Persulfides (RSSH/RSS-) participate in sulfur trafficking and metabolic processes, and are proposed to mediate the signaling effects of H2S. Despite their growing relevance, their chemical properties are poorly understood. Herein, we studied experimentally and computationally the formation, acidity, and nucleophilicity of glutathione persulfide (GSSH/GSS-), the derivative of the abundant cellular thiol, glutathione (GSH). We characterized the kinetics and equilibrium of GSSH formation from glutathione disulfide and H2S. A pKa of 5.45 for GSSH was determined, which is 3.49 units below that of GSH. The reactions of GSSH with the physiologically-relevant electrophiles peroxynitrite and hydrogen peroxide, as well as with the probe monobromobimane, were studied and compared with those of thiols. These reactions occurred through SN2 mechanisms. At neutral pH, GSSH reacted faster than GSH due to increased availability of the anion and, depending on the electrophile, increased reactivity. In addition, GSS- presented higher nucleophilicity with respect to a thiolate with similar basicity. This can be interpreted in terms of the so-called alpha effect, i.e. the increased reactivity of a nucleophile when the atom adjacent to the nucleophilic atom has high electron density. The magnitude of the alpha effect correlated with the Brønsted nucleophilic factor, βnuc, for the reactions with thiolates and with the ability of the leaving group. Our study constitutes the first determination of the pKa of a biological persulfide and the first examination of the alpha effect in sulfur nucleophiles, and sheds light on the chemical basis of the biological properties of persulfides.
Hydrogen sulfide (H2S/HS–) can be formed in mammalian tissues and exert physiological effects. It can react with metal centers and oxidized thiol products such as disulfides (RSSR) and sulfenic acids (RSOH). Reactions with oxidized thiol products form persulfides (RSSH/RSS–). Persulfides have been proposed to transduce the signaling effects of H2S through the modification of critical cysteines. They are more nucleophilic and acidic than thiols and, contrary to thiols, also possess electrophilic character. In this review, we summarize the biochemistry of hydrogen sulfide and persulfides, focusing on redox aspects. We describe biologically relevant one- and two-electron oxidants and their reactions with H2S and persulfides, as well as the fates of the oxidation products. The biological implications are discussed.
Persulfides (RSSH/RSS−) can be formed in protein and non-protein thiols (RSH) through several different pathways, some of which are dependent on hydrogen sulfide (H2S/HS−). In addition to their roles in biosynthetic processes, persulfides are possible transducers of physiological effects of H2S through the modification of critical cysteines. Persulfides have a very rich biological chemistry that is currently under investigation. They are more nucleophilic and acidic than thiols and, unlike thiols, they can also be electrophilic. They are especially good one-electron reductants. Methods to detect their formation are under continuous development. In this minireview we describe the pathways of formation of persulfides, their biochemical properties and the techniques available for their detection, and we discuss the possible implications of their formation in biological systems.
Cystathionine β-synthase
(CBS) is an enzyme involved in sulfur
metabolism that catalyzes the pyridoxal phosphate-dependent condensation
of homocysteine with serine or cysteine to form cystathionine and
water or hydrogen sulfide (H2S), respectively. CBS possesses
a b-type heme coordinated by histidine and cysteine.
Fe(III)-CBS is inert toward exogenous ligands, while Fe(II)-CBS is
reactive. Both Fe(III)- and Fe(II)-CBS are sensitive to mercury compounds.
In this study, we describe the kinetics of the reactions with mercuric
chloride (HgCl2) and p-chloromercuribenzoic
acid. These reactions were multiphasic and resulted in five-coordinate
CBS lacking thiolate ligation, with six-coordinate species as intermediates.
Computational QM/MM studies supported the feasibility of formation
of species in which the thiolate is proximal to both the iron ion
and the mercury compound. The reactions of Fe(II)-CBS were faster
than those of Fe(III)-CBS. The observed rate constants of the first
phase increased hyperbolically with concentration of the mercury compounds,
with limiting values of 0.3–0.4 s–1 for Fe(III)-CBS
and 40 ± 4 s–1 for Fe(II)-CBS. The data were
interpreted in terms of alternative models of conformational selection
or induced fit. Exposure of Fe(III)-CBS to HgCl2 led to
heme release and activity loss. Our study reveals the complexity of
the interactions between mercury compounds and CBS.
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