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 J.; Milošević, Verica; Gomes, José‐Eduardo; Benhar, Moran; González‐Zorn, Bruno; Ivanović‐Burmazović, Ivana; 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.2019.10.007

Cited by 271 publications

(326 citation statements)

References 85 publications

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“…Based on our model of substrate inhibition, we speculate that regulation of MPST by thioredoxin might be important for promoting target persulfidation under oxidizing conditions where it is postulated to serve a protective function (41)(42)(43)(44). Thus, conditions that decrease the concentration of reduced thioredoxin might promote sulfur transfer from MPST to other low molecular weight acceptors or to proteins while also enhancing the overall reaction rate (Fig.…”

Section: Discussionmentioning

confidence: 94%

Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically-relevant concentrations

Yadav

Vitvitsky

Carballal

et al. 2020

Journal of Biological Chemistry

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3-Mercaptopyruvate sulfur transferase (MPST) catalyzesthe desulfuration of 3mercaptopyruvate (3-MP) and transfers sulfane sulfur from an enzyme-bound persulfide intermediate to thiophilic acceptors such as thioredoxin and cysteine. Hydrogen sulfide (H2S), a signaling molecule implicated in many physiological processes, can be released from the persulfide product of the MPST reaction. Two splice variants of MPST, differing by 20 amino acids at the N-terminus, give rise to the cytosolic MPST1 and mitochondrial MPST2 isoforms. Here, we characterized the poorly studied MPST1 variant and demonstrated that substitutions in its Ser-His-Asp triad, proposed to serve a general acid-base role, minimally affect catalytic activity. We estimated the 3-MP concentration in murine liver, kidney and brain tissues, finding that it ranges from 0.4 μmol•kg -1 in brain to 1.4 μmol•kg -1 in kidney. We also show that N-acetylcysteine, a widely used antioxidant, is a poor substrate for MPST and unlikely to function as a thiophilic acceptor. Thioredoxin exhibits substrate inhibition, increasing the KM for 3-MP ~15-fold compared with other sulfur acceptors. Kinetic simulations at physiologically relevant substrate concentrations predicted that the proportion of sulfur transfer to thioredoxin increases ~3.5-fold as its concentration decreases from 10 to 1 µM, while the total MPST reaction 1 H2S: hydrogen sulfide, MPST: mercaptopyruvate sulfur transferase; 3-MP: 3-mercaptopyruvate; rate increases ~7-fold. The simulations also predicted that cysteine is a quantitatively significant sulfane sulfur acceptor, revealing MPST's potential to generate low molecular weight persulfides. We conclude that the MPST1 and 2 isoforms are kinetically indistinguishable and that thioredoxin modulates the MPSTcatalyzed reaction in a physiologically relevant concentration range.

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Section: Discussionmentioning

confidence: 94%

Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically-relevant concentrations

Yadav

Vitvitsky

Carballal

et al. 2020

Journal of Biological Chemistry

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“…Signaling roles of thiol persulfidation have recently begun to emerge. In addition, recent research points to an important role of persulfidation in protecting proteins from irreversible oxidation [27,28]. The target specificity of the various thiol modifications is an important aspect of redox signaling.…”

Section: Reactive Oxygen and Nitrogen Species Antioxidants And Thiomentioning

confidence: 99%

Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Benhar

2020

Antioxidants

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It is well appreciated that biological reactive oxygen and nitrogen species such as hydrogen peroxide, superoxide and nitric oxide, as well as endogenous antioxidant systems, are important modulators of cell survival and death in diverse organisms and cell types. In addition, oxidative stress, nitrosative stress and dysregulated cell death are implicated in a wide variety of pathological conditions, including cancer, cardiovascular and neurological diseases. Therefore, much effort is devoted to elucidate the molecular mechanisms linking oxidant/antioxidant systems and cell death pathways. This review is focused on thiol redox modifications as a major mechanism by which oxidants and antioxidants influence specific regulated cell death pathways in mammalian cells. Growing evidence indicates that redox modifications of cysteine residues in proteins are involved in the regulation of multiple cell death modalities, including apoptosis, necroptosis and pyroptosis. In addition, recent research suggests that thiol redox switches play a role in the crosstalk between apoptotic and necrotic forms of regulated cell death. Thus, thiol-based redox circuits provide an additional layer of control that determines when and how cells die.

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“…3-MST possesses two redox-sensitive molecular switches that act as redox sensors to regulate its activity and catalyze the production of H 2 S, persulfides and polysulfides [37,[39][40][41]. Persulfide formation protects protein thiols groups from irreversible oxidation [42], while hydrogen sulfide has direct and indirect antioxidant effects [43]. Although H 2 S has the potential to scavenge ROS, it is generally assumed to be a weak ROS scavenger [44].…”

Section: Discussionmentioning

confidence: 99%

“…Although H 2 S has the potential to scavenge ROS, it is generally assumed to be a weak ROS scavenger [44]. H 2 S can modify the activity of proteins with important roles in redox homeostasis, including superoxide dismutase 1 (SOD1) and SHC-transforming protein 1 isoform (p66SHC) [42,44,45]. Moreover, H 2 S activates nuclear factor erythroid 2-related factor 2 (NRF2) by sulfhydrating the NRF2 repressor kelch-like ECH-associated protein 1 (KEAP1) [46].…”

Section: Discussionmentioning

confidence: 99%

Generation and Characterization of a CRISPR/Cas9—Induced 3-mst Deficient Zebrafish

et al. 2020

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3-mercaptopyruvate sulfurtransferase (3-MST) is an enzyme capable of synthesizing hydrogen sulfide (H2S) and polysulfides. In spite of its ubiquitous presence in mammalian cells, very few studies have investigated its contribution to homeostasis and disease development, thus the role of 3-MST remains largely unexplored. Here, we present a clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR–associated protein-9 (Cas9) induced 3-mst mutant zebrafish line, which will allow the study of 3-MST’s role in several biological processes. The 3-mst zebrafish orthologue was identified using a bioinformatic approach and verified by its ability to produce H2S in the presence of 3-mercaptopyruvate (3-MP). Its expression pattern was analyzed during zebrafish early development, indicating predominantly an expression in the heart and central nervous system. As expected, no detectable levels of 3-Mst protein were observed in homozygous mutant larvae. In line with this, H2S levels were reduced in 3-mst−/− zebrafish. Although the mutants showed no obvious morphological deficiencies, they exhibited increased lethality under oxidative stress conditions. The elevated levels of reactive oxygen species, detected following 3-mst deletion, are likely to drive this phenotype. In line with the increased ROS, we observed accelerated fin regenerative capacity in 3-mst deficient zebrafish. Overall, we provide evidence for the expression of 3-mst in zebrafish, confirm its important role in redox homeostasis and indicate the enzyme’s possible involvement in the regeneration processes.

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

Cited by 271 publications

References 85 publications

Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically-relevant concentrations

Thioredoxin regulates human mercaptopyruvate sulfurtransferase at physiologically-relevant concentrations

Oxidants, Antioxidants and Thiol Redox Switches in the Control of Regulated Cell Death Pathways

Generation and Characterization of a CRISPR/Cas9—Induced 3-mst Deficient Zebrafish

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