Chemistry and Redox Biology of Mycothiol

Reyes, Aníbal M.; Pedre, Brandán; Armas, María Inés De; Tossounian, Maria-Armineh; Radí, Rafael; Messens, Joris; Trujillo, Madia

doi:10.1089/ars.2017.7074

Cited by 54 publications

(65 citation statements)

References 160 publications

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“…simple oxidation by molecular O 2 (32,(36)(37)(38) . Its midpoint potential for a thiol is consequently unusually high, being þ0•06 V v. −0•2 to −0•4 V for typical thiols including glutathione (4,(39)(40)(41) and mycothiol (42,43) , and −0•193 V for the also somewhat oxidising thiol cofactor coenzyme M, which is 2-mercaptoethanesulfonate (44) . Its reaction with hydroxyl radicals (OH • ) is virtually instantaneous, while it reacts only more slowly with H 2 O 2 and/or O 2…”

Section: Discovery and Structurementioning

confidence: 99%

The biology of ergothioneine, an antioxidant nutraceutical

et al. 2020

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Ergothioneine (ERG) is an unusual thio-histidine betaine amino acid that has potent antioxidant activities. It is synthesised by a variety of microbes, especially fungi (including in mushroom fruiting bodies) and actinobacteria, but is not synthesised by plants and animals who acquire it via the soil and their diet, respectively. Animals have evolved a highly selective transporter for it, known as solute carrier family 22, member 4 (SLC22A4) in humans, signifying its importance, and ERG may even have the status of a vitamin. ERG accumulates differentially in various tissues, according to their expression of SLC22A4, favouring those such as erythrocytes that may be subject to oxidative stress. Mushroom or ERG consumption seems to provide significant prevention against oxidative stress in a large variety of systems. ERG seems to have strong cytoprotective status, and its concentration is lowered in a number of chronic inflammatory diseases. It has been passed as safe by regulatory agencies, and may have value as a nutraceutical and antioxidant more generally.

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Section: Discovery and Structurementioning

confidence: 99%

The biology of ergothioneine, an antioxidant nutraceutical

et al. 2020

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“…However, it releases σ R when it is inactivated by the oxidation of reactive cysteine thiols. Recently, the redox potential of σ R –RsrA complex was determined to be −193 ± 2.0 mV (Rajasekar et al , ), suggesting that nearly all zinc‐bound RsrA exists in a reduced form in mycothiol redox buffer, whose redox potential is estimated to be −230 mV slightly higher than that of glutathione (−240 mV) (Rajasekar et al , ; Reyes et al , ). When oxidized by treatments with hydrogen peroxide or diamide, or exposed to air in the absence of DTT, multiple disulfide bonds are formed in RsrA that contain seven cysteines (Kang et al , ).…”

Section: Activation Of Sigr System By Oxidizing Rsramentioning

confidence: 99%

SigR, a hub of multilayered regulation of redox and antibiotic stress responses

Park

Lee

Roe

2019

Molecular Microbiology

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Signal-specific activation of alternative sigma factors redirects RNA polymerase to induce transcription of distinct sets of genes conferring protection against the damage the signal and the related stresses incur. In Streptomyces coelicolor, σ R (SigR), a member of ECF12 subfamily of Group IV sigma factors, responds to thiol-perturbing signals such as oxidants and electrophiles, as well as to translation-blocking antibiotics. Oxidants and electrophiles interact with and inactivate the zinc-containing anti-sigma factor, RsrA, via disulfide bond formation or alkylation of reactive cysteines, subsequently releasing σ R for target gene induction. Translation-blocking antibiotics induce the synthesis of σ R , via the WhiB-like transcription factor, WblC/WhiB7. Signal transduction via RsrA produces a dramatic transient response that involves positive feedback to produce more SigR as an unstable isoform σ R � and negative feedbacks to degrade σ R � , and reduce oxidized RsrA that subsequently sequester σ R and σ R � . Antibiotic stress brings about a prolonged response by increasing stable σ R levels. The third negative feedback, which occurs via IF3, lowers the translation efficiency of the sigRp1 transcript that utilizes a non-canonical start codon. σ R is a global regulator that directly activates > 100 transcription units in S. coelicolor, including genes for thiol homeostasis, protein quality control, sulfur metabolism, ribosome modulation and DNA repair. Close homologues in Actinobacteria, such as σ H in Mycobacteria and Corynebacteria, show high conservation of the signal transduction pathways and target genes, thus reflecting the robustness of this type of regulation in response to redox and antibiotic stresses.

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“…One of these mechanisms that is clearly different from the human host is the use of a different low-molecular weight (LMW) defense mechanism. In the human host, the tripeptide GSH (␥-L-glutamyl-L-cysteinylgly-cine) is the main LMW thiol, whereas in M. tuberculosis, mycothiol (MSH; 1-D-myo-inosityl 2-(N-acetylcysteinyl)amido-2deoxy-␣-D-glucopyranoside) is the main LMW thiol involved in detoxification and in maintaining redox homeostasis (8,9). Protein S-mycothiolation, which is a post-translational modification that protects sensitive cysteines from overoxidation, is probably the link between stress resistance and mycothiol (10).…”

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confidence: 99%

The antibacterial prodrug activator Rv2466c is a mycothiol-dependent reductase in the oxidative stress response of Mycobacterium tuberculosis

Rosado

Wahni

Degiacomi

et al. 2017

Journal of Biological Chemistry

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The gene encodes an oxidoreductase enzyme annotated as DsbA. It has a CPWC active-site motif embedded within its thioredoxin fold domain and mediates the activation of the prodrug TP053, a thienopyrimidine derivative that kills both replicating and nonreplicating bacilli. However, its mode of action and actual enzymatic function in have remained enigmatic. In this study, we report that Rv2466c is essential for bacterial survival under HO stress. Further, we discovered that Rv2466c lacks oxidase activity; rather, it receives electrons through the mycothiol/mycothione reductase/NADPH pathway to activate TP053, preferentially via a dithiol-disulfide mechanism. We also found that Rv2466c uses a monothiol-disulfide exchange mechanism to reduce -mycothiolated mixed disulfides and intramolecular disulfides. Genetic, phylogenetic, bioinformatics, structural, and biochemical analyses revealed that Rv2466c is a novel mycothiol-dependent reductase, which represents a mycoredoxin cluster of enzymes within the DsbA family different from the glutaredoxin cluster to which mycoredoxin-1 (Mrx1 or Rv3198A) belongs. To validate this DsbA-mycoredoxin cluster, we also characterized a homologous enzyme of (NCgl2339) and observed that it demycothiolates and reduces a mycothiol arsenate adduct with kinetic properties different from those of Mrx1. In conclusion, our work has uncovered a DsbA-like mycoredoxin that promotes mycobacterial resistance to oxidative stress and reacts with free mycothiol and mycothiolated targets. The characterization of the DsbA-like mycoredoxin cluster reported here now paves the way for correctly classifying similar enzymes from other organisms.

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Chemistry and Redox Biology of Mycothiol

Abstract: 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.

Cited by 54 publications

References 160 publications

The biology of ergothioneine, an antioxidant nutraceutical

The biology of ergothioneine, an antioxidant nutraceutical

SigR, a hub of multilayered regulation of redox and antibiotic stress responses

The antibacterial prodrug activator Rv2466c is a mycothiol-dependent reductase in the oxidative stress response of Mycobacterium tuberculosis

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