Mycothiol/Mycoredoxin 1-dependent Reduction of the Peroxiredoxin AhpE from Mycobacterium tuberculosis

Hugo, Martín; Laer, Koen Van; Reyes, Aníbal M.; Vertommen, Didier; Messens, Joris; Radí, Rafael; Trujillo, Madia

doi:10.1074/jbc.m113.510248

Cited by 50 publications

(59 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As expected, the formation of the CgMsrA(C91S,C204S,C213S)-SS-Mrx1(C15S) mixed disulfide was not observed (Fig. 8E, lane 3), suggesting that the cysteine in Mrx1(C15S) reacted with the sulfur atom of MSH in CgMsrA(C91S,C204S,C213S)-SSM, yielding reduced CgMsrA (C91S,C204S,C213S) and Mrx1(C15S)-SSM through a monothiol mechanism of reduction, in line with the result of Hugo et al reported for Mycobacterium tuberculosis AphE (52). Thus, CgMsrA could be reduced through the Mrx1/MSH/Mtr pathway via a 1-Cys mechanism upon oxidative stress, with its Cys56, in this case, first becoming the sulfenic acid form and then being S-mycothiolated.…”

Section: Figsupporting

confidence: 75%

“…8D). Interestingly, the mycothiolation/demycothiolation regeneration mechanism mediated by Mrx1 has also been reported for M. tuberculosis AhpE regeneration recently (52). Thus, besides protecting metabolic enzymes, such as methionine synthase (MetE) and maltodextrin phosphorylase (MalP), mycothiolation appears to play a role in regeneration of antioxidative enzymes, such as MsrA and AhpE, under oxidative stresses (36,52).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Corynebacterium glutamicum Methionine Sulfoxide Reductase A Uses both Mycoredoxin and Thioredoxin for Regeneration and Oxidative Stress Resistance

Zhang

Chaudhry

et al. 2015

Appl Environ Microbiol

View full text Add to dashboard Cite

A erobic metabolism and oxidative stress lead to the production and accumulation of reactive oxygen species (ROS). ROS induce oxidative damage to macromolecules, such as proteins, lipids, and DNA, ultimately inducing cell death and disease. In proteins, oxidation modification occurs mainly at the sulfur-containing amino acids, such as cysteine (Cys) and methionine (Met) (1). Oxidation of methionine leads to the formation of the R and S diastereomers of methionine sulfoxide (MetO) and results in either conformational change or loss of function of proteins (2). However, this oxidation can be reversed by the action of methionine sulfoxide reductase (Msr), a ubiquitous monomeric enzyme that reduces both free and protein-bound MetO by employing sulfenic acid chemistry (3). Two structurally unrelated classes of Msrs, MsrAs and MsrBs, reduce the S and R MetO diastereoisomers, respectively. MsrA has been implicated in physiological processes, such as protection of cells against oxidative damage and extension of the life span, and acts as a virulence factor in some bacterial pathogens (4-6).MsrAs can be classified into three groups, 3-Cys, 2-Cys, and 1-Cys MsrAs, according to the number of redox-active Cys residues. Three-Cys MsrAs, such as the Escherichia coli and Bos taurus enzymes, have three Cys residues involved in catalysis, one of which functions as a catalytic residue and the other two as resolving residues (7,8). Two-Cys MsrAs, such as the Saccharomyces cerevisiae and Streptococcus pneumoniae enzymes, possess a single resolving Cys in addition to the catalytic Cys (4, 9). The 3-Cys and 2-Cys MsrAs present similar catalytic mechanisms. First, the catalytic Cys residue attacks a sulfoxide moiety of the substrate and then forms a sulfenic acid intermediate, with a concomitant release of Met as a product. Second, the sulfenic acid of the catalytic Cys forms an intramolecular disulfide bond with a resolving Cys. For 2-Cys MsrAs, this disulfide bond is directly reduced by a reducing agent to regenerate the active form of the enzyme, such as thioredoxin (Trx), which is a natural reducing agent for Msrs. For 3-Cys MsrAs, which perform an extra thiol-disulfide exchange reaction, the first disulfide bond is further reduced by the second

show abstract

Section: Figsupporting

confidence: 75%

Section: Discussionmentioning

confidence: 99%

Corynebacterium glutamicum Methionine Sulfoxide Reductase A Uses both Mycoredoxin and Thioredoxin for Regeneration and Oxidative Stress Resistance

