// Workers AI · dad joke modeWhat did persulfidation say? "I'm sulfide-ing with laughter
Persulfidation (referred to in older literature as sulfhydration) is a type of post-translational modification of proteins involving addition of a sulfur molecule onto a reactive thiol (-SH) group of a cysteine residue, forming a species known as a hydropersulfide (-SSH).[1] Persulfidation occurs in plants,[2] animals,[3] and throughout all kingdoms.[4] It is a redox mechanism that regulates diverse biological processes in hydrogen sulfide (H2S) signaling by regulating protein functions and/or subcellular localizations.[5][6] Protein persulfidation is thought to be major mechanism by which H2S acts as an antioxidant, in addition to the bioorganic chemistry of persulfides themselves.
Hydropersulfides are unstable and react readily with thiols, making identification and quantification difficult.[7] Typical chemistry for detecting protein persulfidation takes advantage of the nucleophilicity of the persulfide anion, which is the major protonation state at physiological pH: alkylating agents such as iodoacetamide derivatives and N-ethylmaleimide have traditionally been used to trap persulfides as disulfides for analysis. However, disulfides β to olefins and carbonyl groups, which may be formed by these trapping reagents, are also susceptible to elemental sulfur extrusion to form thioethers.[8][9]
Selective detection of persulfides on proteins may be accomplished using a "tag-switch" protocol:[4]
HS-Protein-S-S– + 2 Tag1 → Tag1-S-Protein-S-S-Tag1
Tag1-S-Protein-S-S-Tag-1 + Tag2 → Tag1-S-Protein-S-Tag2 + Tag1-S–
All of the nucleophilic cysteine modifications (cysteine, cysteine sulfenate, cysteine persulfide) are functionalized with an electrophilic "tag" (Tag1) while disulfides and higher oxidation states such as sulfinate and sulfonate are not modified. Only the reaction of a persulfide with an alkylating agent produces an electrophilic species (a disulfide), which can react with a weak nucleophile conjugated to a second tag (Tag2) to "switch" the tag on the trapped persulfide.
This modification can be reversed back into a thiol by exogenous chemical reducing agents such as dithiothreitol (DTT) or TCEP, biological reducing agents such as glutathione, and proteins such as thioredoxin or glutaredoxin.[10][11]
References
[edit]- ↑ M.R. Filipovic, Persulfidation (S-sulfhydration) and H2S. Handbook of experimental pharmacology 230 (2015) 29-59
- ↑ A. Aroca, A. Serna, C. Gotor, and L. Romero, C., S-sulfhydration: a cysteine posttranslational modification in plant systems. Plant Physiology 168 (2015) 334-342
- ↑ .K. Mustafa, M.M. Gadalla, N. Sen, S. Kim, W. Mu, S.K. Gazi, R.K. Barrow, G. Yang, R. Wang, and S.H. Snyder, H2S Signals Through Protein S-Sulfhydration. Sci. Signal. 2 (2009) ra72
- 1 2 Zivanovic J, Kouroussis E, Kohl JB, Adhikari B, Bursac B, Schott-Roux S, Petrovic D, Miljkovic JL, Thomas-Lopez D, Jung Y, Miler M, Mitchell S, Milosevic V, Gomes JE, Benhar M, Gonzalez-Zorn B, Ivanovic-Burmazovic I, Torregrossa R, Mitchell JR, Whiteman M, Schwarz G, Snyder SH, Paul BD, Carroll KS, Filipovic MR. Selective Persulfide Detection Reveals Evolutionarily Conserved Antiaging Effects of S-Sulfhydration. Cell Metab. 30(6), 1152-1170 (2019)
- ↑ A. Aroca, C. Gotor, and L.C. Romero, Hydrogen Sulfide Signaling in Plants: Emerging Roles of Protein Persulfidation. Frontiers in plant science 9 (2018)
- ↑ Filipovic MR, Zivanovic J, Alvarez B, Banerjee R. Chemical Biology of H(2)S Signaling through Persulfidation. Chem Rev. 118(3), 1253-1337 (2018)
- ↑ Yang, Chun-tao; Devarie-Baez, Nelmi O.; Hamsath, Akil; Fu, Xiao-Dong; Xian, Ming (2020). "S-Persulfidation: Chemistry, Chemical Biology, and Significance in Health and Disease". Antioxidants & Redox Signaling. 33 (15): 1092–1114. doi:10.1089/ars.2019.7889. PMC 7583347. PMID 31547682.
- ↑ Bogdándi, Virág; Ida, Tomoaki; Sutton, Thomas R; Bianco, Christopher; Ditrói, Tamás; Koster, Grielof; Henthorn, Hillary A; Minnion, Magda; Toscano, John P; van der Vliet, Albert; Pluth, Michael D; Feelisch, Martin; Fukuto, Jon M; Akaike, Takaaki; Nagy, Péter (2019). "Speciation of reactive sulfur species and their reactions with alkylating agents: do we have any clue about what is present inside the cell?". British Journal of Pharmacology. 176 (4): 646–670. doi:10.1111/bph.14394. ISSN 1476-5381. PMC 6346080. PMID 29909607.
- ↑ Schilling, Danny; Barayeu, Uladzimir; Steimbach, Raphael R.; Talwar, Deepti; Miller, Aubry K.; Dick, Tobias P. (2022). "Commonly Used Alkylating Agents Limit Persulfide Detection by Converting Protein Persulfides into Thioethers". Angewandte Chemie International Edition. 61 (30) e202203684. doi:10.1002/anie.202203684. ISSN 1521-3773. PMC 9401046. PMID 35506673.
- ↑ Wedmann R, Onderka C, Wei S, Szijártó IA, Miljkovic JL, Mitrovic A, Lange M, Savitsky S, Yadav PK, Torregrossa R, Harrer EG, Harrer T, Ishii I, Gollasch M, Wood ME, Galardon E, Xian M, Whiteman M, Banerjee R, Filipovic MR. Improved tag-switch method reveals that thioredoxin acts as depersulfidase and controls the intracellular levels of protein persulfidation. Chem Sci. 7(5), 3414-3426 (2016)
- ↑ É. Dóka, I. Pader, A. Bíró, K. Johansson, Q. Cheng, K. Ballagó, J.R. Prigge, D. Pastor-Flores, T.P. Dick, E.E. Schmidt, E.S.J. Arnér, and P. Nagy, A novel persulfide detection method reveals protein persulfide- and polysulfide-reducing functions of thioredoxin and glutathione systems. Science Advances 2 (2016)