Abstract
Low molecular weight (LMW) thiols function as thiol-redox buffers to maintain the reduced state of the cytoplasm. The best studied LMW thiol is the tripeptide glutathione (GSH) present in all eukaryotes and Gram-negative bacteria. Firmicutes bacteria, including Bacillus and Staphylococcus species utilize the redox buffer bacillithiol (BSH) while Actinomycetes produce the related redox buffer mycothiol (MSH). In eukaryotes, proteins are post-translationally modified to S-glutathionylated proteins under conditions of oxidative stress. S-glutathionylation has emerged as major redox-regulatory mechanism in eukaryotes and protects active site cysteine residues against overoxidation to sulfonic acids. First studies identified S-glutathionylated proteins also in Gram-negative bacteria. Advances in mass spectrometry have further facilitated the identification of protein S-bacillithiolations and S-mycothiolation as BSH- and MSH-mixed protein disulfides formed under oxidative stress in Firmicutes and Actinomycetes, respectively. In Bacillus subtilis, protein S-bacillithiolation controls the activities of the redox-sensing OhrR repressor and the methionine synthase MetE in vivo. In Corynebacterium glutamicum, protein S-mycothiolation was more widespread and affected the functions of the maltodextrin phosphorylase MalP and thiol peroxidase (Tpx). In addition, novel bacilliredoxins (Brx) and mycoredoxins (Mrx1) were shown to function similar to glutaredoxins in the reduction of BSH- and MSH-mixed protein disulfides. Here we review the current knowledge about the functions of the bacterial thiol-redox buffers glutathione, bacillithiol, and mycothiol and the role of protein S-thiolation in redox regulation and thiol protection in model and pathogenic bacteria.
Highlights
The cytoplasm is a reducing environment and protein thiols are maintained in their reduced state by low molecular weight (LMW) thiol-redox buffers and enzymatic thiol-disulfide oxidoreductases, including the thioredoxin and glutaredoxin systems (Fahey, 2013; Van Laer et al, 2013)
Arsenate reacts with MSH to an arseno-(V)-MSH complex that is reduced by Mrx1 releasing As(III) and Mrx1SSM that is recycled by the MSH/Mtr/NADPH electron pathway (Ordonez et al, 2009; Villadangos et al, 2011). It remains to be shown if AhpE is mycothiolated under oxidative stress in M. tuberculosis cells in vivo. These results show that Mrx1 functions as glutaredoxin homolog in C. glutamicum and M. tuberculosis in the reduction of S-mycothiolated peroxiredoxins (Tpx and AhpE), when coupled to the MSH/Mtr/NADPH electron pathway and as electron donor for arsenate reductase in arsenate detoxification
We provide an overview about the biosynthesis pathways and functions of the bacterial redox buffers glutathione, bacillithiol and mycothiol and their regulatory roles for protein S-thiolations
Summary
The cytoplasm is a reducing environment and protein thiols are maintained in their reduced state by low molecular weight (LMW) thiol-redox buffers and enzymatic thiol-disulfide oxidoreductases, including the thioredoxin and glutaredoxin systems (Fahey, 2013; Van Laer et al, 2013). Protein S-glutathionylation has emerged as major redox-regulatory mechanism that controls the activity of redox sensing transcription factors and protects active site Cys residues against irreversible oxidation to sulfonic acids (Dalle-Donne et al, 2009). We confirmed that strong disulfide stress responses are caused by HOCl in different Gram-positive bacteria in vivo and detected mixed protein disulfides with Cys, BSH, and MSH as major oxidation products (Chi et al, 2011, 2013, 2014).
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