Sulfur as a signaling nutrient through hydrogen sulfide

Abstract

Hydrogen sulfide (H₂S) has emerged as an important signaling molecule with beneficial effects on various cellular processes affecting, for example, cardiovascular and neurological functions. The physiological importance of H₂S is motivating efforts to develop strategies for modulating its levels. However, advancement in the field of H₂S-based therapeutics is hampered by fundamental gaps in our knowledge of how H₂S is regulated, its mechanism of action, and its molecular targets. This review provides an overview of sulfur metabolism; describes recent progress that has shed light on the mechanism of H₂S as a signaling molecule; and examines nutritional regulation of sulfur metabolism, which pertains to health and disease.

Keywords: hydrogen sulfide; nutrition; signaling; sulfide oxidation; sulfur metabolism.

Figure 1

Simplified scheme of sulfur metabolism with an emphasis on the H₂S-generating reactions. In addition to the amino acids methionine and cysteine, the other significant dietary inputs into the pathway are the vitamins B₂ (flavin), B₆ (pyridoxal phosphate), and B₁₂ and zinc. Abbreviations: AdoHcy, S-adenosylhomocysteine; AdoMet, S-adenosylmethionine; BHMT, betaine homocysteine methyltransferase; CAT, cysteine/aspartate aminotransferase; CBS, cystathionine β-synthase; CDO, cysteine dioxygenase; CoA, coenzyme A; CSE, γ-cystathionase; DMG, dimethylglycine; GCS, γ-glutamylcysteine synthetase; GS, glutathione synthetase; GSH, glutathione; H₂S, hydrogen sulfide; MAT, methionine adenosyltransferase; MeTHF, 5-methyltetrahydrofolate; MS, methionine synthase; MSR, methionine synthase reductase; MST/Trx, mercaptopyruvate sulfurtransferase/thioredoxin; MTHFR, methylenetetrahydrofolate reductase; THF, tetrahydrofolate; Trx, thioredoxin; Zn, zinc.

Figure 2

Switching of methionine metabolism between the disposal (a) and conservation (b) modes is regulated by AdoMet. The thick arrows qualitatively depict increased metabolic flux. The dashed lines indicate activation (red ) and inhibition (blue) by AdoMet to control flux in response to low and high methionine supply. Abbreviations: AHC, AdoHcy hydrolase; GNMT, glycine N-methyltransferase; MAT-I/III, liver-specific methionine adenosyltransferase isoforms I and III; MT, methyltransferase.

Figure 3

The mitochondrial sulfide oxidation pathway. Sulfide quinone oxidoreductase (SQR) constitutes the first enzyme in this pathway and oxidizes H₂S, generating a protein-bound persulfide. Two routes for the transfer of the persulfide to sulfite ( path 1) or to an alternative acceptor (Ac in path 2) are shown. In path 1, the thiosulfate formed in the SQR-catalyzed reaction has to be converted to glutathione disulfide (GSSH) for further oxidation by ethylmalonic encephalopathy 1 (ETHE1). In path 2, if glutathione (GSH) is the acceptor, then the resulting GSSH product can directly serve as the substrate for ETHE1. However, if some other molecule serves as the proximal persulfide acceptor from SQR, then a sulfurtransferase (ST) such as rhodanese (Rhd) would likely be necessary to transfer the persulfide group to GSH for further oxidation. CSA and SO denote cysteine sulfinic acid and sulfite oxidase, respectively.

Figure 4

Molecular mechanisms for protein persulfidation. Persulfidation of targets can occur via several mechanisms, including ➀ a nucleophilic attack of sulfide on a disulfide, ➁ cysteine sulfenic acid, or ➂ cysteine-S-nitrosothiol; ➃ a reaction between a protein thiolate and H₂S₂ or polysulfide; or ➄ a transsulfuration reaction in which the sulfane sulfur from an existing persulfide is transferred to a different acceptor. Abbreviations: HNO, nitroxyl; HSSH, hydrogen disulfide; SNO, S-nitrosocysteine; SOH, sulfenic acid; SSH, persulfide.

Figure 5

Potential molecular mechanisms for H₂S signaling via S-nitrosothiol (HSNO) or sulfhydration of electrophiles. (a) Formation of HSNO results in cross talk between the NO and H₂S signaling pathways. HSNO can mediate transnitrosylation directly or can react further with another mole of H₂S, generating HNO. (b) Sulfhydration of electrophiles 8-nitro-cGMP and 15-deoxy-Δ12,14-prostaglandin (15d-PGJ2) by H₂S forms the corresponding thio adducts. Abbreviations: HNO, nitroxyl; HSSH, hydrogen disulfide; SNO, S-nitrosocysteine.

Figure 6

Reaction of H₂S with heme. The product of the interaction between H₂S and ferric heme is dictated by the properties of the heme pocket. Although H₂S coordinates to the ferric heme ion without additional redox chemistry in polar (high-dielectric-constant) sites, reduction to the ferrous heme is favored in nonpolar (low-dielectric-constant) sites.