Redox biochemistry of hydrogen sulfide

Abstract

H(2)S, the most recently discovered gasotransmitter, might in fact be the evolutionary matriarch of this family, being both ancient and highly reduced. Disruption of gamma-cystathionase in mice leads to cardiovascular dysfunction and marked hypertension, suggesting a key role for this enzyme in H(2)S production in the vasculature. However, patients with inherited deficiency in gamma-cystathionase apparently do not present vascular pathology. A mitochondrial pathway disposes sulfide and couples it to oxidative phosphorylation while also exposing cytochrome c oxidase to this metabolic poison. This report focuses on the biochemistry of H(2)S biogenesis and clearance, on the molecular mechanisms of its action, and on its varied biological effects.

FIGURE 1.

H₂S biogenesis and catabolism. a, The enzymes in the transsulfuration pathway, CBS and CSE, catalyze multiple H₂S-producing reactions, and the dominant reaction is shown in red. CAT and MST are components of the cysteine catabolism pathway. The preferred sulfur acceptor of MST is not known. b, components of the mitochondrial sulfide oxidation pathway that couple to the electron transfer chain. Q is ubiquinone. This figure was adapted from Ref. .

FIGURE 2.

Molecular mechanisms for H₂S targeting. a, H₂S can ligate to ferric heme in globins, and depending on the stereoelectronic properties of the distal heme site, can remain bound to, dissociate from, or reduce the iron center. b, persulfidation of proteins requires attack of H₂S to an oxidized side chain, e.g. a sulfenic acid or disulfide. c, once formed, persulfides need to be protected from small molecule thiols (e.g. glutathione) or thiol groups on the same or different proteins. Conversely, the same chemical reactions can be exploited to liberate H₂S from the “stored sulfur” pool. GSH is glutathione.