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Abstract:

The oxidation of cellular thiol-containing compounds, such as glutathione and protein Cys residues, is considered to play an important role in many biological processes. Among possible oxidants, hydrogen peroxide (H 2O 2) is known to be produced in many cell types as a response to a variety of extracellular stimuli and could work as an intracellular messenger. This reaction has been reported to proceed through a S N2 mechanism, but despite its importance, the reaction is not completely understood at the atomic level. In this work, we elucidate the reaction mechanism of thiol oxidation by H 2O 2 for a model methanethiolate system using state of the art hybrid quantum-classical (QM-MM) molecular dynamics simulations. Our results show that the solvent plays a key role in positioning the reactants, that there is a significant charge redistribution in the first stages of the reaction, and that there is a hydrogen transfer process between H 2O 2 oxygen atoms that occurs after reaching the transition state. These observations challenge the S N2 mechanism hypothesis for this reaction. Specifically, our results indicate that the reaction is driven by a tendency of the slightly charged peroxidatic oxygen to become even more negative in the product via an electrophilic attack on the negative sulfur atom. This is inconsistent with the S N2 mechanism, which predicts a protonated sulfenic acid and hydroxyl anion as stable intermediates. These intermediates are not found. Instead, the reaction proceeds directly to unprotonated sulfenic acid and water. © 2012 American Chemical Society.

Registro:

Documento: Artículo
Título:Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm
Autor:Zeida, A.; Babbush, R.; González Lebrero, M.C.; Trujillo, M.; Radi, R.; Estrin, D.A.
Filiación:Departamento de Química Inorgánica, Analítica Y Química-Física, Universidad de Buenos Aires, Ciudad Universitaria, C1428EHA Buenos Aires, Argentina
IQUIFIB-Dpto. Química Biológica, Facultad de Farmacia Y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina
Departamento de Bioquímica, Center for Free Radical and Biomedical Research, Universidad de la República, Av. Gral Flores 2125, Montevideo, Uruguay
Department of Chemistry, Harvard University, 12 Oxford Street, Cambridge, MA 02138, United States
Palabras clave:hydrogen peroxide; hydroxyl group; methanethiol; oxygen; sulfenic acid derivative; sulfur; thiol; transition element; water; aqueous solution; article; chemical reaction; electrophilicity; molecular dynamics; oxidation; Hydrogen Peroxide; Molecular Dynamics Simulation; Oxidation-Reduction; Sulfhydryl Compounds
Año:2012
Volumen:25
Número:3
Página de inicio:741
Página de fin:746
DOI: http://dx.doi.org/10.1021/tx200540z
Título revista:Chemical Research in Toxicology
Título revista abreviado:Chem. Res. Toxicol.
ISSN:0893228X
CODEN:CRTOE
CAS:hydrogen peroxide, 7722-84-1; methanethiol, 74-93-1; oxygen, 7782-44-7; sulfur, 13981-57-2, 7704-34-9; water, 7732-18-5; Hydrogen Peroxide, 7722-84-1; Sulfhydryl Compounds; methylmercaptan, 74-93-1
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_0893228X_v25_n3_p741_Zeida

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Citas:

---------- APA ----------
Zeida, A., Babbush, R., González Lebrero, M.C., Trujillo, M., Radi, R. & Estrin, D.A. (2012) . Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm. Chemical Research in Toxicology, 25(3), 741-746.
http://dx.doi.org/10.1021/tx200540z
---------- CHICAGO ----------
Zeida, A., Babbush, R., González Lebrero, M.C., Trujillo, M., Radi, R., Estrin, D.A. "Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm" . Chemical Research in Toxicology 25, no. 3 (2012) : 741-746.
http://dx.doi.org/10.1021/tx200540z
---------- MLA ----------
Zeida, A., Babbush, R., González Lebrero, M.C., Trujillo, M., Radi, R., Estrin, D.A. "Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm" . Chemical Research in Toxicology, vol. 25, no. 3, 2012, pp. 741-746.
http://dx.doi.org/10.1021/tx200540z
---------- VANCOUVER ----------
Zeida, A., Babbush, R., González Lebrero, M.C., Trujillo, M., Radi, R., Estrin, D.A. Molecular basis of the mechanism of thiol oxidation by hydrogen peroxide in aqueous solution: Challenging the S N2 paradigm. Chem. Res. Toxicol. 2012;25(3):741-746.
http://dx.doi.org/10.1021/tx200540z