Thiol Redox and p<i>K</i><sub>a</sub> Properties of Mycothiol, the Predominant Low‐Molecular‐Weight Thiol Cofactor in the Actinomycetes

Sharma, Sunil V.; Laer, Koen Van; Messens, Joris; Hamilton, Chris J.

doi:10.1002/cbic.201600228

Cited by 25 publications

(27 citation statements)

References 33 publications

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“…The decrease in activity observed in the absence of Cys 22 might be due to a higher reactivity of its resolving cysteine sulfur compared with the reactivity of the MSH sulfur. The pK a of the Cys 22 sulfur (8.17) is already lower than the pK a of the MSH sulfur (8.76) (50), and it will most likely even be lowered by hydrogen bonding with the carboxylate of Asp 16 (Fig. 6, B and C).…”

Section: Rv2466c Is a Dsba-like Mycoredoxin That Activates Tp053mentioning

confidence: 96%

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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Section: Rv2466c Is a Dsba-like Mycoredoxin That Activates Tp053mentioning

confidence: 96%

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 mechanism by which sulfoxide synthases mediate oxygen activation and guide the activated Figure 3); proton transfer from an active site tyrosine (Tyr377) to this species facilitates oxidation of the substrate cysteine to a thiyl radical (18) which then attacks the imidazole ring of the second substrate (A, Figure 3). 32,33 Oxygen transfer and deprotonation of this intermediate (19) complete the reaction cycle. This model has been challenged by two independent computational studies.…”

Section: Description Of the Mechanistic And Structural Basis For Ovotmentioning

confidence: 99%

On ovothiol biosynthesis and biological roles: from life in the ocean to therapeutic potential

Castellano

Seebeck

2018

Nat. Prod. Rep.

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Covering: up to 2018Ovothiols are sulfur-containing natural products biosynthesized by marine invertebrates, microalgae, and bacteria. These compounds are characterized by unique chemical properties suggestive of numerous cellular functions. For example, ovothiols may be cytoprotectants against oxidative stress, serve as building blocks of more complex structures and may act as molecular messengers for inter- and intracellular signaling. Detailed understanding of ovothiol physiological role in marine organisms may unearth novel concepts in cellular redox biochemistry and highlight the therapeutic potential of this antioxidant. The recent discovery of ovothiol biosynthetic genes has paved the way for a systematic investigation of ovothiol-modulated cellular processes. In this highlight we review the early research on ovothiol and we discuss key questions that may now be addressed using genome-based approaches. This highlight article provides an overview of recent progress towards elucidating the biosynthesis, function and potential application of ovothiols.

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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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Thiol Redox and pK_a Properties of Mycothiol, the Predominant Low‐Molecular‐Weight Thiol Cofactor in the Actinomycetes

Cited by 25 publications

References 33 publications

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

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

On ovothiol biosynthesis and biological roles: from life in the ocean to therapeutic potential

The biology of ergothioneine, an antioxidant nutraceutical

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Thiol Redox and pKa Properties of Mycothiol, the Predominant Low‐Molecular‐Weight Thiol Cofactor in the Actinomycetes

Cited by 25 publications

References 33 publications

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

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

On ovothiol biosynthesis and biological roles: from life in the ocean to therapeutic potential

The biology of ergothioneine, an antioxidant nutraceutical

Contact Info

Product

Resources

About

Thiol Redox and pK_a Properties of Mycothiol, the Predominant Low‐Molecular‐Weight Thiol Cofactor in the Actinomycetes