Zeida, A.; Reyes, A.M.; Lichtig, P.; Hugo, M.; Vazquez, D.S.; Santos, J.; González Flecha, F.L.; Radi, R.; Estrin, D.A.; Trujillo, M. "Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis" (2015) Biochemistry. 54(49):7237-7247
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Peroxiredoxins (Prxs) constitute a ubiquitous family of Cys-dependent peroxidases that play essential roles in reducing hydrogen peroxide, peroxynitrite, and organic hydroperoxides in almost all organisms. Members of the Prx subfamilies show differential oxidizing substrate specificities that await explanations at a molecular level. Among them, alkyl hydroperoxide reductases E (AhpE) is a novel subfamily comprising Mycobacterium tuberculosis AhpE and AhpE-like proteins expressed in some bacteria and archaea. We previously reported that MtAhpE reacts ∼104 times faster with an arachidonic acid derived hydroperoxide than with hydrogen peroxide, and suggested that this surprisingly high reactivity was related to the presence of a hydrophobic groove at the dimer interface evidenced in the crystallography structure of the enzyme. In this contribution we experimentally confirmed the existence of an exposed hydrophobic patch in MtAhpE. We found that fatty acid hydroperoxide reduction by the enzyme showed positive activation entropy that importantly contributed to catalysis. Computational dynamics indicated that interactions of fatty acid-derived hydroperoxides with the enzyme properly accommodated them inside the active site and modifies enzyme's dynamics. The computed reaction free energy profile obtained via QM/MM simulations is consistent with a greater reactivity in comparison with hydrogen peroxide. This study represents new insights on the understanding of the molecular basis that determines oxidizing substrate selectivity in the peroxiredoxin family, which has not been investigated at an atomic level so far. © 2015 American Chemical Society.


Documento: Artículo
Título:Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis
Autor:Zeida, A.; Reyes, A.M.; Lichtig, P.; Hugo, M.; Vazquez, D.S.; Santos, J.; González Flecha, F.L.; Radi, R.; Estrin, D.A.; Trujillo, M.
Filiación:Departamento de Química Inorgánica, Analítica y Química-Física, INQUIMAE, CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, 1053, Argentina
IQUIFIB, UBA-CONICET, Departamento de Química Biológica, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, 1053, Argentina
Departamento de Bioquímica, Center for Free Radical and Biomedical Research, Facultad de Medicina, Universidad de la República, Montevideo, 11800, Uruguay
German Institute of Human Nutrition, University of Potsdam, Germany
Palabras clave:Dimers; Enzymes; Free energy; Hydrogen peroxide; Hydrophobicity; Oxidation; Peroxides; Plants (botany); Activation entropies; Alkyl hydroperoxide; Arachidonic acids; Computational dynamics; Mycobacterium tuberculosis; Organic hydroperoxides; Oxidizing substrates; Reaction free energy; Fatty acids; arachidonic acid; fatty acid; hydrogen peroxide; hydroperoxide; hydroperoxide reductase e; peroxiredoxin; unclassified drug; bacterial protein; peroxiredoxin; Article; binding site; catalysis; conformational transition; controlled study; crystal structure; crystallography; entropy; enzyme activity; enzyme specificity; molecular dynamics; Mycobacterium tuberculosis; nonhuman; priority journal; protein conformation; protein expression; quantum yield; chemistry; enzyme specificity; enzymology; molecular dynamics; protein multimerization; Bacterial Proteins; Molecular Dynamics Simulation; Mycobacterium tuberculosis; Peroxiredoxins; Protein Multimerization; Substrate Specificity
Página de inicio:7237
Página de fin:7247
Título revista:Biochemistry
Título revista abreviado:Biochemistry
CAS:arachidonic acid, 506-32-1, 6610-25-9, 7771-44-0; hydrogen peroxide, 7722-84-1; peroxiredoxin, 207137-51-7; Bacterial Proteins; Peroxiredoxins


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---------- APA ----------
Zeida, A., Reyes, A.M., Lichtig, P., Hugo, M., Vazquez, D.S., Santos, J., González Flecha, F.L.,..., Trujillo, M. (2015) . Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis. Biochemistry, 54(49), 7237-7247.
---------- CHICAGO ----------
Zeida, A., Reyes, A.M., Lichtig, P., Hugo, M., Vazquez, D.S., Santos, J., et al. "Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis" . Biochemistry 54, no. 49 (2015) : 7237-7247.
---------- MLA ----------
Zeida, A., Reyes, A.M., Lichtig, P., Hugo, M., Vazquez, D.S., Santos, J., et al. "Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis" . Biochemistry, vol. 54, no. 49, 2015, pp. 7237-7247.
---------- VANCOUVER ----------
Zeida, A., Reyes, A.M., Lichtig, P., Hugo, M., Vazquez, D.S., Santos, J., et al. Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis. Biochemistry. 2015;54(49):7237-7247.