Emerging mechanisms of glutathione‐dependent chemistry in biology and disease

Janssen–Heininger, Yvonne M. W.; Nolin, James D.; Hoffman, Sidra M.; Velden, Jos van der; Tully, Jane E.; Lahue, Karolyn G.; Abdalla, Sarah; Chapman, David G.; Reynaert, Niki L.; Vliet, Albert van der; Anathy, Vikas

doi:10.1002/jcb.24551

Cited by 38 publications

(21 citation statements)

References 50 publications

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“…While some proteins form intermolecular disulfide bonds with other thiol oxidoreductases (e.g., thioredoxins), many proteins also undergo reversible redox chemistry with small molecule thiols like GSH [54]. Therefore, we explored whether DVSF could be used to detect GSH conjugates of several proteins that are prone to S -glutathionylation during oxidative stress (Fig.…”

Section: Resultsmentioning

confidence: 99%

Trapping redox partnerships in oxidant-sensitive proteins with a small, thiol-reactive cross-linker

Allan

Loberg

Chepngeno

et al. 2016

Free Radical Biology and Medicine

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A broad range of redox-regulated proteins undergo reversible disulfide bond formation on oxidation-prone cysteine residues. Heightened reactivity of the thiol groups in these cysteines also increases susceptibility to modification by organic electrophiles, a property that can be exploited in the study of redox networks. Here, we explored whether divinyl sulfone (DVSF), a thiol-reactive bifunctional electrophile, cross-links oxidant-sensitive proteins to their putative redox partners in cells. To test this idea, previously identified oxidant targets involved in oxidant defense (namely, peroxiredoxins, methionine sulfoxide reductases, sulfiredoxin, and glutathione peroxidases), metabolism, and proteostasis were monitored for cross-link formation following treatment of Saccharomyces cerevisiae with DVSF. Several proteins screened, including multiple oxidant defense proteins, underwent intermolecular and/or intramolecular cross-linking in response to DVSF. Specific redox-active cysteines within a subset of DVSF targets were found to influence cross-linking; in addition, DVSF-mediated cross-linking of its targets was impaired in cells first exposed to oxidants. Since cross-linking appeared to involve redox-active cysteines in these proteins, we examined whether potential redox partners became cross-linked to them upon DVSF treatment. Specifically, we found that several substrates of thioredoxins were cross-linked to the cytosolic thioredoxin Trx2 in cells treated with DVSF. However, other DVSF targets, like the peroxiredoxin Ahp1, principally formed intra-protein cross-links upon DVSF treatment. Moreover, additional protein targets, including several known to undergo S-glutathionylation, were conjugated via DVSF to glutathione. Our results indicate that DVSF is of potential use as a chemical tool for irreversibly trapping and discovering thiol-based redox partnerships within cells.

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Section: Resultsmentioning

confidence: 99%

Trapping redox partnerships in oxidant-sensitive proteins with a small, thiol-reactive cross-linker

Allan

Loberg

Chepngeno

et al. 2016

Free Radical Biology and Medicine

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“…Methionine is also involved in glutathione formation, which serves as an antioxidant [ 111 ]. Lowered glutathione level is a biomarker of oxidative stress [ 112 ], and may contribute to chronic inflammation and cancer development [ 113 ]. These observations suggest that lowered methionine levels may also play a role in the precipitation of cancer cell proliferation, through the reduction in antioxidant capacity.…”

Section: Discussionmentioning

confidence: 99%

Association between Metabolites and the Risk of Lung Cancer: A Systematic Literature Review and Meta-Analysis of Observational Studies

et al. 2020

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Globally, lung cancer is the most prevalent cancer type. However, screening and early detection is challenging. Previous studies have identified metabolites as promising lung cancer biomarkers. This systematic literature review and meta-analysis aimed to identify metabolites associated with lung cancer risk in observational studies. The literature search was performed in PubMed and EMBASE databases, up to 31 December 2019, for observational studies on the association between metabolites and lung cancer risk. Heterogeneity was assessed using the I2 statistic and Cochran’s Q test. Meta-analyses were performed using either a fixed-effects or random-effects model, depending on study heterogeneity. Fifty-three studies with 297 metabolites were included. Most identified metabolites (252 metabolites) were reported in individual studies. Meta-analyses were conducted on 45 metabolites. Five metabolites (cotinine, creatinine riboside, N-acetylneuraminic acid, proline and r-1,t-2,3,c-4-tetrahydroxy-1,2,3,4-tetrahydrophenanthrene) and five metabolite groups (total 3-hydroxycotinine, total cotinine, total nicotine, total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (sum of concentrations of the metabolite and its glucuronides), and total nicotine equivalent (sum of total 3-hydroxycotinine, total cotinine and total nicotine)) were associated with higher lung cancer risk, while three others (folate, methionine and tryptophan) were associated with lower lung cancer risk. Significant heterogeneity was detected across most studies. These significant metabolites should be further evaluated as potential biomarkers for lung cancer.

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“…The result suggested that Cys 249 is a functionally important S ‐glutathiolation site in C1‐M‐C2. S ‐glutathiolation has been reported to alter protein function by modifying protein‐protein interactions or inducing changes in the structural conformation of a modified protein (53). S ‐glutathiolation at Cys 249 occurs near the phosphorylation sites and is therefore likely to have an impact on protein kinase interaction with cMyBP‐C and subsequent phosphorylation.…”

Section: Discussionmentioning

confidence: 99%

S‐glutathiolation impairs phosphoregulation and function of cardiac myosin‐binding protein C in human heart failure

et al. 2016

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Cardiac myosin-binding protein C (cMyBP-C) regulates actin-myosin interaction and thereby cardiac myocyte contraction and relaxation. This physiologic function is regulated by cMyBP-C phosphorylation. In our study, reduced site-specific cMyBP-C phosphorylation coincided with increased S-glutathiolation in ventricular tissue from patients with dilated or ischemic cardiomyopathy compared to nonfailing donors. We used redox proteomics, to identify constitutive and disease-specific Sglutathiolation sites in cMyBP-C in donor and patient samples, respectively. Among those, a cysteine cluster in the vicinity of the regulatory phosphorylation sites within the myosin S2 interaction domain C1-M-C2 was identified and showed enhanced S-glutathiolation in patients. In vitro S-glutathiolation of recombinant cMyBP-C C1-M-C2 occurred predominantly at Cys 249 , which attenuated phosphorylation by protein kinases. Exposure to glutathione disulfide induced cMyBP-C S-glutathiolation, which functionally decelerated the kinetics of Ca 2+ -activated force development in ventricular myocytes from wild-type, but not those from Mybpc3-targeted knockout mice. These oxidation events abrogate protein kinase-mediated phosphorylation of cMyBP-C and therefore potentially contribute to the reduction of its phosphorylation and the contractile dysfunction observed in human heart

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Emerging mechanisms of glutathione‐dependent chemistry in biology and disease

Cited by 38 publications

References 50 publications

Trapping redox partnerships in oxidant-sensitive proteins with a small, thiol-reactive cross-linker

Trapping redox partnerships in oxidant-sensitive proteins with a small, thiol-reactive cross-linker

Association between Metabolites and the Risk of Lung Cancer: A Systematic Literature Review and Meta-Analysis of Observational Studies

S‐glutathiolation impairs phosphoregulation and function of cardiac myosin‐binding protein C in human heart failure

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