H2S Synthesizing Enzymes: Biochemistry and Molecular Aspects

Abstract

Hydrogen sulfide (H2S) is a biologically active gas that is synthesized naturally by three enzymes, cystathionine γ-lyase (CSE), cystathionine β-synthetase (CBS) and 3-mercaptopyruvate sulfurtransferase (3-MST). These enzymes are constitutively present in a wide array of biological cells and tissues and their expression can be induced by a number of disease states. It is becoming increasingly clear that H2S is an important mediator of a wide range of cell functions in health and in disease. This review therefore provides an overview of the biochemical and molecular regulation of H2S synthesizing enzymes both in physiological conditions and their modulation in disease states with particular focus on their regulation in asthma, atherosclerosis and diabetes. The importance of small molecule inhibitors in the study of molecular pathways, the current use of common H2S synthesizing enzyme inhibitors and the relevant characteristics of mice in which these enzymes have been genetically deleted will also be summarized. With a greater understanding of the molecular regulation of these enzymes in disease states, as well as the availability of novel small molecules with high specificity targeted towards H2S producing enzymes, the potential to regulate the biological functions of this intriguing gas H2S for therapeutic effect can perhaps be brought one step closer.

Effect of endotoxemia in mice genetically deficient in cystathionine-γ-lyase, cystathionine-β-synthase or 3-mercaptopyruvate sulfurtransferase

“…Moreover, there are also studies demonstrating that H 2 S donation can be detrimental (18–20), and there are even studies demonstrating that pharmacological inhibitors of H 2 S biosynthesis can be detrimental in certain models of critical illness (31,32). While some of these discrepancies may be attributable to the differences in the experimental models used, some of the explanation is likely to be related to the well-known bell-shaped dose-response character (1–10) of H 2 S, where lower concentrations of the mediator exert distinctly different (often opposite) pharmacological effects than higher concentrations; indeed, lower concentrations, and delayed administration of H 2 S donors are often found protective, while higher concentrations are often detrimental. It should also be noted that H 2 S exerts differential effects on various functions in different cell types and different organs (e.g., vascular functions, pro-inflammatory signaling, redox/oxidant processes, cell death effector pathways, cellular bioenergetic pathways); modulation of some of these effects may be ultimately beneficial for the outcome of critical illness, while modulation of others may be detrimental.…”

“…Three major hydrogen sulfide (H 2 S)-producing enzymes have been identified: cystathionine-γ-lyase (CSE), cystathionine-β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase (3MST) (1–10). H 2 S is known to regulate a multitude of physiological and pathophysiological functions in the vascular, immune and nervous system (1–10).…”

“…H 2 S is known to regulate a multitude of physiological and pathophysiological functions in the vascular, immune and nervous system (1–10). …”

Possible role of hydrogen sulfide as an endogenous relaxation factor in the rat bladder and prostate

“…H 2 S biosynthesis is mediated by two mechanisms. The first involves two enzymes responsible for the metabolism of L‐cysteine, cystathionine β‐synthase (CBS) and cystathionine γ‐lyase (CSE), while the second involves the combined action of 3‐mercaptopyruvate sulfurtransferase (MPST) and cysteine aminotransferase (CAT) . CBS and CSE produce H 2 S from L‐cysteine.…”

TET2 Protects against oxLDL-Induced HUVEC Dysfunction by Upregulating the CSE/H2S System

“…It has been widely involved in various physiological and pathological processes (Huang and Moore, 2015). In the cardiovascular system, H 2 S is physiologically generated by cystathionine-γ-lyase (CSE) (Zhao et al, 2001; Ishii et al, 2004).…”