How super is supersulfide?: Reconsidering persulfide reactivity in cellular biology

In an attempt to understand the cellular mechanisms of H2S signalling, recent research has focused on supersulfide (i.e., alkyl and inorganic hydropersulfide) formation and subsequent reactivity. While our understanding of supersulfides in biology has rapidly advanced, there are some chemical features of this unique functional group that require re-evaluation. Persulfides, such as glutathione hydropersulfide, have been called “supersulfide” as it is assumed that the alkyl hydropersulfide (RSSH) functional group is a superior nucleophile compared to the corresponding thiol (RSH) due to the alpha effect. However, recent quantum mechanical calculations and experimental data show that persulfides are not “super” nucleophiles, but rather potent electrophiles in cellular biology. It is proposed here that persulfides, via their electrophilic signalling effects, induces a cellular hormesis effect, which may explain the observed effects of altered RSSH production. Therefore, the electrophilic and thiol oxidant properties of persulfides should considered in cellular biology.