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Hydrogen sulfide: its production, release and functions

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Abstract

Hydrogen sulfide (H2S), which is a well-known toxic gas, has been recognized as a signal molecule as well as a cytoprotectant. It is produced by three enzymes, cystathionine β-synthase, cystathionine γ-lyase and 3-mercaptopyruvate sulfurtransferase along with cysteine aminotransferase. In addition to an immediate release of H2S from producing enzymes, it can be stored as bound sulfane sulfur, which may release H2S in response to physiological stimuli. As a signal molecule, it modulates neuronal transmission, relaxes smooth muscle, regulates release of insulin and is involved in inflammation. Because of its reputation as a toxic gas, the function as a cytoprotectant has been overlooked: the nervous system and cardiovascular system are protected from oxidative stress. In this review, enzymatic production, release mechanism and functions of H2S are focused on.

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References

  • Abe K, Kimura H (1996) The possible role of hydrogen sulfide as an endogenous neuromodulator. J Neurosci 16:1066–1071

    PubMed  CAS  Google Scholar 

  • Aizenman E, Lipton SA, Loring RH (1989) Selective modulation of NMDA responses by reduction and oxidation. Neuron 2:1257–1263

    Article  PubMed  CAS  Google Scholar 

  • Ali MY, Ping CY, Mok YY, Ling L, Whiteman M, Bhatia M, Moore PK (2006) Regulation of vascular nitric oxide in vitro and in vivo; a new role for endogenous hydrogen sulphide? Br J Pharmacol 149:625–634

    Article  PubMed  CAS  Google Scholar 

  • Bannai S, Kitamura E (1980) Transport interaction of l-cystine and l-glutamate in human diploid fibroblasts in culture. J Biol Chem 255:2372–2376

    PubMed  CAS  Google Scholar 

  • Bian JS, Yong QC, Pan TT, Feng ZN, Ali MY, Zhou S, Moore PK (2006) Role of hydrogen sulfide in the cardioprotection caused by ischemic preconditioning in the rat heart and cardiac myocytes. J Pharmacol Exp Ther 316:670–678

    Article  PubMed  CAS  Google Scholar 

  • Brookes N, Turner RJ (1994) K(+)-induced alkalinization in mouse cerebral astrocytes mediated by reversal of electrogenic Na(+)-HCO3- cotransport. Am J Physiol 267:C1633–C1640

    PubMed  CAS  Google Scholar 

  • Charles AC (1994) Glia-neuron intercellular calcium signaling. Dev Neurosci 16:196–206

    Article  PubMed  CAS  Google Scholar 

  • Chen G, Suzuki H, Weston AH (1988) Acetylcholine releases endothelium-derived hyperpolarizing factor and EDRF from rat blood vessels. Br J Pharmacol 95:1165–1174

    PubMed  CAS  Google Scholar 

  • Chen X, Jhee KH, Kruger WD (2004) Production of the neuromodulator H2S by cystathionine beta-synthase via the condensation of cysteine and homocysteine. J Biol Chem 279:52082–52086

    Article  PubMed  CAS  Google Scholar 

  • Chiku T, Padovani D, Zhu W, Singh S, Vitvitsky V, Banerjee R (2009) H2S biogenesis by human cystathionine gamma-lyase leads to the novel sulfur metabolites lanthionine and homolanthionine and is responsive to the grade of hyperhomocysteinemia. J Biol Chem 284:11601–11612

    Article  PubMed  CAS  Google Scholar 

  • Choi DW (1988) Glutamate neurotoxicity and diseases of the nervous system. Neuron 1:623–634

    Article  PubMed  CAS  Google Scholar 

  • Cooper AJ (1983) Biochemistry of sulfur-containing amino acids. Annu Rev Biochem 52:187–222

    Article  PubMed  CAS  Google Scholar 

  • Cornell-Bell AH, Finkbeiner SM, Cooper MS, Smith SJ (1990) Glutamate induces calcium waves in cultured astrocytes: long-range glial signaling. Science 247:470–473

