Alternative Thiol-Based Redox Systems.

The maintenance of thiol-redox homeostasis is vital to the survival of living organisms. Sulfur-based low-molecular weight compounds and proteins synthesized by cells provide efficient and specific ways to counteract oxidative stress and regulate cellular processes. For these tasks, most organisms share the glutathione and thioredoxin NADPH-dependent redox systems. However, in certain lineages, evolution has taken different paths that led to the emergence of novel cysteine-based low-molecular weight redox cofactors, around which new redox systems evolved. These include the sugar-based cysteinyl derivatives mycothiol and bacillithiol, and ergothioneine (EGT), which are present in different phyla from bacteria. Within Eukarya, some fungi contain EGT, whereas trypanothione is unique to species from the Euglenozoa family. This Forum compiles the state-of-the-art knowledge about these noncanonical redox systems of pathogenic organisms. The functions in physiology and pathogenicity, as well as structural and biochemical specializations that these system components evolved, are thoroughly discussed. Antioxid. Redox Signal. 28, 407-409.

Chemistry and Redox Biology of Mycothiol.

SIGNIFICANCE: 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. CRITICAL ISSUES: 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 DIRECTIONS: 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.