Zhang

Chaudhry

et al. 2015

Appl Environ Microbiol

View full text Add to dashboard Cite

show abstract

“…The ability of Mrx1 to couple the reducing power of mycothiol to reduce oxidized cellular proteins was recently demonstrated in AhpE of M . tb 55 . It is conceivable that Mrx-1 may use mycothiol as a cofactor and reduce WhiB4.…”

Section: Resultsmentioning

confidence: 99%

WhiB4 Regulates the PE/PPE Gene Family and is Essential for Virulence of Mycobacterium marinum

Xiang

et al. 2017

Sci Rep

View full text Add to dashboard Cite

During the course of infection, pathogenic mycobacteria including Mycobacterium tuberculosis (M. tb) encounter host environments of variable oxygen tension, ranging from the hypoxic center of granulomas to the most oxygenated region in the lung cavities. Mycobacterial responses to changes of oxygen tension are critically related to infection outcomes, such as latency and reactivation. WhiB4 is an iron-sulfur containing transcription factor that is highly sensitive to oxygen exposure. In this study, we found that WhiB4 of Mycobacterium marinum (M. marinum), a pathogenic mycobacterial species that is closely related to M. tb, is required for its virulence. M. marinum ΔwhiB4 exhibited defective intracellular replication in macrophages and diminished virulence in zebrafish. Histology analysis revealed that the host had successfully controlled ΔwhiB4 bacteria, forming well-organized granulomas. RNA-seq analysis identified a large number of pe/ppe genes that were regulated by WhiB4, which provides an explanation for the essential role of WhiB4 in M. marinum virulence. Several antioxidant enzymes were also upregulated in ΔwhiB4, supporting its role in modulation of oxidative stress response. Taken together, we have provided new insight into and proposed a model to explain the physiological role of WhiB4.

show abstract

“…The Mrx1/Mtr/MSH pathway is also involved in reduction of the peroxiredoxin AhpE in M . tuberculosis 14 .…”

Section: Introductionmentioning

confidence: 99%

Monitoring global protein thiol-oxidation and protein S-mycothiolation in Mycobacterium smegmatis under hypochlorite stress

Hillion

Bernhardt

Busche

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Mycothiol (MSH) is the major low molecular weight (LMW) thiol in Actinomycetes. Here, we used shotgun proteomics, OxICAT and RNA-seq transcriptomics to analyse protein S-mycothiolation, reversible thiol-oxidations and their impact on gene expression in Mycobacterium smegmatis under hypochlorite stress. In total, 58 S-mycothiolated proteins were identified under NaOCl stress that are involved in energy metabolism, fatty acid and mycolic acid biosynthesis, protein translation, redox regulation and detoxification. Protein S-mycothiolation was accompanied by MSH depletion in the thiol-metabolome. Quantification of the redox state of 1098 Cys residues using OxICAT revealed that 381 Cys residues (33.6%) showed >10% increased oxidations under NaOCl stress, which overlapped with 40 S-mycothiolated Cys-peptides. The absence of MSH resulted in a higher basal oxidation level of 338 Cys residues (41.1%). The RseA and RshA anti-sigma factors and the Zur and NrdR repressors were identified as NaOCl-sensitive proteins and their oxidation resulted in an up-regulation of the SigH, SigE, Zur and NrdR regulons in the RNA-seq transcriptome. In conclusion, we show here that NaOCl stress causes widespread thiol-oxidation including protein S-mycothiolation resulting in induction of antioxidant defense mechanisms in M. smegmatis. Our results further reveal that MSH is important to maintain the reduced state of protein thiols.

show abstract

Mycothiol/Mycoredoxin 1-dependent Reduction of the Peroxiredoxin AhpE from Mycobacterium tuberculosis

Cited by 50 publications

References 46 publications

Corynebacterium glutamicum Methionine Sulfoxide Reductase A Uses both Mycoredoxin and Thioredoxin for Regeneration and Oxidative Stress Resistance

Corynebacterium glutamicum Methionine Sulfoxide Reductase A Uses both Mycoredoxin and Thioredoxin for Regeneration and Oxidative Stress Resistance

WhiB4 Regulates the PE/PPE Gene Family and is Essential for Virulence of Mycobacterium marinum

Monitoring global protein thiol-oxidation and protein S-mycothiolation in Mycobacterium smegmatis under hypochlorite stress

Contact Info

Product

Resources

About