Significance: Hydrogen sulfide (H2S), produced by the desulfuration of cysteine or homocysteine, functions as a signaling molecule in an array of physiological processes including regulation of vascular tone, the cellular stress response, apoptosis, and inflammation. Recent Advances: The low steady-state levels of H2S in mammalian cells have been recently shown to reflect a balance between its synthesis and its clearance. The subversion of enzymes in the cytoplasmic trans-sulfuration pathway for producing H2S from cysteine and/or homocysteine versus producing cysteine from homocysteine, presents an interesting regulatory problem. Critical Issues: It is not known under what conditions the enzymes operate in the canonical trans-sulfuration pathway and how their specificity is switched to catalyze the alternative H2S-producing reactions. Similarly, it is not known if and whether the mitochondrial enzymes, which oxidize sulfide and persulfide (or sulfane sulfur), are regulated to increase or decrease H2S or sulfane-sulfur pools. Future Directions: In this review, we focus on the enzymology of H2S homeostasis and discuss H2S-based signaling via persulfidation and thionitrous acid. Antioxid. Redox Signal. 20, 770–782.
Get full access to this article
View all access options for this article.
References
1.
AgrawalN and BanerjeeR. Human polycomb 2 protein is a SUMO E3 ligase and alleviates substrate-induced inhibition of cystathionine beta-synthase sumoylation. PLoS One, 3: e4032, 2008.
2.
AkagiR. Purification and characterization of cysteine aminotransferase from rat liver cytosol. Acta Med Okayama, 36: 187–197, 1982.
3.
BartholomewTC, PowellGM, DodgsonKS, and CurtisCG. Oxidation of sodium sulphide by rat liver, lungs and kidney. Biochem Pharmacol, 29: 2431–2437, 1980.
4.
BeattyPW and ReedDJ. Involvement of the cystathionine pathway in the biosynthesis of glutathione by isolated rat hepatocytes. Arch Biochem Biophys, 204: 80–87, 1980.
5.
BirchmeierW and ChristenP. Syncatalytic enzyme modification: characteristic features and differentiation from affinity labeling. Methods Enzymol, 46: 41–48, 1977.
6.
BranzoliU and MasseyV. Evidence for an active site persulfide residue in rabbit liver aldehyde oxidase. J Biol Chem, 249: 4346–4349, 1974.
7.
BritoJA, SousaFL, StelterM, BandeirasTM, VonrheinC, TeixeiraM, PereiraMM, and ArcherM. Structural and functional insights into sulfide:quinone oxidoreductase. Biochemistry, 48: 5613–5622, 2009.
8.
ChenX, JheeKH, and KrugerWD. Production of the neuromodulator H2S by cystathionine beta-synthase via the condensation of cysteine and homocysteine. J Biol Chem, 279: 52082–52086, 2004.
9.
CherneyMM, ZhangY, JamesMN, and WeinerJH. Structure-activity characterization of sulfide:quinone oxidoreductase variants. J Struct Biol, 178: 319–328, 2012.
10.
CherneyMM, ZhangY, SolomonsonM, WeinerJH, and JamesMN. Crystal structure of sulfide:quinone oxidoreductase from Acidithiobacillus ferrooxidans: insights into sulfidotrophic respiration and detoxification. J Mol Biol, 398: 292–305, 2010.
11.
ChikuT, PadovaniD, ZhuW, SinghS, VitvitskyV, and BanerjeeR. H2S biogenesis by 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, 2009.
12.
CurtisCG, BartholomewTC, RoseFA, and DodgsonKS. Detoxication of sodium 35 S-sulphide in the rat. Biochem Pharmacol, 21: 2313–2321, 1972.
13.
De LucaG, RuggeriP, and MacaioneS. Cystathionase activity in rat tissues during development. Ital J Biochem, 23: 371–379, 1974.
14.
DickhoutJG, CarlisleRE, JeromeDE, Mohammed-AliZ, JiangH, YangG, ManiS, GargSK, BanerjeeR, KaufmanRJ, MacleanKN, WangR, and AustinRC. Integrated stress response modulates cellular redox state via induction of cystathionine gamma-lyase: cross-talk between integrated stress response and thiol metabolism. J Biol Chem, 287: 7603–7614, 2012.
