Abstract
In addition to nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) has recently emerged as the novel gasotransmitter involved in the regulation of the nervous system, cardiovascular functions, inflammatory response, gastrointestinal system, and renal function. H2S is synthesized from l-cysteine and/or l-homocysteine by cystathionine β-synthase, cystathionine γ-lyase, and cysteine aminotransferase together with 3-mercaptopyruvate sulfurtransferase. In addition, H2S is enzymatically metabolized in mitochondria by sulfide:quinone oxidoreductase, persulfide dioxygenase, and sulfite oxidase to thiosulfate, sulfite, and sulfate which enables to regulate its level by factors such as oxygen pressure, mitochondria density, or efficacy of mitochondrial electron transport. H2S modifies protein structure and function through the so-called sulfuration or persulfidation, that is, conversion of cysteine thiol (–SH) to persulfide (–SSH) groups. This, as well as other signaling mechanisms, is partially mediated by more oxidized H2S-derived species, polysulfides (H2Sn). In addition, H2S is able to react with reactive oxygen and nitrogen species to form other signaling molecules such as thionitrous acid (HSNO), nitrosopersulfide (SSNO−), and nitroxyl (HNO). All H2S-synthesizing enzymes are expressed in the vascular wall, and H2S has been demonstrated to regulate vascular tone, endothelial barrier permeability, angiogenesis, vascular smooth muscle cell proliferation and apoptosis, and inflammatory reaction. H2S-modifying therapies are promising approach for diseases such as arterial hypertension, diabetic angiopathy, and atherosclerosis.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Abe K, Kimura H (1966) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16:1066–1071
Wang R (2014) Gasotransmitters: growing pains and joys. Trends Biochem Sci 39:227–232
Wang R (2012) Physiological implications of hydrogen sulfide: a whiff exploration that blossomed. Physiol Rev 92:791–896
Li Q, Lancaster JR (2013) Chemical foundations of hydrogen sulfide biology. Nitric Oxide 35:21–34
Kabil O, Banerjee R (2014) Enzymology of H2S biogenesis, decay and signaling. Antioxid Redox Signal 20:770–782
Singh S, Padovani D, Leslie RA, Chiku T, Banerjee R (2009) Relative contributions of cystathionine β-synthase and γ-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. J Biol Chem 284:22457–22466
Vicente JB, Colaço HG, Mendes MI, Sarti P, Leandro P, Giuffrè A (2014) NO* binds human cystathionine β-synthase quickly and tightly. J Biol Chem 289:8579–8587
Carballal S, Cuevasanta E, Marmisolle I, Kabil O, Gherasim C, Ballou DP, Banerjee R, Alvarez B (2013) Kinetics of reversible reductive carbonylation of heme in human cystathionine β-synthase. Biochemistry 52:4553–4562
Chiku T, Padovani D, Zhu W, Singh S, Vitvitsky V, Banerjee R (2009) H2S biogenesis by human cystathionine γ-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia. J Biol Chem 284:11601–11612
Ida T, Sawa T, Ihara H, Tsuchiya Y, Watanabe Y, Kumagai Y, Suematsu M, Motohashi H, Fujii S, Matsunaga T, Yamamoto M, Ono K, Devarie-Baez NO, Xian M, Fukuto JM, Akaike T (2014) Reactive cysteine persulfides and S-polythiolation regulate oxidative stress and redox signaling. Proc Natl Acad Sci U S A 111:7606–7611
Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, Kimura H (2009) 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal 11:703–714
Shibuya N, Mikami Y, Kimura Y, Nagahara N, Kimura H (2009) Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J Biochem 146:623–626
