Biochimica et Biophysica Acta (BBA) - Proteins and Proteomics
ReviewH2S and its role in redox signaling☆,☆☆
Introduction
Sulfur-based chemistry is exploited by nature for maintaining cellular redox homeostasis, for redox-based signaling and for neutralizing reactive oxygen and nitrogen species. Reactive cysteine residues in the proteome are important constituents of redox signaling pathways. Reversible changes in the oxidation state of cysteines allow them to function as redox switches in multiple signaling pathways [1] and these residues are often targets of modifications. Additionally, transition metal centers with sulfur ligands can participate in redox-signaling pathways and function as biological redox sensors. Some key messengers used for communication through these redox hotspots are reactive oxygen species (ROS) and reactive nitrogen species (RNS) along with the gaseous signaling molecules such as CO, NO and H2S. Recognition of H2S as a signaling molecule in mammals took longer than NO and CO perhaps due to its long reputation as an environmental toxin and the prevailing view that it was primarily relevant to microbial metabolism. However, since the first report of a physiological role for endogenously produced H2S in mammals [2], there has been an explosion in the literature of its varied biological effects (Fig. 1). Among the signaling mechanisms invoked for H2S, cysteine persulfidation is the one that is most commonly cited [3]. However, the technical problems associated with existing methods for the detection of proteomic persulfidation raise concerns about the validity of the identified targets [4] in addition to raising questions about how target specificity is achieved. The chemical versatility of H2S and the multiplicity of its reported targets suggest that additional mechanisms might be involved in H2S signaling.
Fundamental gaps in our understanding of how intracellular H2S is regulated hamper in turn, our understanding of its mechanism of action and target selectivity. At least three enzymes, cystathionine β-synthase (CBS), cystathione γ-lyase (CSE) [5], [6], and 3-mercaptopyruvate sulfurtransferase (MST) [7], [8], contribute to H2S production (Fig. 2a). Housekeeping enzymes produce H2S and it is not known whether signaling by H2S as with NO and CO, can be regulated by increased enzymatic synthesis. It is also not known how H2S biogenesis is selectively regulated relative to the canonical transsulfuration reactions catalyzed by CBS and CSE [9], [10]. The low tissue concentration of H2S is a product of both the H2S biogenesis and oxidation fluxes [11].
Section snippets
H2S production
H2S is produced endogenously from cysteine and homocysteine via various reactions catalyzed by CBS and CSE [5], [6] and from 3-mercaptopyruvate in a reaction catalyzed by MST [7], [8] (Fig. 2a). 3-Mercaptopyruvate is derived via a transamination reaction between cysteine and α-ketoglutarate catalyzed by cysteine aminotransferase (CAT), which is identical to aspartate aminotransferase [12]. MST catalyzes the desulfuration of 3-mercaptopyruvate generating an MST-bound persulfide at an active site
Chemical properties of H2S
H2S is a weak acid and readily ionizes in aqueous solution with pKa1 and pKa2 values of 6.9 and > 12 respectively [49]. Therefore at physiological pH, approximately two thirds of total H2S is in the anionic sulfide (HS−) form. Further ionization to S2− requires alkaline conditions. Hence, the concentration of the sulfide dianion is negligible under cellular conditions. H2S is lipophilic and can freely diffuse through membranes [50]. While the electronic configuration of sulfur is similar to that
Protein persulfidation
An increasing number of reports suggest the importance of protein persulfidation in H2S-based signaling [77]. In principle, persulfidation can occur by one of at least three mechanisms: (i) nucleophilic attack of a sulfide anion on an oxidized cysteine residue, e.g. sulfenic acid, S-nitrosyl or disulfide, (ii) via transsulfuration from an existing persulfide carried by a small molecule like GSSH or a protein, or (iii) by attack of a cysteine thiol on H2S2 [78] (Fig. 2a,b) or polysulfide [79].