15.
FilipovicMR, MiljkovicJ, NauserT, RoyzenM, KlosK, ShubinaTE, KoppenolWH, LippardSJ, and Ivanovic-BurmazovicI. Chemical characterization of the smallest S-nitrosothiol, HSNO; cellular cross-talk of H2S and S-nitrosothiols. J Am Chem Soc, 134: 12016–12027, 2012.
16.
FinkelsteinJD, KyleWE, MartinJL, and PickAM. Activation of cystathionine synthase by adenosylmethionine and adenosylethionine. Biochem Biophys Res Commun, 66: 81–87, 1975.
17.
FurneJ, SaeedA, and LevittMD. Whole tissue hydrogen sulfide concentrations are orders of magnitude lower than presently accepted values. Am J Physiol Regul Integr Comp Physiol, 295: R1479–R1485, 2008.
18.
GehringH and ChristenP. Syncatalytic conformational changes in mitochondrial aspartate aminotransferases. Evidence from modification and demodification of Cys 166 in the enzyme from chicken and pig. J Biol Chem, 253: 3158–3163, 1978.
19.
GossSJ. Characterization of cystathionine synthase as a selectable, liver-specific trait in rat hepatomas. J Cell Sci, 82: 309–320, 1986.
20.
GoubernM, AndriamihajaM, NubelT, BlachierF, and BouillaudF. Sulfide, the first inorganic substrate for human cells. FASEB J, 21: 1699–1706, 2007.
21.
GriesbeckC, SchutzM, SchodlT, BatheS, NauschL, MedererN, VielreicherM, and HauskaG. Mechanism of sulfide-quinone reductase investigated using site-directed mutagenesis and sulfur analysis. Biochemistry, 41: 11552–11565, 2002.
22.
HardingHP, ZhangY, and RonD. Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature, 397: 271–274, 1999.
23.
HargroveJL. Persulfide generated from L-cysteine inactivates tyrosine aminotransferase. Requirement for a protein with cysteine oxidase activity and gamma-cystathionase. J Biol Chem, 263: 17262–17269, 1988.
24.
HargroveJL, TrotterJF, AshlineHC, and KrishnamurtiPV. Experimental diabetes increases the formation of sulfane by transsulfuration and inactivation of tyrosine aminotransferase in cytosols from rat liver. Metab Clin Exp, 38: 666–672, 1989.
25.
HildebrandtTM and GrieshaberMK. Three enzymatic activities catalyze the oxidation of sulfide to thiosulfate in mammalian and invertebrate mitochondria. FEBS J, 275: 3352–3361, 2008.
26.
HosokiR, MatsukiN, and KimuraH. The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide. Biochem Biophys Res Commun, 237: 527–531, 1997.
27.
IshigamiM, HirakiK, UmemuraK, OgasawaraY, IshiiK, and KimuraH. A source of hydrogen sulfide and a mechanism of its release in the brain. Antioxid Redox Signal, 11: 205–214, 2009.
28.
IshiiI, AkahoshiN, YuXN, KobayashiY, NamekataK, KomakiG, and KimuraH. Murine cystathionine gamma-lyase: complete cDNA and genomic sequences, promoter activity, tissue distribution and developmental expression. Biochem J, 381: 113–123, 2004.
29.
JacksonMR, MelideoSL, and JornsMS. Human sulfide:quinone oxidoreductase catalyzes the first step in hydrogen sulfide metabolism and produces a sulfane sulfur metabolite. Biochemistry, 51: 6804–6815, 2012.
30.
JacobsRL, HouseJD, BrosnanME, and BrosnanJT. Effects of streptozotocin-induced diabetes and of insulin treatment on homocysteine metabolism in the rat. Diabetes, 47: 1967–1970, 1998.
31.
JarabakR and WestleyJ. Steady-state kinetics of 3-mercaptopyruvate sulfurtransferase from bovine kidney. Arch Biochem Biophys, 185: 458–465, 1978.
