Regulators of the transsulfuration pathway

Abstract

The transsulfuration pathway is a metabolic pathway where transfer of sulfur from homocysteine to cysteine occurs. The pathway leads to the generation of several sulfur metabolites, which include cysteine, GSH and the gaseous signalling molecule hydrogen sulfide (H S). Precise control of this pathway is critical for maintenance of optimal cellular function and, therefore, the key enzymes of the pathway, cystathionine β-synthase and cystathionine γ-lyase, are regulated at multiple levels. Disruption of the transsulfuration pathway contributes to the pathology of several conditions such as vascular dysfunction, Huntington's disease and during ageing. Treatment with donors of hydrogen sulfide and/or stimulation of this pathway have proved beneficial in several of these disorders. In this review, we focus on the regulation of the transsulfuration pathway pertaining to cysteine and H S, which could be targeted to develop novel therapeutics.

Discovery of a redox-thiol switch regulating cellular energy metabolism

“…We chose INS1 cells because the levels of the H 2 S-producing enzyme CTH, was undetectable in the absence of ER stress ( Fig 4E) and thus made this cell line a good candidate to determine the effects of CTH expression on the sulfhydrome. We have previously shown that during chronic ER stress in MIN6 cells, increased protein S-sulfhydration was in good correlation with increased expression of the transcription factor ATF4 and its transcription target, the CTH gene (Sbodio et al, 2018). In order to get more insights on the regulation of the sulfhydromes by the ATF4/CTH axis-mediated de novo H 2 S synthesis ( Fig 4A), we overexpressed the transcription factor ATF4 or GFP (green fluorescent protein) as a negative control in INS1 cells and applied the TMT-BTA assay to cell lysates.…”

“…The higher levels of protein S-sulfhydration in hepatocytes as compared to the EndoC-BH3 cells, was further supported by the higher expression levels of the H 2 S-generating enzymes in these cells ( Fig 2F). De novo synthesis of H 2 S is mediated by three enzymes: CTH (cystathionine γ lyase), CBS (cystathionine β synthase) and 3-MST (3-mercaptopyruvate sulfurtransferase) (Sbodio et al, 2018). Therefore, the levels of sulfhydrated proteins are in good correlation with the levels of the H 2 S-generating enzymes in these cells (Fig 2).…”

“…There are three H 2 S-generating enzymes, CTH, CBS and MST, in mammalian cells (Sbodio et al, 2018). Unlike the other two, CTH protein expression is transcriptionally induced by the stress-induced master transcription factor-ATF4, thus linking H 2 S synthesis to diverse physiological and pathological stress conditions (Paul and Snyder, 2015;Sbodio et al, 2018).…”

“…H 2 S reacts with and modifies protein cysteine thiol groups to form persulfide bonds, known as protein S-sulfhydration. Because H 2 S is unstable, and its synthesis is regulated (Sbodio et al, 2018), protein S-sulfhydration serves as a mechanism to regulate protein functions with an impact in cellular metabolism (Mustafa et al, 2009, Gao et al, 2015.…”

Highlighted mechanistic aspects in the chemical biology of reactive sulfur species

“…Sbodio et al . contributed with an insightful summary on these regulatory pathways and their malfunctioning (Sbodio et al ., ). The authors discuss these mechanisms in relation to the pathophysiological consequences of dysregulated trans‐sulfuration and provide novel strategies to tackle associated diseases.…”