Chemical Biology of H₂S Signaling through Persulfidation

Abstract

Signaling by HS is proposed to occur via persulfidation, a posttranslational modification of cysteine residues (RSH) to persulfides (RSSH). Persulfidation provides a framework for understanding the physiological and pharmacological effects of HS. Due to the inherent instability of persulfides, their chemistry is understudied. In this review, we discuss the biologically relevant chemistry of HS and the enzymatic routes for its production and oxidation. We cover the chemical biology of persulfides and the chemical probes for detecting them. We conclude by discussing the roles ascribed to protein persulfidation in cell signaling pathways.

N-Acetyl Cysteine Functions as a Fast-Acting Antioxidant by Triggering Intracellular H2S and Sulfane Sulfur Production

“…It is however not clear if non-enzymatic transpersulfidation from GSSH to roGFP2 can be efficient in producing roGFP2 persulfidation. This is perhaps unlikely, since unhindered hydropersulfides seem to prefer attack at the inner sulfur atom, to release H 2 S, which is a better leaving group (Filipovic et al, 2017). Transpersulfidation (i.e.…”

“…Both inorganic (Na 2 S 2 , Na 2 S 3 , Na 2 S 4 ) and organic (DMTS, DATS) polysulfides were confirmed to induce intracellular roGFP2 oxidation in a compartment-independent manner. It is well known that solubilized polysulfides are intrinsically unstable and subject to rapid disproportionation into multiple species (Filipovic et al, 2017). Inside cells they are also subject to reduction.…”

BODIPY‐Based Fluorescent Probes for Biothiols

“…Biothiols, including cysteine (Cys), homocysteine (Hcy), reduced glutathione (GSH), and hydrogen sulfide (H 2 S), play crucial roles in biological systems. As the simplest biothiol, H 2 S is produced endogenously through both enzymatic and non‐enzymatic processes . Abnormal levels of H 2 S may result in various problems such as Huntington's, Parkinson's, and Alzheimer's diseases .…”

“…As the simplest biothiol, H 2 S is produced endogenously through both enzymatic and non‐enzymatic processes . Abnormal levels of H 2 S may result in various problems such as Huntington's, Parkinson's, and Alzheimer's diseases . Aberrant levels of Cys have an impact on liver damage, skin lesion, hair depigmentation, slow growth, and cancer, etc .…”

Strategies for the Design of Donors and Precursors of Reactive Sulfur Species

“…While the first small‐molecule RSSH was prepared in 1954, RSSH chemistry is still an underdeveloped area of research . This is mainly because RSSH are very unstable and difficult to handle.…”