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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todo:paper_00062960_v54_n49_p7237_Zeida2023-10-03T14:04:35Z Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis 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. 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. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar 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 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 |
| 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. |
| format |
JOUR |
| author |
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. |
| author_facet |
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. |
| author_sort |
Zeida, A. |
| 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 |
| url |
http://hdl.handle.net/20.500.12110/paper_00062960_v54_n49_p7237_Zeida |
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