Mikami Y, Shibuya N, Kimura Y, Nagahara N, Ogasawara Y, Kimura H (2011) Thioredoxin and dihydrolipoic acid are required for 3-mercaptopyruvate sulfurtransferase to produce hydrogen sulfide. Biochem J 439:479–485
Shibuya N, Koike S, Tanaka M, Ishigami-Yuasa M, Kimura Y, Ogasawara Y, Fukui K, Nagahara N, Kimura H (2013) A novel pathway for the production of hydrogen sulfide from D-cysteine in mammalian cells. Nat Commun 4:1366
Hildebrandt TM, Grieshaber MK (2008) Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria. FEBS J 275:3352–3361
Bouillaud F, Blachier F (2011) Mitochondria and sulfide: a very old story of poisoning, feeding, and signaling? Antioxid Redox Signal 15:379–391
Jackson MR, Melideo SL, Jorns MS (2012) Human sulfide:quinone oxidoreductase catalyzes the first step in hydrogen sulfide metabolism and produces a sulfane sulfur metabolite. Biochemistry 51:6804–6815
Olson KR (2012) Mitochondrial adaptations to utilize hydrogen sulfide for energy and signaling. J Comp Physiol B 182:881–897
Libiad M, Yadav PK, Vitvitsky V, Martinov M, Banerjee R (2014) Organization of the human mitochondrial hydrogen sulfide oxidation pathway. J Biol Chem 289:30901–30910
Olson KR (2008) Hydrogen sulfide and oxygen sensing: implications in cardiorespiratory control. J Exp Biol 211:2727–2734
Olson KR (2011) Hydrogen sulfide is an oxygen sensor in the carotid body. Respir Physiol Neurobiol 179:103–110
Mustafa AK, Gadalla MM, Sen N, Kim S, Mu W, Gazi SK, Barrow RK, Yang G, Wang R, Snyder SH (2009) H2S signals through protein S-sulfhydration. Sci Signal 2:ra72
Mustafa AK, Sikka G, Gazi SK, Steppan J, Jung SM, Bhunia AK, Barodka VM, Gazi FK, Barrow RK, Wang R, Amzel LM, Berkowitz DE, Snyder SH (2011) Hydrogen sulfide as endothelium-derived hyperpolarizing factor sulfhydrates potassium channels. Circ Res 109:1259–1268
Krishnan N, Fu C, Pappin DJ, Tonks NK (2011) H2S-Induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response. Sci Signal 4:ra86
Sen N, Paul BD, Gadalla MM, Mustafa AK, Sen T, Xu R, Kim S, Snyder SH (2012) Hydrogen sulfide-linked sulfhydration of NF-κB mediates its antiapoptotic actions. Mol Cell 45:13–24
Yang G, Zhao K, Ju Y, Mani S, Cao Q, Puukila S, Khaper N, Wu L, Wang R (2013) Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf2. Antioxid Redox Signal 18:1906–1919
Guo C, Liang F, Shah Masood W, Yan X (2014) Hydrogen sulfide protected gastric epithelial cell from ischemia/reperfusion injury by Keap1 S-sulfhydration, MAPK dependent anti-apoptosis and NF-κB dependent anti-inflammation pathway. Eur J Pharmacol 725:70–78
Altaany Z, Ju Y, Yang G, Wang R (2014) The coordination of S-sulfhydration, S-nitrosylation, and phosphorylation of endothelial nitric oxide synthase by hydrogen sulfide. Sci Signal 7:ra87
Vandiver MS, Paul BD, Xu R, Karuppagounder S, Rao F, Snowman AM, Ko HS, Lee YI, Dawson VL, Dawson TM, Sen N, Snyder SH (2013) Sulfhydration mediates neuroprotective actions of parkin. Nat Commun 4:1626
Mazza R, Pasqua T, Cerra MC, Angelone T, Gattuso A (2013) Akt/eNOS signaling and PLN S-sulfhydration are involved in H2S-dependent cardiac effects in frog and rat. Am J Physiol Regul Integr Comp Physiol 305:R443–R451
Liu DH, Huang X, Meng XM, Zhang CM, Lu HL, Kim YC, Xu WX (2014) Exogenous H2S enhances mice gastric smooth muscle tension through S-sulfhydration of Kv4.3, mediating the inhibition of the voltage-dependent potassium current. Neurogastroenterol Motil 26:1705–1716
Zhao K, Ju Y, Li S, Altaany Z, Wang R, Yang G (2014) S-sulfhydration of MEK1 leads to PARP-1 activation and DNA damage repair. EMBO Rep 15:792–800
