An Update on Thiol Signaling: S-Nitrosothiols, Hydrogen Sulfide and a Putative Role for Thionitrous Acid

Abstract

Long considered vital to antioxidant defenses, thiol chemistry has more recently been recognized to be of fundamental importance to cell signaling. S-nitrosothiols-such as S-nitrosoglutathione (GSNO)-and hydrogen sulfide (H₂S) are physiologic signaling thiols that are regulated enzymatically. Current evidence suggests that they modify target protein function primarily through post-translational modifications. GSNO is made by NOS and other metalloproteins; H₂S by metabolism of cysteine, homocysteine and cystathionine precursors. GSNO generally acts independently of NO generation and has a variety of gene regulatory, immune modulator, vascular, respiratory and neuronal effects. Some of this physiology is shared with H₂S, though the mechanisms differ. Recent evidence also suggests that molecules resulting from reactions between GSNO and H₂S, such as thionitrous acid (HSNO), could also have a role in physiology. Taken together, these data suggest important new potential targets for thiol-based drug development.

Keywords: S-nitrosothiols; antioxidants; hydrogen sulfide; thionitrous acid.

Figure 1

Eukaryotic thiol chemistry and the generation of thiol-based signaling molecules. Orange highlight shows product signaling molecules. AKR1A1—aldoketoreductase family 1 member 1A, CAT—cysteine aspartate aminotransferase, CBS—cystathionine b-synthase, CSE—cystathionine gamma lyase, CDO—cysteine deoxygenase, CoA—Coenzyme A, C-SNO—S-nitrosocysteine, GSNO—S-nitrosoglutathione, GSNOR—S-nitrosoglutathione reductase, GS—glutathione synthase, GCS—glutamylcysteine synthase, MAT—methionine adenosyltransferase; SAM- S-adenosyl methionine; 3MST—3 mercaptopuruvate sulfur transferase, PTA—pantetheinase, SNO-CoA—S-nitroso-Coenzyme A, γGT—γ-glutamyl transpeptidase.