Vasorelaxation
H2S functions as an endothelial-derived hyperpolarizing factor (EDHF) and its vasorelaxant activity is ascribed primarily to activation of KATP channels [18], [62], [85], [86], [87], [124]. The effect of H2S on relaxation of blood vessels is sensitive to the presence of KATP channel inhibitors and believed to involve direct channel activation by H2S [85], [86], [124], [125]. Alternatively, an indirect mechanism can be considered as inhibition of cytochrome c oxidase results in reduced ATP
Summary
As fast-moving as the field of H2S biochemistry has become, the pace is tempered by the many gaps in our understanding of the molecular mechanisms underlying sulfide oxidation, H2S homeostasis and H2S signaling targets. These gaps in knowledge also represent opportunities for moving the field forward. The controversies surrounding the sometimes dichotomous effects of H2S (e.g. it is both pro- and anti-inflammatory) highlight the problems associated with interpreting studies performed with a
References (216)
- et al.
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.
(2009) - et al.
Relative contributions of cystathionine beta-synthase and gamma-cystathionase to H2S biogenesis via alternative trans-sulfuration reactions
J. Biol. Chem.
(2009) - et al.
Enzymatic desulfuration of beta-mercaptopyruvate to pyruvate
J. Biol. Chem.
(1954) - et al.
Involvement of the cystathionine pathway in the biosynthesis of glutathione by isolated rat hepatocytes
Arch. Biochem. Biophys.
(1980) - et al.
The mercaptopyruvate sulfurtransferase of Trichomonas vaginalis links cysteine catabolism to the production of thioredoxin persulfide
J. Biol. Chem.
(2009) - et al.
Structure and kinetic analysis of H2S production by human mercaptopyruvate sulfurtransferase
J. Biol. Chem.
(2013) - et al.
PLP-dependent H2S biogenesis
Biochim. Biophys. Acta
(2011) - et al.
Taurine biosynthesis by neurons and astrocytes
J. Biol. Chem.
(2011) - et al.
Mammalian cysteine metabolism: new insights into regulation of cysteine metabolism
J. Nutr.
(2006) - et al.
Allosteric communication between the pyridoxal 5′-phosphate (PLP) and heme sites in the H2S generator human cystathionine beta-synthase
J. Biol. Chem.
(2012)
Detoxication of sodium 35 S-sulphide in the rat
Biochem. Pharmacol.
Oxidation of sodium sulphide by rat liver, lungs and kidney
Biochem. Pharmacol.
Crystal structure of sulfide:quinone oxidoreductase from Acidithiobacillus ferrooxidans: insights into sulfidotrophic respiration and detoxification
J. Mol. Biol.
Intermediary metabolism of L-cysteinesulfinic acid in animal tissues
Arch. Biochem. Biophys.
A protective role of hydrogen sulfide against oxidative stress in rat gastric mucosal epithelium
Toxicology
Hydrogen sulfide protects rat lung from ischemia-reperfusion injury
Life Sci.
Hydrogen sulphide: a novel inhibitor of hypochlorous acid-mediated oxidative damage in the brain?
Biochem. Biophys. Res. Commun.
Evidence for the formation of a novel nitrosothiol from the gaseous mediators nitric oxide and hydrogen sulphide
Biochem. Biophys. Res. Commun.
Reactivity of hydrogen sulfide with peroxynitrite and other oxidants of biological interest
Free Radic. Biol. Med.
Kinetic factors that control the fate of thiyl radicals in cells
Methods Enzymol.
The reaction of H(2)S with oxidized thiols: generation of persulfides and implications to H(2)S biology
Arch. Biochem. Biophys.
Perthiols as antioxidants: radical-scavenging and prooxidative mechanisms
Methods Enzymol.
On the mechanism of inactivation of xanthine oxidase by cyanide
J. Biol. Chem.
Evidence for an active site persulfide residue in rabbit liver aldehyde oxidase
J. Biol. Chem.
Persulfide generated from L-cysteine inactivates tyrosine aminotransferase. Requirement for a protein with cysteine oxidase activity and gamma-cystathionase
J. Biol. Chem.
Hydrogen sulfide-linked sulfhydration of NF-kappaB mediates its antiapoptotic actions
Mol. Cell
The possible role of hydrogen sulfide as an endogenous smooth muscle relaxant in synergy with nitric oxide
Biochem. Biophys. Res. Commun.
Actions and interactions of nitric oxide, carbon monoxide and hydrogen sulphide in the cardiovascular system and in inflammation—a tale of three gases!
Pharmacol. Ther.