Stubbert D, Prysyazhna O, Rudyk O, Scotcher J, Burgoyne JR, Eaton P (2014) Protein kinase G Iα oxidation paradoxically underlies blood pressure lowering by the reductant hydrogen sulfide. Hypertension 64:1344–1351
Ono K, Akaike T, Sawa T, Kumagai Y, Wink DA, Tantillo DJ, Hobbs AJ, Nagy P, Xian M, Lin J, Fukuto JM (2014) Redox chemistry and chemical biology of H2S, hydropersulfides, and derived species: implications of their possible biological activity and utility. Free Radic Biol Med 77:82–94
Greiner R, Pálinkás Z, Bäsell K, Becher D, Antelmann H, Nagy P, Dick TP (2013) Polysulfides link H2S to protein thiol oxidation. Antioxid Redox Signal 19:1749–1765
Koike S, Ogasawara Y, Shibuya N, Kimura H, Ishii K (2013) Polysulfide exerts a protective effect against cytotoxicity caused by t-buthylhydroperoxide through Nrf2 signaling in neuroblastoma cells. FEBS Lett 587:3548–3555
Filipovic MR, JL M, Nauser T, Royzen M, Klos K, Shubina T, Koppenol WH, Lippard SJ, Ivanović-Burmazović I (2012) Chemical characterization of the smallest S-nitrosothiol, HSNO; cellular cross-talk of H2S and S-nitrosothiols. J Am Chem Soc 134:12016–12027
Bruce King S (2013) Potential biological chemistry of hydrogen sulfide (H2S) with the nitrogen oxides. Free Radic Biol Med 55:1–7
Ondrias K, Stasko A, Cacanyiova S, Sulova Z, Krizanova O, Kristek F, Malekova L, Knezl V, Breier A (2008) H2S and HS− donor NaHS releases nitric oxide from nitrosothiols, metal nitrosyl complex, brain homogenate and murine L1210 leukaemia cells. Pflugers Arch 457:271–279
Cortese-Krott MM, Fernandez BO, Santos JL, Mergia E, Grman M, Nagy P, Kelm M, Butler A, Feelisch M (2014) Nitrosopersulfide (SSNO−) accounts for sustained NO bioactivity of S-nitrosothiols following reaction with sulfide. Redox Biol 2:234–244
Yong QC, Hu LF, Wang S, Huang D, Bian JS (2010) Hydrogen sulfide interacts with nitric oxide in the heart: possible involvement of nitroxyl. Cardiovasc Res 88:482–491
Sivakumaran V, Stanley BA, Tocchetti CG, Ballin JD, Caceres V, Zhou L, Keceli G, Rainer PP, Lee DI, Huke S, Ziolo MT, Kranias EG, Toscano JP, Wilson GM, O’Rourke B, Kass DA, Mahaney JE, Paolocci N (2013) HNO enhances SERCA2a activity and cardiomyocyte function by promoting redox-dependent phospholamban oligomerization. Antioxid Redox Signal 19:1185–1197
Eberhardt M, Dux M, Namer B, Miljkovic J, Cordasic N, Will C, Kichko TI, de la Roche J, Fischer M, Suárez SA, Bikiel D, Dorsch K, Leffler A, Babes A, Lampert A, Lennerz JK, Jacobi J, Martí MA, Doctorovich F, Högestätt ED, Zygmunt PM, Ivanovic-Burmazovic I, Messlinger K, Reeh P, Filipovic MR (2014) H2S and NO cooperatively regulate vascular tone by activating a neuroendocrine HNO-TRPA1-CGRP signalling pathway. Nat Commun 5:4381
Pietri R, Román-Morales E, López-Garriga J (2011) Hydrogen sulfide and hemeproteins: knowledge and mysteries. Antioxid Redox Signal 15:393–404
Pálinkás Z, Furtmüller PG, Nagy A, Jakopitsch C, Pirker KF, Magierowski M, Jasnos K, Wallace JL, Obinger C, Nagy P (2015) Interactions of hydrogen sulfide with myeloperoxidase. Br J Pharmacol 172:1516–1532
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2019 Springer Science+Business Media, LLC, part of Springer Nature
About this protocol
Cite this protocol
Bełtowski, J. (2019). Synthesis, Metabolism, and Signaling Mechanisms of Hydrogen Sulfide: An Overview. In: Bełtowski, J. (eds) Vascular Effects of Hydrogen Sulfide. Methods in Molecular Biology, vol 2007. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9528-8_1
Download citation
DOI: https://doi.org/10.1007/978-1-4939-9528-8_1
Published:
Publisher Name: Humana, New York, NY
Print ISBN: 978-1-4939-9527-1
Online ISBN: 978-1-4939-9528-8
eBook Packages: Springer Protocols