32.
KabilO and BanerjeeR. The redox biochemistry of hydrogen sulfide. J Biol Chem, 285: 21903–21907, 2010.
33.
KabilO and BanerjeeR. Characterization of patient mutations in human persulfide dioxygenase (ETHE1) involved in H2S catabolism. J Biol Chem, 287: 44561–44567, 2012.
34.
KabilO, VitvitskyV, XieP, and BanerjeeR. The quantitative significance of the transsulfuration enzymes for H2S production in murine tissues. Antioxid Redox Signal, 15: 363–372, 2011.
35.
KabilO, WeeksCL, CarballalS, GherasimC, AlvarezB, SpiroTG, and BanerjeeR. Reversible heme-dependent regulation of human cystathionine beta-synthase by a flavoprotein oxidoreductase. Biochemistry, 50: 8261–8263, 2011.
36.
KabilO, ZhouY, and BanerjeeR. Human cystathionine beta-synthase is a target for sumoylation. Biochemistry, 45: 13528–13536, 2006.
37.
KanekoY, KimuraY, KimuraH, and NikiI. 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, 2006.
38.
KoehntopKD, EmersonJP, and QueLJr., The 2-His-1-carboxylate facial triad: a versatile platform for dioxygen activation by mononuclear non-heme iron(II) enzymes. J Biol Inorg Chem, 10: 87–93, 2005.
39.
KojA, FrendoJ, and JanikZ. [35S]thiosulphate oxidation by rat liver mitochondria in the presence of glutathione. Biochem J, 103: 791–795, 1967.
40.
KrishnanN, FuC, PappinDJ, and TonksNK. H2S-induced sulfhydration of the phosphatase PTP1B and its role in the endoplasmic reticulum stress response. Sci Signal, 4: ra86, 2011.
41.
LevittMD, Abdel-RehimMS, and FurneJ. Free and acid-labile hydrogen sulfide concentrations in mouse tissues: anomalously high free hydrogen sulfide in aortic tissue. Antioxid Redox Signal, 15: 373–378, 2011.
42.
MacleanKN, GaustadnesM, OliveriusovaJ, JanosikM, KrausE, KozichV, KeryV, SkovbyF, RudigerN, IngerslevJ, StablerSP, AllenRH, and KrausJP. High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations. Hum Mutat, 19: 641–655, 2002.
43.
MarciaM, ErmlerU, PengG, and MichelH. The structure of Aquifex aeolicus sulfide:quinone oxidoreductase, a basis to understand sulfide detoxification and respiration. Proc Natl Acad Sci U S A, 106: 9625–9630, 2009.
44.
MasseyV and EdmondsonD. On the mechanism of inactivation of xanthine oxidase by cyanide. J Biol Chem, 245: 6595–6598, 1970.
45.
McCoyJG, BaileyLJ, BittoE, BingmanCA, AcetiDJ, FoxBG, and PhillipsGNJr., Structure and mechanism of mouse cysteine dioxygenase. Proc Natl Acad Sci U S A, 103: 3084–3089, 2006.
46.
McCoyJG, BingmanCA, BittoE, HoldorfMM, MakaroffCA, and PhillipsGNJr., Structure of an ETHE1-like protein from Arabidopsis thaliana. Acta Crystallogr D Biol Crystallogr, 62: 964–970, 2006.
47.
MeisterA, FraserPE, and TiceSV. Enzymatic desulfuration of beta-mercaptopyruvate to pyruvate. J Biol Chem, 206: 561–575, 1954.
48.
MineriR, RimoldiM, BurlinaAB, KoskullS, PerlettiC, HeeseB, von DobelnU, MereghettiP, Di MeoI, InvernizziF, ZevianiM, UzielG, and TirantiV. Identification of new mutations in the ETHE1 gene in a cohort of 14 patients presenting with ethylmalonic encephalopathy. J Med Genet, 45: 473–478, 2008.
49.
