Hydropersulfides: H-Atom Transfer Agents Par Excellence

Abstract

Hydropersulfides (RSSH) are formed endogenously via the reaction of the gaseous biotransmitter hydrogen sulfide (HS) and disulfides (RSSR) and/or sulfenic acids (RSOH). RSSH have been investigated for their ability to store HS in vivo and as a line of defense against oxidative stress, from which it is clear that RSSH are much more reactive to two-electron oxidants than thiols. Herein we describe the results of our investigations into the H-atom transfer chemistry of RSSH, contrasting it with the well-known H-atom transfer chemistry of thiols. In fact, RSSH are excellent H-atom donors to alkyl (k ∼ 5 × 10 M s), alkoxyl (k ∼ 1 × 10 M s), peroxyl (k ∼ 2 × 10 M s), and thiyl (k > 1 × 10 M s) radicals, besting thiols by as little as 1 order and as much as 4 orders of magnitude. The inherently high reactivity of RSSH to H-atom transfer is based largely on thermodynamic factors; the weak RSS-H bond dissociation enthalpy (∼70 kcal/mol) and the associated high stability of the perthiyl radical make the foregoing reactions exothermic by 15-34 kcal/mol. Of particular relevance in the context of oxidative stress is the reactivity of RSSH to peroxyl radicals, where favorable thermodynamics are bolstered by a secondary orbital interaction in the transition state of the formal H-atom transfer that drives the inherent reactivity of RSSH to match that of α-tocopherol (α-TOH), nature's premier radical-trapping antioxidant. Significantly, the reactivity of RSSH eclipses that of α-TOH in H-bond-accepting media because of their low H-bond acidity (α ∼ 0.1). This affords RSSH a unique versatility compared to other highly reactive radical-trapping antioxidants (e.g., phenols, diarylamines, hydroxylamines, sulfenic acids), which tend to have high H-bond acidities. Moreover, the perthiyl radicals that result are highly persistent under autoxidation conditions and undergo very rapid dimerization (k = 5 × 10 M s) in lieu of reacting with O or autoxidizable substrates.

The reaction of hydrogen sulfide with disulfides: formation of a stable trisulfide and implications for biological systems

“…It is noteworthy that hydropersulfides are considered to be good reductants (superior to, for example, thiols and akin to ascorbate and/or tocopherols) (e.g. Bianco et al ., ; Chauvin et al ., ). Thus, in spite of the fact that RSSH species are formally oxidized with respect of the corresponding RSH, they are significantly more reducing and may possibly be responsible for the greater reducing capacity observed.…”

The hydrogen atom transfer reactivity of sulfinic acids

“…compare Δ G ° ∼ –16 and ∼0 kcal mol –1 for reactions of sulfenic acids and thiols with peroxyl radicals versus Δ G ° = –34 and –18 kcal mol –1 for reactions of sulfenic acids and thiols with primary alkyl or alkoxyl radicals). However, previous work from our group 31 , 56 , 57 suggests that there is more to it; specifically, that HAT to peroxyl radicals is enabled by secondary orbital interactions, wherein filled π or non-bonding orbitals on the group attached to the atom from which the H-atom is being transferred interact with the proximal end of the peroxyl radical π* MO. 73 Upon oxidation of the electron-rich sulfur atom in the sulfenic acid to a sulfinic acid, this secondary orbital interaction is expected to be significantly reduced.…”

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

“…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.…”