title: Chemistry and Redox Biology of Mycothiol.
abstract: Mycothiol (MSH, AcCys-GlcN-Ins) is the main low-molecular weight (LMW) thiol of most Actinomycetes, including the human pathogen Mycobacterium tuberculosis that affects millions of people worldwide. Strains with decreased MSH content show increased susceptibilities to hydroperoxides and electrophilic compounds. In M. tuberculosis, MSH modulates the response to several antituberculosis drugs. Enzymatic routes involving MSH could provide clues for specific drug design. Recent Advances: Physicochemical data argue against a rapid, nonenzymatic reaction of MSH with oxidants, disulfides, or electrophiles. Moreover, exposure of the bacteria to high concentrations of two-electron oxidants resulted in protein mycothiolation. The recently described glutaredoxin-like protein mycoredoxin-1 (Mrx-1) provides a route for catalytic reduction of mycothiolated proteins, protecting critical cysteines from irreversible oxidation. The description of MSH/Mrx-1-dependent activities of peroxidases helped to explain the higher susceptibility to oxidants observed in Actinomycetes lacking MSH. Moreover, the first mycothiol-S-transferase, member of the DinB superfamily of proteins, was described. In Corynebacterium, both the MSH/Mrx-1 and the thioredoxin pathways reduce methionine sulfoxide reductase A. A novel tool for in vivo imaging of the MSH/mycothiol disulfide (MSSM) status allows following changes in the mycothiol redox state during macrophage infection and its relationship with antibiotic sensitivity.
  
  
  
  Redundancy of MSH with other LMW thiols is starting to be unraveled and could help to rationalize the differences in the reported importance of MSH synthesis observed in vitro versus in animal infection models.
  
  
  
  Future work should be directed to establish the structural bases of the specificity of MSH-dependent enzymes, thus facilitating drug developments. Antioxid. Redox Signal. 28, 487-504.
authors.affiliation: 1 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República , Montevideo, Uruguay .|2 Center for Free Radical and Biomedical Research , Universidad de la República, Montevideo, Uruguay .
authors.forename: Aníbal M
authors.initials: AM
authors.lastname: Reyes
authors.affiliation: 3 Center for Structural Biology , VIB, Brussels, Belgium .|4 Brussels Center for Redox Biology , Brussels, Belgium .|5 Structural Biology Brussels, Vrije Universiteit Brussel , Brussels, Belgium .
authors.forename: Brandán
authors.initials: B
authors.lastname: Pedre
authors.affiliation: 1 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República , Montevideo, Uruguay .|2 Center for Free Radical and Biomedical Research , Universidad de la República, Montevideo, Uruguay .
authors.forename: María Inés
authors.initials: MI
authors.lastname: De Armas
authors.affiliation: 3 Center for Structural Biology , VIB, Brussels, Belgium .|4 Brussels Center for Redox Biology , Brussels, Belgium .|5 Structural Biology Brussels, Vrije Universiteit Brussel , Brussels, Belgium .
authors.forename: Maria-Armineh
authors.initials: MA
authors.lastname: Tossounian
authors.affiliation: 1 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República , Montevideo, Uruguay .|2 Center for Free Radical and Biomedical Research , Universidad de la República, Montevideo, Uruguay .
authors.forename: Rafael
authors.initials: R
authors.lastname: Radi
authors.affiliation: 3 Center for Structural Biology , VIB, Brussels, Belgium .|4 Brussels Center for Redox Biology , Brussels, Belgium .|5 Structural Biology Brussels, Vrije Universiteit Brussel , Brussels, Belgium .
authors.forename: Joris
authors.initials: J
authors.lastname: Messens
authors.affiliation: 1 Departamento de Bioquímica, Facultad de Medicina, Universidad de la República , Montevideo, Uruguay .|2 Center for Free Radical and Biomedical Research , Universidad de la República, Montevideo, Uruguay .
authors.forename: Madia
authors.initials: M
authors.lastname: Trujillo
mesh_terms: D003545:Cysteine / Q000737:chemistry* / Q000378:metabolism; D006020:Glycopeptides / Q000737:chemistry* / Q000378:metabolism; D007294:Inositol / Q000737:chemistry* / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000378:metabolism* / Q000472:pathogenicity; D016877:Oxidants / Q000737:chemistry / Q000378:metabolism*; D010084:Oxidation-Reduction; D018384:Oxidative Stress; D010544:Peroxidases / Q000737:chemistry / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000737:chemistry / Q000378:metabolism*
chemical_list: D006020:Glycopeptides; D016877:Oxidants; D013438:Sulfhydryl Compounds; C089265:mycothiol; D007294:Inositol; D010544:Peroxidases; D003545:Cysteine
keywords: Actinomycetes; mycobacteria; mycoredoxin-1; mycothiol; tuberculosis