MorikawaT, KajimuraM, NakamuraT, HishikiT, NakanishiT, YukutakeY, NagahataY, IshikawaM, HattoriK, TakenouchiT, TakahashiT, IshiiI, MatsubaraK, KabeY, UchiyamaS, NagataE, GadallaMM, SnyderSH, and SuematsuM. Hypoxic regulation of the cerebral microcirculation is mediated by a carbon monoxide-sensitive hydrogen sulfide pathway. Proc Natl Acad Sci U S A, 109: 1293–1298, 2012.
50.
MosharovE, CranfordMR, and BanerjeeR. The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes. Biochemistry, 39: 13005–13011, 2000.
51.
MuddSH, LevyHL, and KrausJP. Disorders of transsulfuration. In: The Online Metabolic and Molecular Bases of Inherited Disease, edited by ScriverCR, BeaudetAL, SlyWS, ValleD, VogelsteinB, KinzlerKW, and ChildsB. New York: The McGraw-Hill Companies; 2001, pp. 2007–2056.
52.
MukherjeeA, CranswickMA, ChakrabartiM, PaineTK, FujisawaK, MunckE, and QueLJr., Oxygen activation at mononuclear nonheme iron centers: a superoxo perspective. Inorg Chem, 49: 3618–3628, 2010.
53.
MustafaAK, GadallaMM, SenN, KimS, MuW, GaziSK, BarrowRK, YangG, WangR, and SnyderSH. H2S signals through protein S-sulfhydration. Sci Signal, 2: ra72, 2009.
NagaharaN, ItoT, KitamuraH, and NishinoT. 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, 1998.
56.
NagaharaN and KatayamaA. Post-translational regulation of mercaptopyruvate sulfurtransferase via a low redox potential cysteine-sulfenate in the maintenance of redox homeostasis. J Biol Chem, 280: 34569–34576, 2005.
57.
NagaharaN, OkazakiT, and NishinoT. Cytosolic mercaptopyruvate sulfurtransferase is evolutionarily related to mitochondrial rhodanese. Striking similarity in active site amino acid sequence and the increase in the mercaptopyruvate sulfurtransferase activity of rhodanese by site-directed mutagenesis. J Biol Chem, 270: 16230–16235, 1995.
58.
NagaharaN, YoshiiT, AbeY, and MatsumuraT. Thioredoxin-dependent enzymatic activation of mercaptopyruvate sulfurtransferase. An intersubunit disulfide bond serves as a redox switch for activation. J Biol Chem, 282: 1561–1569, 2007.
59.
NagyP and WinterbournCC. Rapid reaction of hydrogen sulfide with the neutrophil oxidant hypochlorous acid to generate polysulfides. Chem Res Toxicol, 23:1541–1543, 2010.
60.
OgasawaraY, IsodaS, and TanabeS. 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, 1994.
61.
PrudovaA, AlbinM, BaumanZ, LinA, VitvitskyV, and BanerjeeR. Testosterone regulation of homocysteine metabolism modulates redox status in human prostate cancer cells. Antioxid Redox Signal, 9: 1875–1881, 2007.
62.
PrudovaA, BaumanZ, BraunA, VitvitskyV, LuSC, and BanerjeeR. S-adenosylmethionine stabilizes cystathionine beta-synthase and modulates redox capacity. Proc Natl Acad Sci U S A, 103: 6489–6494, 2006.
63.
PuranikM, WeeksCL, LahayeD, KabilO, TaokaS, NielsenSB, GrovesJT, BanerjeeR, and SpiroTG. Dynamics of carbon monoxide binding to cystathionine beta-synthase. J Biol Chem, 281: 13433–13438, 2006.
64.
QueLJr., The oxo/peroxo debate: a nonheme iron perspective. J Biol Inorg Chem, 9: 684–690, 2004.
65.
RatnamS, MacleanKN, JacobsRL, BrosnanME, KrausJP, and BrosnanJT. Hormonal regulation of cystathionine beta-synthase expression in liver. J Biol Chem, 277: 42912–42918, 2002.
66.
SenN, PaulBD, GadallaMM, MustafaAK, SenT, XuR, KimS, and SnyderSH. Hydrogen sulfide-linked sulfhydration of NF-kappaB mediates its antiapoptotic actions. Mol Cell, 45: 13–24, 2012.