    Article  PubMed  CAS  Google Scholar 

  • Dani JW, Chernjavsky A, Smith SJ (1992) Neuronal activity triggers calcium waves in hippocampal astrocyte networks. Neuron 8:429–440

    Article  PubMed  CAS  Google Scholar 

  • Daniels KM, Stipanuk MH (1982) The effect of dietary cysteine level on cysteine metabolism in rats. J Nutr 112:2130–2141

    PubMed  CAS  Google Scholar 

  • Devai I, Delaune RD (2002) Effectiveness of selected chemicals for controlling emission of malodorous sulfur gases in sewage sludge. Environ Technol 23:319–329

    Article  PubMed  CAS  Google Scholar 

  • di Villa Bianca R, Sorrentino R, Maffia P, Mirone V, Imbimbo C, Fusco F, De Palma R, Ignarro LJ, Cirino G (2009) Hydrogen sulfide as a mediator of human corpus cavernosum smooth-muscle relaxation. Proc Natl Acad Sci USA 106:4513–4518

    Article  Google Scholar 

  • Diwakar L, Ravindranath V (2007) Inhibition of cystathionine-gamma-lyase leads to loss of glutathione and aggravation of mitochondrial dysfunction mediated by excitatory amino acid in the CNS. Neurochem Int 50:418–426

    Article  PubMed  CAS  Google Scholar 

  • Elrod JW, Calvert JW, Morrison J, Doeller JE, Kraus DW, Tao L, Jiao X, Scalia R, Kiss L, Szabo C et al (2007) Hydrogen sulfide attenuates myocardial ischemia-reperfusion injury by preservation of mitochondrial function. Proc Natl Acad Sci USA 104:15560–15565

    Article  PubMed  CAS  Google Scholar 

  • Enokido Y, Suzuki E, Iwasawa K, Namekata K, Okazawa H, Kimura H (2005) Cystathionine beta-synthase, a key enzyme for homocysteine metabolism, is preferentially expressed in the radial glia/astrocyte lineage of developing mouse CNS. FASEB J 19:1854–1856

    PubMed  CAS  Google Scholar 

  • Frendo J, Wrobel M (1997) The activity of 3-mercaptopyruvate sulfurtransferase in erythrocytes from patients with polycythemia vera. Acta Biochim Pol 44:771–773

    PubMed  CAS  Google Scholar 

  • Furchgott RF, Zawadzki JV (1980) The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature 288:373–376

    Article  PubMed  CAS  Google Scholar 

  • Furne J, Saeed A, Levitt MD (2008) Whole tissue hydrogen sulfide concentrations are orders of magnitude lower than presently accepted values. Am J Physiol Regul Integr Comp Physiol 295:R1479–R1485

    Article  PubMed  CAS  Google Scholar 

  • Geng B, Chang L, Pan C, Qi Y, Zhao J, Pang Y, Du J, Tang C (2004) Endogenous hydrogen sulfide regulation of myocardial injury induced by isoproterenol. Biochem Biophys Res Commun 318:756–763

    Article  PubMed  CAS  Google Scholar 

  • Haydon PG (2001) Glia: listening and talking to the synapse. Nat Rev Neurosci 2:185–193

    Article  PubMed  CAS  Google Scholar 

  • Hebb DO (1949) The organization of behavior. Wiley, New York

    Google Scholar 

  • Heurteaux C, Bertaina V, Widmann C, Lazdunski M (1993) K+ channel openers prevent global ischemia-induced expression of c-fos, c-jun, heat shock protein, and amyloid beta-protein precursor genes and neuronal death in rat hippocampus. Proc Natl Acad Sci USA 90:9431–9435

    Article  PubMed  CAS  Google Scholar 

  • Higgins CF (1995) The ABC of channel regulation. Cell 82:693–696

    Article  PubMed  CAS  Google Scholar 

  • Hosoki R, Matsuki N, Kimura H (1997) The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun 237:527–531

