The chemical biology of protein hydropersulfides: Studies of a possible protective function of biological hydropersulfide generation

Abstract

The recent discovery of significant hydropersulfide (RSSH) levels in mammalian tissues, fluids and cells has led to numerous questions regarding their possible physiological function. Cysteine hydropersulfides have been found in free cysteine, small molecule peptides as well as in proteins. Based on their chemical properties and likely cellular conditions associated with their biosynthesis, it has been proposed that they can serve a protective function. That is, hydropersulfide formation on critical thiols may protect them from irreversible oxidative or electrophilic inactivation. As a prelude to understanding the possible roles and functions of hydropersulfides in biological systems, this study utilizes primarily chemical experiments to delineate the possible mechanistic chemistry associated with cellular protection. Thus, the ability of hydropersulfides to protect against irreversible electrophilic and oxidative modification was examined. The results herein indicate that hydropersulfides are very reactive towards oxidants and electrophiles and are modified readily. However, reduction of these oxidized/modified species is facile generating the corresponding thiol, consistent with the idea that hydropersulfides can serve a protective function for thiol proteins.

The chemical biology of the persulfide (RSSH)/perthiyl (RSS·) redox couple and possible role in biological redox signaling

“…The in situ generation of hydropersulfides can be accomplished using a penicillamine-based donor species MCPD giving the hydropersulfide MCP-SSH [22,23,35] (Figure 1a). …”

“…The results presented herein indicate an accessible RSSH/RSS· (or RSS − /RSS·) redox couple with both redox partners being fairly stable to, for example, reaction with O 2 or NO. Although purely speculative at this time, it is intriguing to consider that cellular oxidative stress, conditions likely conducive to hydropersulfide formation [22], can generate persulfides in proteins, allowing them to then participate in a redox or electron transfer process. That is, a protein thiol may not possess the proper redox properties to participate in an electron transfer or redox event, but conversion to the corresponding persulfide may act as a “redox gate” allowing such chemistry to occur (Figure 10).…”

“…Recent work from this lab and others has shown that RSSH exhibit enhanced thiol-like chemistry compared to the corresponding thiol [20,21,22]. That is, RSSH are more nucleophilic and reducing (both one- and two-electron) compared to thiols and it is speculated that these properties may be important to their physiological utility.…”

The chemical biology of HNO signaling

“…Thus, it may be expected that the reaction of HNO with a persulfide is significantly faster than with the corresponding thiol. Indeed, it was found that HNO was capable of reacting with a hydropersulfide [24], although the chemical details of this interaction await clarification. Interestingly, when compared to the corresponding thiol, the HNO-modified persulfide was more easily reduced back to the thiol by an exogenous reductant (dithiothreitol, DTT).…”

Hydropersulfides, the new kids in the COPD inflammatory town

“…The rush of discovery for H 2 S and its derivative compounds started in the late 1980s by reports of potential biological roles of H 2 S in modulatory and signalling pathways 4. The associated probable health benefits generated a renewed interest in the study of H 2 S, as reflected in the exponential increase in the number of publications 4…”