Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 295, Issue 46, Pages 15466-15481Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.RA120.014728
Keywords
persulfide; thiol; hydrogen sulfide; glutathione; α effect; pKa; sulfhydryl; sulfur; enzyme mechanism
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Funding
- Comision Sectorial de Investigacion Cientifica (CSIC)
- Universidad de la Republica [GRUPOS_2014_C632-348, GRU-POS_2018_47, I+D_2016_541, I+D 2016_367, Centros_2015]
- Agencia Nacional de Investigacion e Innovacion (ANII), Uruguay [FCE_1_2017_1_136043]
- Ministerio de Educacion y Cultura, Uruguay [I/FVF2017/069]
- Universidad de Buenos Aires [UBACYT 20020130100097BA]
- Agencia Nacional de Promocion Cientifica y Tecnologica, Argentina [PICT 2014-1022, PICT 2015-2761]
- Consejo Nacional de Investigaciones Cientificas y Tecnicas (CONICET), Argentina
- Comision Academica de Posgrado, Universidad de la Republica
- PEDECIBA, Uruguay
- Programa Escala Docente, Asociacion de Universidades Grupo Montevideo
- Instituto de Quimica Fisica de los Materiales, Medio Ambiente y Energia (INQUIMAE) clusters, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires
- Espacio Interdisciplinario, Universidad de la Republica, Grant Centros_2015
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Persulfides (RSSH/RSS-) participate in sulfur trafficking and metabolic processes, and are proposed to mediate the signaling effects of hydrogen sulfide (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 pK(a) 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, and with the probe monobromobimane, were studied and compared with those of thiols. These reactions occurred through S(N)2 mechanisms. At neutral pH, GSSH reacted faster than GSH because of 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 Bronsted nucleophilic factor, beta(nuc), for the reactions with thiolates and with the ability of the leaving group. Our study constitutes the first determination of the pK(a) 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.
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