    Article  PubMed  CAS  Google Scholar 

  • Hu LF, Lu M, Wu ZY, Wong PT, Bian JS (2009) Hydrogen sulfide inhibits rotenone-induced apoptosis via preservation of mitochondrial function. Mol Pharmacol 75:27–34

    Article  PubMed  CAS  Google Scholar 

  • Ichinohe A, Kanaumi T, Takashima S, Enokido Y, Nagai Y, Kimura H (2005) Cystathionine beta-synthase is enriched in the brains of Down’s patients. Biochem Biophys Res Commun 338:1547–1550

    Article  PubMed  CAS  Google Scholar 

  • Ishigami M, Hiraki K, Umemura K, Ogasawara Y, Ishii K, Kimura H (2009) A source of hydrogen sulfide and a mechanism of its release in the brain. Antioxid Redox Signal 11:205–214

    Article  PubMed  CAS  Google Scholar 

  • Ishii I, Akahoshi N, Yu XN, Kobayashi Y, Namekata K, Komaki G, Kimura H (2004) Murine cystathionine gamma-lyase: complete cDNA and genomic sequences, promoter activity, tissue distribution and developmental expression. Biochem J 381:113–123

    Article  PubMed  CAS  Google Scholar 

  • Johansen D, Ytrehus K, Baxter GF (2006) Exogenous hydrogen sulfide (H2S) protects against regional myocardial ischemia-reperfusion injury—evidence for a role of K ATP channels. Basic Res Cardiol 101:53–60

    Article  PubMed  CAS  Google Scholar 

  • Kaneko Y, Kimura Y, Kimura H, Niki I (2006) l-cysteine inhibits insulin release from the pancreatic beta-cell: possible involvement of metabolic production of hydrogen sulfide, a novel gasotransmitter. Diabetes 55:1391–1397

    Article  PubMed  CAS  Google Scholar 

  • Kimura Y, Kimura H (2004) Hydrogen sulfide protects neurons from oxidative stress. FASEB J 18:1165–1167

    PubMed  CAS  Google Scholar 

  • Kimura Y, Dargusch R, Schubert D, Kimura H (2006) Hydrogen sulfide protects HT22 neuronal cells from oxidative stress. Antioxid Redox Signal 8:661–670

    Article  PubMed  CAS  Google Scholar 

  • Kimura Y, Goto Y, Kimura H (2010) Hydrogen sulfide increases glutathione production and suppresses oxidative stress in mitochondria. Antioxid Redox Signal 12:1–13

    Article  PubMed  CAS  Google Scholar 

  • Koenitzer JR, Isbell TS, Patel HD, Benavides GA, Dickinson DA, Patel RP, Darley-Usmar VM, Lancaster JR Jr, Doeller JE, Kraus DW (2007) Hydrogen sulfide mediates vasoactivity in an O2-dependent manner. Am J Physiol Heart Circ Physiol 292:H1953–H1960

    Article  PubMed  CAS  Google Scholar 

  • Kombian SB, Reiffenstein RJ, Colmers WF (1993) The actions of hydrogen sulfide on dorsal raphe serotonergic neurons in vitro. J Neurophysiol 70:81–96

    PubMed  CAS  Google Scholar 

  • Kuo SM, Lea TC, Stipanuk MH (1983) Developmental pattern, tissue distribution, and subcellular distribution of cysteine: alpha-ketoglutarate aminotransferase and 3-mercaptopyruvate sulfurtransferase activities in the rat. Biol Neonate 43:23–32

    Article  PubMed  CAS  Google Scholar 

  • Lin MT, Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443:787–795

    Article  PubMed  CAS  Google Scholar 

  • Mathai JC, Missner A, Kugler P, Saparov SM, Zeidel ML, Lee JK, Pohl P (2009) No facilitator required for membrane transport of hydrogen sulfide. Proc Natl Acad Sci USA 106:16633–16638

