The physiological role of hydrogen sulfide and beyond

• A novel pathway for the production of H2S from d-cysteine was discussed.
• Application of d-cysteine provides a new therapeutic approach.
• H2S-derived polysulfides formation and subsequent signaling was discussed.

Hydrogen sulfide (H2S) has been considered to be a physiological mediator since the identification of endogenous sulfides in the mammalian brain. H2S is produced from l-cysteine by enzymes such as cystathionine β-synthase (CBS), cystathionine γ-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3MST), and cysteine aminotransferase (CAT). CSE and CAT are regulated by Ca2+. At steady-state low intracellular concentrations of Ca2+, CSE and the 3MST/CAT pathway produce H2S. However, after intracellular concentrations of Ca2+ increase in stimulated cells, the production of H2S by these enzymes decreases. We recently identified a fourth pathway, by which H2S is produced from d-cysteine by the enzymes d-amino acid oxidase (DAO) and 3MST. This pathway is mainly localized in the cerebellum and the kidney. The production of H2S from d-cysteine is 80 times more efficient than that from l-cysteine in the kidney, and the administration of d-cysteine to mice ameliorates renal ischemia-reperfusion injury more effectively than l-cysteine. These results suggest that d-cysteine might be used to treat renal diseases or even increase the success of kidney transplantation. We found that H2S-derived polysulfides exist in the brain and activate transient receptor potential ankyrin-1 (TRPA1) channels 300 times more potently than H2S. Although TRPA1 channels mediate sensory transduction and respond to a variety of stimuli, including cold temperature, pungent compounds and environmental irritants, their endogenous ligand(s) has not been identified. The sulfane sulfur of polysulfides is a reactive electrophile that is readily transferred to a nucleophilic protein thiolate to generate the protein persulfide or bound sulfane sulfur by sulfhydration (as referred to as sulfuration). The bound sulfane sulfur-producing activity of polysulfides is much greater than that of H2S. This review focuses on the physiological roles of H2S and H2S-derived polysulfides as signaling molecules.