67.
ShibuyaN, MikamiY, KimuraY, NagaharaN, and KimuraH. Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide. J Biochem, 146: 623–626, 2009.
68.
ShibuyaN, TanakaM, YoshidaM, OgasawaraY, TogawaT, IshiiK, and KimuraH. 3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain. Antioxid Redox Signal, 11: 703–714, 2009.
69.
SingerTP and KearneyEB. Intermediary metabolism of L-cysteinesulfinic acid in animal tissues. Arch Biochem Biophys, 61: 397–409, 1956.
70.
SinghS, MadzelanP, StasserJ, WeeksCL, BeckerD, SpiroTG, Penner-HahnJ, and BanerjeeR. Modulation of the heme electronic structure and cystathionine beta-synthase activity by second coordination sphere ligands: the role of heme ligand switching in redox regulation. J Inorg Biochem, 103: 689–697, 2009.
71.
SinghS, PadovaniD, LeslieRA, ChikuT, and BanerjeeR. Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions. J Biol Chem, 284: 22457–22466, 2009.
72.
SliwaD, DairouJ, CamadroJM, and SantosR. Inactivation of mitochondrial aspartate aminotransferase contributes to the respiratory deficit of yeast frataxin-deficient cells. Biochem J, 441: 945–953, 2012.
73.
StipanukMH. Metabolism of sulfur-containing amino acids. Annu Rev Nutr, 6: 179–209, 1986.
74.
StipanukMH, LondonoM, LeeJI, HuM, and YuAF. Enzymes and metabolites of cysteine metabolism in nonhepatic tissues of rats show little response to changes in dietary protein or sulfur amino acid levels. J Nutr, 132: 3369–3378, 2002.
75.
TaniguchiT and KimuraT. Role of 3-mercaptopyruvate sulfurtransferase in the formation of the iron-sulfur chromophore of adrenal ferredoxin. Biochim Biophys Acta, 364: 284–295, 1974.
76.
TaokaS and BanerjeeR. Characterization of NO binding to human cystathionine [beta]-synthase:: Possible implications of the effects of CO and NO binding to the human enzyme. J Inorg Biochem, 87: 245–251, 2001.
77.
TaokaS, OhjaS, ShanX, KrugerWD, and BanerjeeR. Evidence for heme-mediated redox regulation of human cystathionine beta-synthase activity. J Biol Chem, 273: 25179–25184, 1998.
78.
TaokaS, WestM, and BanerjeeR. Characterization of the heme and pyridoxal phosphate cofactors of human cystathionine β-synthase reveals nonequivalent active sites. Biochemistry, 38: 2738–2744, 1999.
79.
TheissenU, HoffmeisterM, GrieshaberM, and MartinW. Single eubacterial origin of eukaryotic sulfide:quinone oxidoreductase, a mitochondrial enzyme conserved from the early evolution of eukaryotes during anoxic and sulfidic times. Mol Biol Evol, 20: 1564–1574, 2003.
80.
TirantiV, D'AdamoP, BriemE, FerrariG, MineriR, LamanteaE, MandelH, BalestriP, Garcia-SilvaMT, VollmerB, RinaldoP, HahnSH, LeonardJ, RahmanS, Dionisi-ViciC, GaravagliaB, GaspariniP, and ZevianiM. Ethylmalonic encephalopathy is caused by mutations in ETHE1, a gene encoding a mitochondrial matrix protein. Am J Hum Genet, 74: 239–252, 2004.
81.
TirantiV, ViscomiC, HildebrandtT, Di MeoI, MineriR, TiveronC, LevittMD, PrelleA, FagiolariG, RimoldiM, and ZevianiM. Loss of ETHE1, a mitochondrial dioxygenase, causes fatal sulfide toxicity in ethylmalonic encephalopathy. Nat Med, 15: 200–205, 2009.
82.