    Article  PubMed  CAS  Google Scholar 

  • Murphy E, Steenbergen C (2007) Preconditioning: the mitochondrial connection. Annu Rev Physiol 69:51–67

    Article  PubMed  CAS  Google Scholar 

  • Murphy TH, Miyamoto M, Sastre A, Schnaar RL, Coyle JT (1989) Glutamate toxicity in a neuronal cell line involves inhibition of cystine transport leading to oxidative stress. Neuron 2:1547–1558

    Article  PubMed  CAS  Google Scholar 

  • Nagahara N, Nishino T (1996) Role of amino acid residues in the active site of rat liver mercaptopyruvate sulfurtransferase. CDNA cloning, overexpression, and site-directed mutagenesis. J Biol Chem 271:27395–27401

    Article  PubMed  CAS  Google Scholar 

  • Nagahara N, Ito T, Kitamura H, Nishino T (1998) Tissue and subcellular distribution of mercaptopyruvate sulfurtransferase in the rat: confocal laser fluorescence and immunoelectron microscopic studies combined with biochemical analysis. Histochem Cell Biol 110:243–250

    Article  PubMed  CAS  Google Scholar 

  • Nagai Y, Tsugane M, Oka J, Kimura H (2004) Hydrogen sulfide induces calcium waves in astrocytes. FASEB J 18:557–559

    PubMed  CAS  Google Scholar 

  • O’Dell TJ, Hawkins RD, Kandel ER, Arancio O (1991) Tests of the roles of two diffusible substances in long-term potentiation: evidence for nitric oxide as a possible early retrograde messenger. Proc Natl Acad Sci USA 88:11285–11289

    Article  PubMed  Google Scholar 

  • Ogasawara Y, Ishii K, Togawa T, Tanabe S (1993) Determination of bound sulfur in serum by gas dialysis/high-performance liquid chromatography. Anal Biochem 215:73–81

    Article  PubMed  CAS  Google Scholar 

  • Ogasawara Y, Isoda S, Tanabe S (1994) Tissue and subcellular distribution of bound and acid-labile sulfur, and the enzymic capacity for sulfide production in the rat. Biol Pharm Bull 17:1535–1542

    PubMed  CAS  Google Scholar 

  • Parri HR, Gould TM, Crunelli V (2001) Spontaneous astrocytic Ca2+ oscillations in situ drive NMDAR-mediated neuronal excitation. Nat Neurosci 4:803–812

    Article  PubMed  CAS  Google Scholar 

  • Patacchini R, Santicioli P, Giuliani S, Maggi CA (2005) Pharmacological investigation of hydrogen sulfide (H2S) contractile activity in rat detrusor muscle. Eur J Pharmacol 509:171–177

    Article  PubMed  CAS  Google Scholar 

  • Patel P, Vatish M, Heptinstall J, Wang R, Carson RJ (2009) The endogenous production of hydrogen sulphide in intrauterine tissues. Reprod Biol Endocrinol 7:10

    Article  PubMed  Google Scholar 

  • Richie JP Jr, Lang CA (1987) The determination of glutathione, cyst(e)ine, and other thiols and disulfides in biological samples using high-performance liquid chromatography with dual electrochemical detection. Anal Biochem 163:9–15

    Article  PubMed  CAS  Google Scholar 

  • Sagara Y, Schubert D (1998) The activation of metabotropic glutamate receptors protects nerve cells from oxidative stress. J Neurosci 18:6662–6671

    PubMed  CAS  Google Scholar 

  • Shibuya N, Mikami Y, Kimura Y, Nagahara N, Kimura H (2009a) Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J Biochem 146:623–626

    Article  PubMed  CAS  Google Scholar 

  • Shibuya N, Tanaka M, Yoshida M, Ogasawara Y, Togawa T, Ishii K, Kimura H (2009b) 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal 11:703–714

