Selective Persulfide Detection Reveals Evolutionarily Conserved Antiaging Effects of S-Sulfhydration

Živanović, Jasmina; Kouroussis, Emilia; Kohl, Joshua B.; Adhikari, Bikash; Bursać, Biljana; Schott-Roux, Sonia; Petrovic, Dunja; Miljković, Jan Lj.; Thomas‐López, Daniel; Jung, Young-Eun; Miler, Marko; Mitchell, Sarah; Milošević, Verica; Gomes, José‐Eduardo; Benhar, Moran; González‐Zorn, Bruno; Torregrossa, Roberta; Mitchell, James R.; Whiteman, Matthew; Schwarz, Guenter; Snyder, Solomon H.; Paul, Bindu D.; Carroll, Kate S.; Filipović, Miloš R.

doi:10.1016/j.cmet.2019.12.001

Cited by 68 publications

(113 citation statements)

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“…Reactions with thiolates constitute one of the main decay pathways for persulfides in vivo (16,43,44). To our knowledge, the value of k-1,pH (1.11 M -1 s -1 ) is the first report for the rate constant of a reaction between a low molecular weight (LMW) persulfide and a LMW thiolate at physiological pH.…”

Section: Gssh + Gssgmentioning

confidence: 98%

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Acidity and nucleophilic reactivity of glutathione persulfide

Benchoam

Semelak

Cuevasanta

et al. 2020

Journal of Biological Chemistry

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Persulfides (RSSH/RSS-) participate in sulfur trafficking and metabolic processes, and are proposed to mediate the signaling effects of H2S. Despite their growing relevance, their chemical properties are poorly understood. Herein, we studied experimentally and computationally the formation, acidity, and nucleophilicity of glutathione persulfide (GSSH/GSS-), the derivative of the abundant cellular thiol, glutathione (GSH). We characterized the kinetics and equilibrium of GSSH formation from glutathione disulfide and H2S. A pKa of 5.45 for GSSH was determined, which is 3.49 units below that of GSH. The reactions of GSSH with the physiologically-relevant electrophiles peroxynitrite and hydrogen peroxide, as well as with the probe monobromobimane, were studied and compared with those of thiols. These reactions occurred through SN2 mechanisms. At neutral pH, GSSH reacted faster than GSH due to increased availability of the anion and, depending on the electrophile, increased reactivity. In addition, GSS- presented higher nucleophilicity with respect to a thiolate with similar basicity. This can be interpreted in terms of the so-called alpha effect, i.e. the increased reactivity of a nucleophile when the atom adjacent to the nucleophilic atom has high electron density. The magnitude of the alpha effect correlated with the Brønsted nucleophilic factor, βnuc, for the reactions with thiolates and with the ability of the leaving group. Our study constitutes the first determination of the pKa of a biological persulfide and the first examination of the alpha effect in sulfur nucleophiles, and sheds light on the chemical basis of the biological properties of persulfides.

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Section: Gssh + Gssgmentioning

confidence: 98%

“…RSSO2H and RSSO3H) that can be reduced by cellular reductants systems, while analogous oxidation of thiols yields irreversible oxidation products (i.e. RSO2H and RSO3H) (4,16,24,44).…”

Section: Biological Implicationsmentioning

confidence: 99%

Acidity and nucleophilic reactivity of glutathione persulfide

Benchoam

Semelak

Cuevasanta

et al. 2020

Journal of Biological Chemistry

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“…Pathological conditions associated with so-called ''H 2 Spoor'' disease states-and amenable to correction by H 2 S donors-include (243,295) aging, ischemia, cardiac hypertrophy, heart failure (HF), liver disease (cirrhosis, steatosis), hypertension, atherosclerosis, endothelial dysfunction, diabetic complications, preeclampsia, Alzheimer's disease (AD), and Huntington's disease (HD). Further, Szabo and Papapetropoulos rightly point out that not only H 2 S-poor diseases can be corrected by H 2 S supplementation, since ''there are also several indications where endogenous H 2 S levels are not suppressed, and yet H 2 S donation may be beneficial or warranted.''…”

Section: H 2 S-poor Diseases and Other H 2 S-treatable Pathologiesmentioning

confidence: 99%

“…Direct interference of H 2 S on pathways related to aging was identified in all but one of the hallmarks of aging (195), and it is likely that H 2 S exerts antiaging effects by inhibiting formation of advanced glycation end-products (161) as well as by blocking activation of their receptors (292). In fact, H 2 S has been considered ''the next potent preventive and therapeutic agent in ageing and age-associated diseases'' (289), and Zivanovic et al (295) have stated that ''dietary or pharmacological interventions to increase persulfidation associate with increased longevity and improved capacity to cope with stress stimuli. ''…”

