Signaling molecules: hydrogen sulfide and polysulfide

Abstract

Significance: Hydrogen sulfide (H2S) has been recognized as a signaling molecule as well as a cytoprotectant. It modulates neurotransmission, regulates vascular tone, and protects various tissues and organs, including neurons, the heart, and kidneys, from oxidative stress and ischemia-reperfusion injury. H2S is produced from l-cysteine by cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), and 3-mercaptopyruvate sulfurtransferase (3MST) along with cysteine aminotransferase.

Recent advances: In addition to these enzymes, we recently identified a novel pathway to produce H2S from d-cysteine, which involves d-amino acid oxidase (DAO) along with 3MST. These enzymes are localized in the cytoplasm, mitochondria, and peroxisomes. However, some enzymes translocate to organelles under specific conditions. Moreover, H2S-derived potential signaling molecules such as polysulfides and HSNO have been identified.

Critical issues: The physiological stimulations, which trigger the production of H2S and its derivatives and maintain their local levels, remain unclear.

Future directions: Understanding the regulation of the H2S production and H2S-derived signaling molecules and the specific stimuli that induce their release will provide new insights into the biology of H2S and therapeutic development in diseases involving these substances.

FIG. 1.

Suppression of the H₂S-producing activities of CSE and the 3MST/CAT pathway by Ca²⁺. CSE and the 3MST/CAT pathway produce H₂S in a steady state at low intracellular concentrations of Ca²⁺. When intracellular Ca²⁺ concentrations are increased by Ca²⁺ influx or a Ca²⁺ release from the mitochondria or endoplasmic reticulum, CSE decreases the production of H₂S by 50%, and the 3MST/CAT pathway nearly ceases producing H₂S. CAT, cysteine aminotransferase; CSE, cystathionine γ-lyase; H₂S, hydrogen sulfide; 3MST, 3-mercaptopyruvate sulfurtransferase.

FIG. 2.

Production of H₂S from d-cysteine by the 3MST/DAO pathway. d-Cysteine is metabolized by the peroxisomal enzyme DAO to 3MP, which is transferred to the mitochondria and metabolized by 3MST to H₂S. In the kidney, the production of H₂S from d-cysteine is 60 times higher than that from l-cysteine. DAO, d-amino acid oxidase; 3MP, 3-mercaptopyruvate.

FIG. 3.

Synergistic effect of H₂S and NO on vascular smooth muscle relaxation. The 3MST/CAT pathway mainly produces H₂S in the endothelium, while CSE produces H₂S in smooth muscles. There is a synergistic effect of H₂S on vascular smooth muscle relaxation with NO, which is produced by NOS from arginine. NOS, nitric oxide synthetase.

FIG. 4.

Bound sulfane sulfur. The trisulfide bridge between two cysteine residues in a protein is a persulfide. Elemental sulfur attached to proteins and polysulfides release H₂S under reducing conditions.

FIG. 5.

Activation of TRPA1 channels through the addition of bound sulfane sulfur (sulfhydration or sulfration) by polysulfides produced from H₂S. Polysufides produced from H₂S add bound sulfane sulfur (sulfhydration or sulfuration) to the active cysteine residues located at the amino-terminus of TRPA1 channels to activate the channels. Sulfurated residues may further react with each other and produce cysteine disulfide bonds, which can be reduced back to cysteine residues by DTT, and the channels return to their inactive state. DTT, dithiothreitol; TRAP1, transient receptor potential ankyrin 1.

FIG. 6.

Reduction of the cysteine disulfide bond by H₂S and the addition of bound sulfane sulfur (sulfhydration or sulfuration) to cysteine residues by polysulfides. H₂S (oxidation state: −2) reduces cysteine disulfide bond (oxidation state: −1) to generate two thiols of cysteine residues (oxidation state: −2). Polysulfides (oxidation state of inner sulfur: 0) add bound sulfane sulfur to cysteine residues (sulfhydration or sulfuration). A persulfurated cysteine (oxidation state of inner sulfur 0) reacts with a cysteine (thiol, oxidation state −2) to produce a cysteine disulfide bond.

FIG. 7.

Facilitation of hippocampal LTP induction by H₂S and polysulfides. H₂S reduces cysteine disulfide bond of NMDA receptors to enhance its activity. Polysulfides activate TRPA1 channels in astrocytes to induce Ca²⁺ influx, which triggers a release of the gliotransmitter d-serine that enhances the activity of NMDA receptors. Through these effects, H₂S and polysulfides facilitate the induction of LTP. LTP, long-term potentiation; NMDA, N-methyl d-aspartate.

FIG. 8.

Effective ROS scavenging by GSH, while scavenging by H₂S is less efficient. H₂S enhances the activity of cysteine transporter and cysteine/glutamate antiporter to increase cysteine intracellular concentrations. Through this effect and by enhancing the activity of GCL (γ-GCS), H₂S increases glutathione production. Since the intracellular concentrations of H₂S and glutathione range from 10 nM to 3 μM and from 1 to 10 mM, respectively, glutathione scavenges ROS more efficiently than H₂S. GCL, glutamate cysteine ligase; γ-GCS, γ-glutamylcysteine synthetase; ROS, reactive oxygen species.

FIG. 9.

Nrf2 translocation by detachment from Keap1 through the addition of bound sulfane sulfur by polysulfides. A transcription factor, Nrf2, binds to Keap1, and this complex is ubiquitinated and subsequently degraded. Polysulfides add bound sulfane sulfur (sulfhydration or sulfuration) to cysteine residues in Keap1 that causes conformational changes in Keap1, resulting in the release of Nrf2. Nrf2 translocates to the nucleus to upregulate antioxidant genes such as HO-1 and GCL, resulting in the protection of neurons from oxidative stress. HO-1, heme oxygenase 1; Keap1, Kelch ECH-associating protein 1; Nrf2, nuclear factor erythroid 2-related factor 2.