Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis

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...

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Autores principales:	Santos, Javier, Estrin, Dario Ariel
Publicado:	2015
Materias:	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 Article binding site catalysis conformational transition controlled study crystal structure crystallography entropy enzyme activity enzyme specificity molecular dynamics nonhuman priority journal protein conformation protein expression quantum yield chemistry enzymology protein multimerization Bacterial Proteins Molecular Dynamics Simulation Peroxiredoxins Protein Multimerization Substrate Specificity
Acceso en línea:	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v54_n49_p7237_Zeida http://hdl.handle.net/20.500.12110/paper_00062960_v54_n49_p7237_Zeida
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	paper:paper_00062960_v54_n49_p7237_Zeida
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spelling	paper:paper_00062960_v54_n49_p7237_Zeida2023-06-08T14:30:49Z Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis Santos, Javier Estrin, Dario Ariel 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 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. Fil:Santos, J. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. Fil:Estrin, D.A. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina. 2015 https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v54_n49_p7237_Zeida http://hdl.handle.net/20.500.12110/paper_00062960_v54_n49_p7237_Zeida
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	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
spellingShingle	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 Santos, Javier Estrin, Dario Ariel Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis
topic_facet	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
description	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.
author	Santos, Javier Estrin, Dario Ariel
author_facet	Santos, Javier Estrin, Dario Ariel
author_sort	Santos, Javier
title	Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis
title_short	Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis
title_full	Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis
title_fullStr	Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis
title_full_unstemmed	Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis
title_sort	molecular basis of hydroperoxide specificity in peroxiredoxins: the case of ahpe from mycobacterium tuberculosis
publishDate	2015
url	https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00062960_v54_n49_p7237_Zeida http://hdl.handle.net/20.500.12110/paper_00062960_v54_n49_p7237_Zeida
work_keys_str_mv	AT santosjavier molecularbasisofhydroperoxidespecificityinperoxiredoxinsthecaseofahpefrommycobacteriumtuberculosis AT estrindarioariel molecularbasisofhydroperoxidespecificityinperoxiredoxinsthecaseofahpefrommycobacteriumtuberculosis
_version_	1768544530691260416

Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis

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