Section: H 2 S/ss As Master Cytoprotectorsmentioning

confidence: 99%

SG1002 and Catenated Divalent Organic Sulfur Compounds as Promising Hydrogen Sulfide Prodrugs

Gojon¹,

Morales²

2020

Antioxidants & Redox Signaling

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Significance: Sulfur has a critical role in protein structure/function and redox status/signaling in all living organisms. Although hydrogen sulfide (H 2 S) and sulfane sulfur (SS) are now recognized as central players in physiology and pathophysiology, the full scope and depth of sulfur metabolome's impact on human health and healthy longevity has been vastly underestimated and is only starting to be grasped. Since many pathological conditions have been related to abnormally low levels of H 2 S/SS in blood and/or tissues, and are amenable to treatment by H 2 S supplementation, development of safe and efficacious H 2 S donors deserves to be undertaken with a sense of urgency; these prodrugs also hold the promise of becoming widely used for disease prevention and as antiaging agents. Recent Advances: Supramolecular tuning of the properties of well-known molecules comprising chains of sulfur atoms (diallyl trisulfide [DATS], S 8) was shown to lead to improved donors such as DATS-loaded polymeric nanoparticles and SG1002. Encouraging results in animal models have been obtained with SG1002 in heart failure, atherosclerosis, ischemic damage, and Duchenne muscular dystrophy; with TC-2153 in Alzheimer's disease, schizophrenia, age-related memory decline, fragile X syndrome, and cocaine addiction; and with DATS in brain, colon, gastric, and breast cancer. Critical Issues: Mode-of-action studies on allyl polysulfides, benzyl polysulfides, ajoene, and 12 ringsubstituted organic disulfides and thiosulfonates led several groups of researchers to conclude that the anticancer effect of these compounds is not mediated by H 2 S and is only modulated by reactive oxygen species, and that their central model of action is selective protein S-thiolation. Future Directions: SG1002 is likely to emerge as the H 2 S donor of choice for acquiring knowledge on this gasotransmitter's effects in animal models, on account of its unique ability to efficiently generate H 2 S without byproducts and in a slow and sustained mode that is dose independent and enzyme independent. Efficient tuning of H 2 S donation characteristics of DATS, dibenzyl trisulfide, and other hydrophobic H 2 S prodrugs for both oral and parenteral administration will be achieved not only by conventional structural modification of a lead molecule but also through the new ''supramolecular tuning'' paradigm. Antioxid. Redox Signal. 33, 1010-1045.

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“…Interplay between H 2 O 2 and other signaling molecules, including hydrogen sulfide (H 2 S) and nitric oxide (NO), can generate further oxidants that can facilitate cysteine oxidation (e.g., peroxinitrite) and additional cysteine modifications (e.g., persulfides) and signaling outcomes [ 22 ]. The conversion of sulfenic acid to reversible forms (glutathione adducts, disulfides, persulfides) is thought to safeguard against cysteine overoxidation by H 2 O 2 , and the formation of the (generally) irreversible sulfinic and sulfonic acid (e.g., [ 23 ]).…”

Section: Properties Of H 2 Omentioning

confidence: 99%

Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum

Roscoe

Sevier

2020

Cells

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The endoplasmic reticulum (ER) has emerged as a source of hydrogen peroxide (H2O2) and a hub for peroxide-based signaling events. Here we outline cellular sources of ER-localized peroxide, including sources within and near the ER. Focusing on three ER-localized proteins—the molecular chaperone BiP, the transmembrane stress-sensor IRE1, and the calcium pump SERCA2—we discuss how post-translational modification of protein cysteines by H2O2 can alter ER activities. We review how changed activities for these three proteins upon oxidation can modulate signaling events, and also how cysteine oxidation can serve to limit the cellular damage that is most often associated with elevated peroxide levels.

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Selective Persulfide Detection Reveals Evolutionarily Conserved Antiaging Effects of S-Sulfhydration

Cited by 68 publications

References 0 publications

Acidity and nucleophilic reactivity of glutathione persulfide

Acidity and nucleophilic reactivity of glutathione persulfide

SG1002 and Catenated Divalent Organic Sulfur Compounds as Promising Hydrogen Sulfide Prodrugs

Pathways for Sensing and Responding to Hydrogen Peroxide at the Endoplasmic Reticulum

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