Highlighted mechanistic aspects in the chemical biology of reactive sulfur species

Schwarz, Günter

doi:10.1111/bph.14551

Cited by 3 publications

(4 citation statements)

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“…In particular, the production of GSH from l -cysteine is driven by γ -glutamylcysteine synthetase (γ-GCS) and glutathione synthase (GS) enzymes; while l -taurine is produced by the subsequential action of other three enzymes named cysteine dioxygenase (CDO), cysteine sulfonic acid decarboxylase (CSAD) and hypotaurine dehydrogenase (HDD) ( Fig. 1 ) [ 10 , 16 , 17 ]. In addition to its essential role in protein synthesis, l -cysteine is also a component of the major antioxidant GSH and a potent antioxidant itself.…”

Section: Introductionmentioning

confidence: 99%

Duchenne's muscular dystrophy involves a defective transsulfuration pathway activity

et al. 2021

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Duchenne muscular dystrophy (DMD) is the most frequent X chromosome-linked disease caused by mutations in the gene encoding for dystrophin, leading to progressive and unstoppable degeneration of skeletal muscle tissues. Despite recent advances in the understanding of the molecular processes involved in the pathogenesis of DMD, there is still no cure. In this study, we aim at investigating the potential involvement of the transsulfuration pathway (TSP), and its by-end product namely hydrogen sulfide (H 2 S), in primary human myoblasts isolated from DMD donors and skeletal muscles of dystrophic ( mdx ) mice. In myoblasts of DMD donors, we demonstrate that the expression of key genes regulating the H 2 S production and TSP activity, including cystathionine γ lyase (CSE), cystathionine beta-synthase (CBS), 3 mercaptopyruvate sulfurtransferase (3-MST), cysteine dioxygenase (CDO), cysteine sulfonic acid decarboxylase (CSAD), glutathione synthase (GS) and γ -glutamylcysteine synthetase (γ-GCS) is reduced. Starting from these findings, using Nuclear Magnetic Resonance (NMR) and quantitative Polymerase Chain Reaction (qPCR) we show that the levels of TSP-related metabolites such as methionine, glycine, glutathione, glutamate and taurine, as well as the expression levels of the aforementioned TSP related genes, are significantly reduced in skeletal muscles of mdx mice compared to healthy controls, at both an early (7 weeks) and overt (17 weeks) stage of the disease. Importantly, the treatment with sodium hydrosulfide (NaHS), a commonly used H 2 S donor, fully recovers the impaired locomotor activity in both 7 and 17 old mdx mice. This is an effect attributable to the reduced expression of pro-inflammatory markers and restoration of autophagy in skeletal muscle tissues. In conclusion, our study uncovers a defective TSP pathway activity in DMD and highlights the role of H 2 S-donors for novel and safe adjuvant therapy to treat symptoms of DMD.

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Section: Introductionmentioning

confidence: 99%

Duchenne's muscular dystrophy involves a defective transsulfuration pathway activity

et al. 2021

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“…40 The emerging role of persulfide species as possible mediators of H 2 S signaling, as well as their biochemistry, continues to be uncovered. 5,35,41,42 With the ability to deliver both H 2 S and endogenous persulfide species, organic polysulfide compounds are attractive for biomedical investigation. Previously, we have shown the ability to introduce benzoyl-protected perthiyl (C 6 H 5 CO− SS−) moieties into polymer chains, 43,44 which can react with Lcysteine to generate polymeric persulfide groups and ultimately liberate H 2 S. Inspired by the properties of the naturally occurring polysulfide H 2 S donor DATS, we have developed mPEG conjugates comprising a trisulfide bridge.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Along with nitric oxide and carbon monoxide, hydrogen sulfide (H 2 S) is the third, and most recently discovered, gasotransmitter. − As a lipophilic molecule, H 2 S can pass freely through biological membranes to exert modulatory control over cellular functions and signaling processes and is closely involved with the mode of action of associated sulfur compounds. , The biological benefits of H 2 S and the inherently low level of H 2 S found in certain pathologies have motivated the development of H 2 S-donating compounds as potential therapeutic entities, ,, with a range of donor-conjugated drugs tested in preclinical and clinical trials . However, while most of the published donors show poor water solubility, inorganic salts with high dissolution rates are unlikely to mimic continuous and controlled biosynthesis due to their immediate release .…”

Section: Introductionmentioning

confidence: 99%

“…Further, considered “hyperactivated thiols”, biological persulfides serve as superior antioxidants, being more efficient scavengers of ROS and cellular electrophiles than thiols. , Possible mechanisms include high reactivity of persulfide toward oxidants and electrophiles and the formation of a perthiyl radical, which is readily passivated by radical recombination . The emerging role of persulfide species as possible mediators of H 2 S signaling, as well as their biochemistry, continues to be uncovered. ,,, …”

Section: Introductionmentioning

confidence: 99%

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Trisulfide-Bearing PEG Brush Polymers Donate Hydrogen Sulfide and Ameliorate Cellular Oxidative Stress

et al. 2020

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A potential approach to combat cellular dysfunction is to manipulate cell communication and signaling pathways to restore physiological functions while protecting unaffected cells. For instance, delivering the signaling molecule H 2 S to certain cells has been shown to restore cell viability and re-normalize cell behavior. We have previously demonstrated the ability to incorporate a trisulfide-based H 2 S-donating moiety into linear polymers with good in vitro releasing profiles and demonstrated their potential for ameliorating oxidative stress. Herein, we report two novel series of brush polymers decorated with higher numbers of H 2 S-releasing segments. These materials contain two trisulfide-based monomers co-polymerized with oligo(ethylene glycol methyl ether methacrylate) via reversible addition−fragmentation chain-transfer polymerization. The macromolecules were characterized to have a range of trisulfide densities with similar, well-defined molecular weight distribution, good H 2 S-releasing profiles, and high cellular tolerance. Using an amperometric technique, the H 2 S liberated and total sulfide release were found to depend on concentrations and chemical nature of triggering molecules (glutathione and cysteine) and, importantly, the position of reactive groups within the brush structure. Notably, when introduced to cells at well-tolerated doses, two macromolecular donors which have the same proportion as of the H 2 S-donating monomer (30%) but differ in releasing moiety location show similar cellular H 2 Sreleasing kinetics. These donors can restore reactive oxygen species levels to baseline values, when polymer pretreated cells are exposed to exogenous oxidants (H 2 O 2 ). Our work opens up a new aspect in preparing H 2 S macromolecule donors and their application to arresting cellular oxidative cascades.

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The Effects of Antioxidant Nutraceuticals on Cellular Sulfur Metabolism and Signaling

Olson

Derry

Kent

et al. 2023

Antioxidants & Redox Signaling

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Highlighted mechanistic aspects in the chemical biology of reactive sulfur species

Abstract: Linked Articles This article is part of a themed section on Chemical Biology of Reactive Sulfur Species. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.4/issuetoc

Cited by 3 publications

References 13 publications

Duchenne's muscular dystrophy involves a defective transsulfuration pathway activity

Duchenne's muscular dystrophy involves a defective transsulfuration pathway activity

Trisulfide-Bearing PEG Brush Polymers Donate Hydrogen Sulfide and Ameliorate Cellular Oxidative Stress

The Effects of Antioxidant Nutraceuticals on Cellular Sulfur Metabolism and Signaling

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