reductases that couple the reducing power of mycothiol to redox active proteins in the cell are not known. We report a novel mycothiol-dependent reductase (mycoredoxin-1) with a CGYC catalytic motif. With mycoredoxin-1 and mycothiol deletion strains of Mycobacterium smegmatis, we show that mycoredoxin-1 and mycothiol are involved in the protection against oxidative stress. Mycoredoxin-1 acts as an oxidoreductase exclusively linked to the mycothiol electron transfer pathway and it can reduce S-mycothiolated mixed disulphides. Moreover, we solved the solution structures of oxidized and reduced mycoredoxin-1, revealing a thioredoxin fold with a putative mycothiol-binding site. With HSQC snapshots during electron transport, we visualize the reduction of oxidized mycoredoxin-1 as a function of time and find that mycoredoxin-1 gets S-mycothiolated on its N-terminal nucleophilic cysteine. Mycoredoxin-1 has a redox potential of -218 mV and hydrogen bonding with neighbouring residues lowers the pKa of its N-terminal nucleophilic cysteine. Determination of the oxidized and reduced structures of mycoredoxin-1, better understanding of mycothiol-dependent reactions in general, will likely give new insights in how M. tuberculosis survives oxidative stress in human macrophages.

DOI10.1111/mmi.12030
Alternate JournalMol. Microbiol.
PubMed ID22970802
Grant ListGM061223 / GM / NIGMS NIH HHS / United States
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