    Article  PubMed  CAS  Google Scholar 

  • Shikano K, Long CJ, Ohlstein EH, Berkowitz BA (1988) Comparative pharmacology of endothelium-derived relaxing factor and nitric oxide. J Pharmacol Exp Ther 247:873–881

    PubMed  CAS  Google Scholar 

  • Singh S, Padovani D, Leslie RA, Chiku T, Banerjee R (2009) Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. J Biol Chem 284:22457–22466

    Article  PubMed  CAS  Google Scholar 

  • Stevens CF, Wang Y (1993) Reversal of long-term potentiation by inhibitors of haem oxygenase. Nature 364:147–149

    Article  PubMed  CAS  Google Scholar 

  • Stipanuk MH, Beck PW (1982) Characterization of the enzymic capacity for cysteine desulphhydration in liver and kidney of the rat. Biochem J 206:267–277

    PubMed  CAS  Google Scholar 

  • Streng T, Axelsson HE, Hedlund P, Andersson DA, Jordt SE, Bevan S, Andersson KE, Hogestatt ED, Zygmunt PM (2008) Distribution and function of the hydrogen sulfide-sensitive TRPA1 ion channel in rat urinary bladder. Eur Urol 53:391–399

    Article  PubMed  CAS  Google Scholar 

  • Sunda W, Kieber DJ, Kiene RP, Huntsman S (2002) An antioxidant function for DMSP and DMS in marine algae. Nature 418:317–320

    Article  PubMed  CAS  Google Scholar 

  • Teague B, Asiedu S, Moore PK (2002) The smooth muscle relaxant effect of hydrogen sulphide in vitro: evidence for a physiological role to control intestinal contractility. Br J Pharmacol 137:139–145

    Article  PubMed  CAS  Google Scholar 

  • Toohey JI (1989) Sulphane sulphur in biological systems: a possible regulatory role. Biochem J 264:625–632

    PubMed  CAS  Google Scholar 

  • Verma A, Hirsch DJ, Glatt CE, Ronnett GV, Snyder SH (1993) Carbon monoxide: a putative neural messenger. Science 259:381–384

    Article  PubMed  CAS  Google Scholar 

  • Vitvitsky V, Thomas M, Ghorpade A, Gendelman HE, Banerjee R (2006) A functional transsulfuration pathway in the brain links to glutathione homeostasis. J Biol Chem 281:35785–35793

    Article  PubMed  CAS  Google Scholar 

  • Vornov JJ, Coyle JT (1991) Glutamate neurotoxicity and the inhibition of protein synthesis in the hippocampal slice. J Neurochem 56:996–1006

    Article  PubMed  CAS  Google Scholar 

  • Yang G, Wu L, Jiang B, Yang W, Qi J, Cao K, Meng Q, Mustafa AK, Mu W, Zhang S et al (2008) H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science 322:587–590

    Article  PubMed  CAS  Google Scholar 

  • Zhao W, Wang R (2002) H(2)S-induced vasorelaxation and underlying cellular and molecular mechanisms. Am J Physiol Heart Circ Physiol 283:H474–H480

    PubMed  CAS  Google Scholar 

  • Zhao W, Zhang J, Lu Y, Wang R (2001) The vasorelaxant effect of H(2)S as a novel endogenous gaseous K(ATP) channel opener. EMBO J 20:6008–6016

    Article  PubMed  CAS  Google Scholar 

  • Zhuo M, Small SA, Kandel ER, Hawkins RD (1993) Nitric oxide and carbon monoxide produce activity-dependent long-term synaptic enhancement in hippocampus. Science 260:1946–1950

    Article  PubMed  CAS  Google Scholar 

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This work was supported by a grant from the National Institute of Neuroscience.

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Correspondence to Hideo Kimura.

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Kimura, H. Hydrogen sulfide: its production, release and functions. Amino Acids 41, 113–121 (2011). https://doi.org/10.1007/s00726-010-0510-x

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