UbukaT, OhtaJ, YaoW-B, AbeT, TeraokaT, and KurozumiY. L-Cysteine metabolism via 3-mercaptopyruvate pathway and sulfate formation in rat liver mitochondria. Amino Acids, 2: 143–155, 1992.
83.
UbukaT, UmemuraS, YuasaS, KinutaM, and WatanabeK. Purification and characterization of mitochondrial cysteine aminotransferase from rat liver. Physiol Chem Phys, 10: 483–500, 1978.
84.
UekiI, RomanHB, HirschbergerLL, JuniorC, and StipanukMH. Extrahepatic tissues compensate for loss of hepatic taurine synthesis in mice with liver-specific knockout of cysteine dioxygenase. Am J Physiol Endocrinol Metab, 302: E1292–E1299, 2012.
85.
VitvitskyV, DayalS, StablerS, ZhouY, WangH, LentzSR, and BanerjeeR. Perturbations in homocysteine-linked redox homeostasis in a murine model for hyperhomocysteinemia. Am J Physiol Regul Integr Comp Physiol, 287: R39–R46, 2004.
86.
VitvitskyV, GargSK, and BanerjeeR. Taurine biosynthesis by neurons and astrocytes. J Biol Chem, 286: 32002–32010, 2011.
87.
VitvitskyV, KabilO, and BanerjeeR. High turnover rates for hydrogen sulfide allow for rapid regulation of its tissue concentrations. Antioxid Redox Signal, 17: 22–31, 2012.
88.
VitvitskyV, PrudovaA, StablerS, DayalS, LentzSR, and BanerjeeR. Testosterone regulation of renal cystathionine beta-synthase: implications for sex-dependent differences in plasma homocysteine levels. Am J Physiol Renal Physiol, 293: F594–F600, 2007.
89.
VitvitskyV, ThomasM, GhorpadeA, GendelmanHE, and BanerjeeR. A functional transsulfuration pathway in the brain links to glutathione homeostasis. J Biol Chem, 281: 35785–35793, 2006.
90.
WekRC and CavenerDR. Translational control and the unfolded protein response. Antioxid Redox Signal, 9: 2357–2371, 2007.
91.
WestropGD, GeorgI, and CoombsGH. The mercaptopyruvate sulfurtransferase of Trichomonas vaginalis links cysteine catabolism to the production of thioredoxin persulfide. J Biol Chem, 284: 33485–33494, 2009.
92.
WhitemanM, LiL, KostetskiI, ChuSH, SiauJL, BhatiaM, and MoorePK. Evidence for the formation of a novel nitrosothiol from the gaseous mediators nitric oxide and hydrogen sulphide. Biochem Biophys Res Commun, 343: 303–310, 2006.
93.
WuL, YangW, JiaX, YangG, DuridanovaD, CaoK, and WangR. Pancreatic islet overproduction of H2S and suppressed insulin release in Zucker diabetic rats. Lab Invest, 89: 59–67, 2009.
94.
YamamotoJ, SatoW, KosugiT, YamamotoT, KimuraT, TaniguchiS, KojimaH, MaruyamaS, ImaiE, MatsuoS, YuzawaY, and NikiI. Distribution of hydrogen sulfide (H(2)S)-producing enzymes and the roles of the H(2)S donor sodium hydrosulfide in diabetic nephropathy. Clin Exp Nephrol, 17: 32–40, 2013.
95.
YangG, WuL, JiangB, YangW, QiJ, CaoK, MengQ, MustafaAK, MuW, ZhangS, SnyderSH, and WangR. H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase. Science, 322: 587–590, 2008.
96.
YeS, WuX, WeiL, TangD, SunP, BartlamM, and RaoZ. An insight into the mechanism of human cysteine dioxygenase. Key roles of the thioether-bonded tyrosine-cysteine cofactor. J Biol Chem, 282: 3391–3402, 2007.
97.
YusufM, Kwong HuatBT, HsuA, WhitemanM, BhatiaM, and MoorePK. Streptozotocin-induced diabetes in the rat is associated with enhanced tissue hydrogen sulfide biosynthesis. Biochem Biophys Res Commun, 333: 1146–1152, 2005.