Integrating nitric oxide, nitrite and hydrogen sulfide signaling in the physiological adaptations to hypoxia: a comparative approach
Comp. Biochem. Physiol. A Mol. Integr. Physiol.
Regulation of the mammalian heart function by nitric oxide
Comp. Biochem. Physiol. A Mol. Integr. Physiol.
Thiol-based redox switches in eukaryotic proteins
Antioxid. Redox Signal.
The possible role of hydrogen sulfide as an endogenous neuromodulator
J. Neurosci.
H(2)S signalling through protein sulfhydration and beyond
Nat. Rev. Mol. Cell Biol.
Persulfide reactivity in the detection of protein S-sulfhydration
ACS Chem. Biol.
Vascular endothelium expresses 3-mercaptopyruvate sulfurtransferase and produces hydrogen sulfide
J. Biochem.
The quantitatively important relationship between homocysteine metabolism and glutathione synthesis by the transsulfuration pathway and its regulation by redox changes
Biochemistry
High turnover rates for hydrogen sulfide allow for rapid regulation of its tissue concentrations
Antioxid. Redox Signal.
Purification and characterization of mitochondrial cysteine aminotransferase from rat liver
Physiol. Chem. Phys.
Thioredoxin and dihydrolipoic acid are required for 3-mercaptopyruvate sulfurtransferase to produce hydrogen sulfide
Biochem. J.
The quantitative significance of the transsulfuration enzymes for H2S production in murine tissues
Antioxid. Redox Signal.
Tissue and subcellular distribution of bound and acid-labile sulfur, and the enzymic capacity for sulfide production in the rat
Biol. Pharm. Bull.
H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine gamma-lyase
Science
Tissue and subcellular distribution of mercaptopyruvate sulfurtransferase in the rat: confocal laser fluorescence and immunoelectron microscopic studies combined with biochemical analysis
Histochem. Cell Biol.
3-Mercaptopyruvate sulfurtransferase produces hydrogen sulfide and bound sulfane sulfur in the brain
Antioxid. Redox Signal.
Enzymology of H2S biogenesis, decay and signaling
Antioxid. Redox Signal.
Enzymology of hydrogen sulfide turnover
Perturbations in homocysteine-linked redox homeostasis in a murine model for hyperhomocysteinemia
Am. J. Physiol. Regul. Integr. Comp. Physiol.
Studies on the regulation of glutathione level in rat liver
J. Biochem.
Extrahepatic tissues compensate for loss of hepatic taurine synthesis in mice with liver-specific knockout of cysteine dioxygenase
Am. J. Physiol. Endocrinol. Metab.
Whole tissue hydrogen sulfide concentrations are orders of magnitude lower than presently accepted values
Am. J. Physiol. Regul. Integr. Comp. Physiol.
Cited by (193)
The role of hydrogen sulfide in the retina
2023, Experimental Eye ResearchHydrogen sulfide-induced post-translational modification as a potential drug target
2023, Genes and DiseasesCitation Excerpt :In the non-enzymatic way, the spleen excretes the sulfhemoglobin formed by the combination of H2S in red blood cells with methemoglobin.40 The rate of H2S production in living organisms is very fast, such as in the liver, kidney, and brain of mice, but high concentrations of H2S are harmful to mammals, and the level of H2S in tissues must be strictly controlled, suggesting that the production and metabolism of H2S is a tightly regulated and relatively balanced process41–43 (Fig. 1). S-sulfhydration, also known as S-sulfuration or S-persulfidation, is the recently discovered H2S or polysulfide-induced PTM, which forms persulfides by chemically modifying specific cysteine residues of the target protein.44
Protein persulfidation: Rewiring the hydrogen sulfide signaling in cell stress response
2023, Biochemical PharmacologyInhibition and recovery of ANAMMOX with Na<inf>2</inf>SO<inf>3</inf>: From performance to microbial community analysis
2023, Journal of Environmental Chemical EngineeringA new fluorescent probe for hydrogen sulfide based on naphthalimide derivatives and its biological application
2022, Inorganic Chemistry Communications
- ☆
This article is part of a Special Issue entitled: Thiol-Based Redox Processes.
- ☆☆
This work was supported in part by a grant from the National Institutes of Health (HL58984 to R.B.) and the American Heart Association (13SDG17070096 to O.K.).