H2S and its role in redox signaling

Abstract

Hydrogen sulfide (H2S) has emerged as an important gaseous signaling molecule that is produced endogenously by enzymes in the sulfur metabolic network. H2S exerts its effects on multiple physiological processes important under both normal and pathological conditions. These functions include neuromodulation, regulation of blood pressure and cardiac function, inflammation, cellular energetics and apoptosis. Despite the recognition of its biological importance and its beneficial effects, the mechanism of H2S action and the regulation of its tissue levels remain unclear in part owing to its chemical and physical properties that render handling and analysis challenging. Furthermore, the multitude of potential H2S effects has made it difficult to dissect its signaling mechanism and to identify specific targets. In this review, we focus on H2S metabolism and provide an overview of the recent literature that sheds some light on its mechanism of action in cellular redox signaling in health and disease. This article is part of a Special Issue entitled: Thiol-Based Redox Processes.

Keywords: Hydrogen sulfide; Redox; Thiol.

Fig. 1

Overview of the physiological effects elicited by H₂S.

Fig. 2

Pathways for sulfide biogenesis and clearance. (a) H₂S is synthesized from the amino acids, cysteine and homocysteine via the transsulfuration pathway enzymes, CBS and CSE and by the action of CAT, MST and thioredoxin (Trx) as described in the text. (b) Sulfide oxidation occurs in the mitochondrion. While the first reaction is catalyzed by SQR, the subsequent steps in the pathway remain to be defined. In “path 1” sulfite is shown as the acceptor of sulfane sulfur from SQR while in “path 2”, the acceptor (Ac) is not known and is an intermediate carrier of the sulfane sulfur between SQR and glutathione. The following new abbreviations are used in the figure: Ac (acceptor), GCS (γ-glutamylcysteine synthetase), GS (glutathione synthetase), Rhd (rhodanese), ST (sulfurtransferase).

Fig. 3

Alternative mechanisms for persulfidation. Persulfidation can occur by transsulfuration in which a small molecule or protein persulfide donor transfers the sulfane sulfur to an acceptor (a), by reaction of a protein thiolate with H₂S₂ (b), by attack of sulfide on a disulfide (c), by attack of sulfide on cysteine sulfenic acid or (d) by attack of sulfide on cysteine-S-nitrosothiol.

Fig. 4

Mechanism for crosstalk between NO and H₂S signaling pathways. S-nitrosothiol (HSNO) canbeformed via transnitrosylation and can itself be a donor in anitrosylation reaction or can react with a second mole of H₂S generating HNO.

Fig. 5

Reaction of H₂S with electrophiles. Sulfide can attack electrophiles like 8-nitro-cGMP to form 8-HS-cGMP (top) or fatty acids like 15-deoxy-Δ^12,14-prostaglandin to form the thio-adduct.

Fig. 6

The reaction of H₂S with heme is dictated by the polarity of the heme pocket. A high dielectric (or polar) site favors reduction to ferrous heme whereas a low dielectric (or non-polar) site favors coordination to ferric heme.