H2S biosynthesis and catabolism: new insights from molecular studies

Abstract

Hydrogen sulfide (H₂S) has profound biological effects within living organisms and is now increasingly being considered alongside other gaseous signalling molecules, such as nitric oxide (NO) and carbon monoxide (CO). Conventional use of pharmacological and molecular approaches has spawned a rapidly growing research field that has identified H₂S as playing a functional role in cell-signalling and post-translational modifications. Recently, a number of laboratories have reported the use of siRNA methodologies and genetic mouse models to mimic the loss of function of genes involved in the biosynthesis and degradation of H₂S within tissues. Studies utilising these systems are revealing new insights into the biology of H₂S within the cardiovascular system, inflammatory disease, and in cell signalling. In light of this work, the current review will describe recent advances in H₂S research made possible by the use of molecular approaches and genetic mouse models with perturbed capacities to generate or detoxify physiological levels of H₂S gas within tissues.

Keywords: Biosynthesis; Catabolism; Hydrogen sulfide; Molecular models.

Fig. 1

Generalised overview of H₂S production and degradation within mammalian tissues. The dietary amino acids, methionine and cysteine, serve as the primary substrates for the trans-sulfuration pathway and in the production of H₂S. The levels of H₂S within cells and tissues will be governed by the rates of synthesis by the enzymes cystathionine β synthase (CBS, EC 4.2.1.22), cystathionine-γ-lyase (CSE, EC 4.4.1.1), 3-mercaptopyruvate sulfurtransferase (3-MST, EC 2.8.1.2), versus the rates of oxidation and detoxification by the enzymes ethylmalonic encephalopathy protein 1 (ETHE1, EC: 1.13.11.18) and sulfur:quinone oxidoreductase (SQR, EC 1.8.5.4). Alternatively, the levels of the substrate cysteine may be depleted via the catabolic actions of cysteine dioxygenase (CDO, EC: 1.13.11.20)

Fig. 2

Over the last 10 years, a wide range of H₂S donor molecules have been developed to assist in determining the biological effects of H₂S under differing physiological and pathophysiological states. a H₂S donor molecules commonly used experimentally as research tools to manipulate cellular levels of H₂S gas. b Structures of several inhibitor molecules that target CBS and CSE