S1-1 H2S and beyond

Abstract

Hydrogen sulfide (H 2 S) is a toxic gas that emits an unpleasant smell of rotten eggs. About 20 years ago, the discovery of endogenous sulfide in mammalian brain urged us to study the role of H 2 S in neuronal transmission. We found a neuromodulatory role with cystathionine beta–synthase (CBS) as H 2 S-producing enzyme in the brain. In the following year we demonstrated that H 2 S relaxes vascular smooth muscle in synergy with nitric oxide (NO) with cystathionine gamma–lyase (CSE) as another enzyme. Our finding of a cytoprotective effect of H 2 S on neurons from oxidative stress led to the identification of protecting various tissues and organs from ischemia–reperfusion injury. In addition to the H 2 S-producing pathway with 3-mercaptopyruvate sulfurtransferase (3MST) and cysteine aminotransferase (CAT), we recently found a novel pathway with 3MST and d -amino acid oxidase (DAO) that produces H 2 S from d -cysteine. This pathway is more efficient than l -cysteine pathways in the kidney, and promises the therapeuric application of d -cysteine to the renal ischemic diseases. H 2 S is oxidized to polysufides that exist in the brain and activate transient receptor potential ankyrin 1 (TRPA1) channels in astrocytes more efficiently than parental H 2 S. H 2 S exerts its effect by reducing a target such as a cysteine disulfide bond, whereas polysulfides by adding bound sulfane sulfur to protein thiols (sulfhydration or sulfuration). The physiological roles of H 2 S and polysulfides will be discussed.