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

Mol Microbiol. 2012 Nov;86(4):787-804. doi: 10.1111/mmi.12030. Epub 2012 Sep 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cysteine / metabolism*
  • Disulfides / metabolism
  • Gene Deletion
  • Glycopeptides / metabolism*
  • Inositol / metabolism*
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Mycobacterium smegmatis / enzymology*
  • Mycobacterium smegmatis / genetics
  • Mycobacterium smegmatis / metabolism
  • Mycobacterium smegmatis / physiology*
  • Oxidation-Reduction
  • Oxidative Stress*
  • Oxidoreductases / chemistry
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism*
  • Protein Conformation


  • Disulfides
  • Glycopeptides
  • mycothiol
  • Inositol
  • Oxidoreductases
  • Cysteine