Mycoredoxin‐1 is one of the missing links in the oxidative stress defence mechanism of Mycobacteria |
| |
Authors: | Koen Van Laer Lieven Buts Nicolas Foloppe Didier Vertommen Karolien Van Belle Khadija Wahni Goedele Roos Lennart Nilsson Luis M. Mateos Mamta Rawat Nico A. J. van Nuland Joris Messens |
| |
Affiliation: | 1. Department of Structural Biology, Vlaams Instituut voor Biotechnologie, , Brussels, 1050 Belgium;2. Structural Biology Brussels, Vrije Universiteit Brussel, , Brussels, 1050 Belgium;3. Brussels Center for Redox Biology, , Brussels, 1050 Belgium;4. Department of Biosciences and Nutrition, Karolinska Institutet, , Huddinge, SE‐171 77 Sweden;5. de Duve Institute, Université catholique de Louvain, , Brussels, 1200 Belgium;6. Algemene Chemie, Vrije Universiteit Brussel, , Brussels, 1050 Belgium;7. Department of Molecular Biology, Area of Microbiology, University of León, , León, 24006 Spain;8. Department of Biology, California State University, , Fresno, CA, 93740 USA |
| |
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. |
| |
Keywords: | |
|
|