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. 2015 Dec 15:588:15-24.
doi: 10.1016/j.abb.2015.10.016. Epub 2015 Nov 5.

The chemical biology of hydropersulfides (RSSH): Chemical stability, reactivity and redox roles

Simran S Saund  1 , Victor Sosa  1 , Stephanie Henriquez  2 , Q Nhu N Nguyen  3 , Christopher L Bianco  1 , Shuhei Soeda  1 , Robert Millikin  1 , Corey White  1 , Henry Le  1 , Katsuhiko Ono  1 , Dean J Tantillo  3 , Yoshito Kumagai  4 , Takaaki Akaike  5 , Joseph Lin  6 , Jon M Fukuto  7
Affiliations

The chemical biology of hydropersulfides (RSSH): Chemical stability, reactivity and redox roles

Simran S Saund et al. Arch Biochem Biophys. .

Abstract

Recent reports indicate the ubiquitous prevalence of hydropersulfides (RSSH) in mammalian systems. The biological utility of these and related species is currently a matter of significant speculation. The function, lifetime and fate of hydropersulfides will be assuredly based on their chemical properties and reactivity. Thus, to serve as the basis for further mechanistic studies regarding hydropersulfide biology, some of the basic chemical properties/reactivity of hydropersulfides was studied. The nucleophilicity, electrophilicity and redox properties of hydropersulfides were examined under biological conditions. These studies indicate that hydropersulfides can be nucleophilic or electrophilic, depending on the pH (i.e. the protonation state) and can act as good one- and two-electron reductants. These diverse chemical properties in a single species make hydropersulfides chemically distinct from other, well-known sulfur containing biological species, giving them unique and potentially important biological function.

Keywords: Electrophilicity; Hydropersulfide; Nucleophilicity; Redox regulation; Thiols.

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Figures

Figure 1
Figure 1
pH-Dependency of the reaction of CN− with HE-SSH. HE-SSH was made via reaction of HE-SS-HE with H2S (see Materials and Methods section) and allowed to react for 1,500 seconds (25 min.) prior to the addition of CN− at the levels indicated. Levels of HE-SS−/HE-SS-HE were monitored via HE-SS− absorbance at 340 nm. (A) pH 10, (B) pH 7.2.
Figure 2
Figure 2
1H-NMR Analysis of the reaction of H2S with HE-SS-HE and subsequent reaction of HE-SSH with nucleophiles. (A) 1H-NMR signals for methylene protons adjacent to the sulfur atoms (shown in red) for the products of the reaction of HE-SSHE with NaSH (HE-SSH and HE-SH). (B) Addition of CN− to the HE-SSH/HE-SH product mixture. (C) Addition of N3− to the HE-SSH/HE-SH product mixture (note: same results observed for NH2NH2 and NH2OH).
Figure 3
Figure 3
(A) LUMO for CH3-SSH (SMD(water)-M06-2X/6-31+G(d,p)). (B) Electrostatic potential surface for CH3-SSH. (C) Calculated transition state structure and reaction free energies (kcal/mol) for the reaction of CN− with CH3-SSH at both sulfur atoms.
Figure 4
Figure 4
(A) Loss of HE-SS− absorbance at 340 nm under N2, air and O2 (pH 10). note: the hydropersulfide forming reaction was run for 1500 s prior to allowing exposure to N2, air or O2. (B) Consumption of O2 (measured via a Clarke electrode) by sequential addition of GSH (slope a, final conc. 1 mM), Na2S solution (slope b and c, final conc. 0.1 mM) and GSSG (slope d, final conc. 1 mM). (C) O2 Consumption by commercial Na2S4 with and without pre-treatment with TCEP-resin.
Figure 5
Figure 5
Recovery of oxidized (H2O2) CD148 enzyme activity by various reductants/treatments. Purified, pre-oxidized CD148 was treated with various reductants or controls for 30 min. at 37°C. After treatment, CD148 activity was assayed, using fluorescein diphosphate as a substrate. Fluorescence was measured every minute for 20 min.
Figure 6
Figure 6
Possible mechanism of reduction of oxidized CD148 by a persulfide to the active thiol form.
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