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

Abstract

The recent finding that hydropersulfides (RSSH) are biologically prevalent in mammalian systems has prompted further investigation of their chemical properties in order to provide a basis for understanding their potential functions, if any. Hydropersulfides have been touted as hyper-reactive thiol-like species that possess increased nucleophilicity and reducing capabilities compared to their thiol counterparts. Herein, using persulfide generating model systems, the ability of RSSH species to act as one-electron reductants has been examined. Not unexpectedly, RSSH is relatively easily oxidized, compared to thiols, by weak oxidants to generate the perthiyl radical (RSS·). Somewhat surprisingly, however, RSS· was found to be stable in the presence of both O2 and NO and only appears to dimerize. Thus, the RSSH/RSS· redox couple is readily accessible under biological conditions and since dimerization of RSS· may be a rare event due to low concentrations and/or sequestration within a protein, it is speculated that the general lack of reactivity of individual RSS· species may allow this couple to be utilized as a redox component in biological systems.

Biological hydropersulfides and related polysulfides – a new concept and perspective in redox biology

“…Thus, thiol proteins that may have important function in an oxidative and/or electrophilic stress environment may have increased activity if converted to a hydropersulfide. Also, as alluded to previously, the more physiologically accessible redox couple for RSS − /RSS· compared to RS − /RS· may allow the oxidation of a protein cysteine to the corresponding hydropersulfide to serve as an electron transfer “redox gate” 41. That is, electron transfer through an RS − /RS· couple is prohibitive since RS· is too oxidizing and RS − is too poor a reductant – however, oxidation of the protein thiol to a hydropersulfide could allow electrons to flow since RSS − is a reasonably good reductant and RSS· is not nearly as oxidizing as RS·.…”

“…The fact that RS· is a fairly potent one‐electron oxidant is an indication of the relatively poor ability of RSH to serve as a reductant. On the other hand, perthiyl radicals (RSS·) are relatively weak oxidants and are readily formed from one‐electron oxidation of RSSH/RSS − 41, 42. RSSH/RSS − is a good reductant due to the stability of the oxidized RSS· species.…”

“…In both cases, the stability of the unpaired electron is likely due to an overlap of the orbital containing the unpaired electron with the adjacent orbital containing a lone pair of electrons 43. The lack of reactivity of RSS· is evidenced by the fact that it does not readily react with O 2 and NO, both established scavengers of other radical species 41, 44. Although it has been proposed that the one‐electron redox properties of RSSH/RSS − may have biological function (i.e., can serve as a “redox gate” 41), this has yet to be shown.…”

“…That is, electron transfer through an RS − /RS· couple is prohibitive since RS· is too oxidizing and RS − is too poor a reductant – however, oxidation of the protein thiol to a hydropersulfide could allow electrons to flow since RSS − is a reasonably good reductant and RSS· is not nearly as oxidizing as RS·. Moreover, RSS· has been shown to be relatively unreactive toward the paramagnetic signaling species NO and O 2 , allowing the RSS − /RSS· couple to be usable in aerobic and NO‐rich environments 41, 44. It should be stressed that this idea is speculative at this time and there are no documented examples of this phenomenon.…”

Inorganic Reactive Sulfur-Nitrogen Species: Intricate Release Mechanisms or Cacophony in Yellow, Blue and Red?

“…Fukuto’s group showed that MCP-SSNO ( N -methoxycarbonyl penicillamine nitrosopersulfide), as the product of the interaction of GSNO with persulfide MCP-SSH, is unstable and decomposes to MCP-SS • and • NO through homolytical cleavage [23]. Computational analysis showed that the S-N bond in RSS-NO is extremely weak at room temperature (1.85 Å in CH 3 SSNO, 1.953 Å in cis -HSSNO and 1.878 Å in trans -HSSNO) in comparison to SSNO − (1.73 Å, or 1.676 Å in cis -SSNO − and 1.695 Å in trans -SSNO − ) [22,23]. This shortening of S-N bond in the anion SSNO − leads to the partial double bond character of the S-N bond [23].…”