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

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Title: Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis.
Authors: Zeida, Ari1, Reyes, Aníbal M.2, Lichtig, Pablo1, Hugo, Martín2, Vazquez, Diego S.3, Santos, Javier3, Flecha, F. Luis González3, Radi, Rafael2, Estrin, Dario A.1 dario@qi.fcen.uba.ar, Trujillo, Madia2 madiat@fmed.edu.uy
Source: Biochemistry. 12/15/2015, Vol. 54 Issue 49, p7237-7247. 11p.
Subjects: Peroxiredoxins, Hydroperoxides, Enzyme specificity, Mycobacterium tuberculosis, Peroxynitrite, Protein expression
Abstract: 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. [ABSTRACT FROM AUTHOR]
Copyright of Biochemistry is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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DbLabel: Engineering Source
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PubType: Academic Journal
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  Data: Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis.
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  Data: <searchLink fieldCode="AR" term="%22Zeida%2C+Ari%22">Zeida, Ari</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Reyes%2C+Aníbal+M%2E%22">Reyes, Aníbal M.</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Lichtig%2C+Pablo%22">Lichtig, Pablo</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Hugo%2C+Martín%22">Hugo, Martín</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Vazquez%2C+Diego+S%2E%22">Vazquez, Diego S.</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Santos%2C+Javier%22">Santos, Javier</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Flecha%2C+F%2E+Luis+González%22">Flecha, F. Luis González</searchLink><relatesTo>3</relatesTo><br /><searchLink fieldCode="AR" term="%22Radi%2C+Rafael%22">Radi, Rafael</searchLink><relatesTo>2</relatesTo><br /><searchLink fieldCode="AR" term="%22Estrin%2C+Dario+A%2E%22">Estrin, Dario A.</searchLink><relatesTo>1</relatesTo><i> dario@qi.fcen.uba.ar</i><br /><searchLink fieldCode="AR" term="%22Trujillo%2C+Madia%22">Trujillo, Madia</searchLink><relatesTo>2</relatesTo><i> madiat@fmed.edu.uy</i>
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  Data: <searchLink fieldCode="JN" term="%22Biochemistry%22">Biochemistry</searchLink>. 12/15/2015, Vol. 54 Issue 49, p7237-7247. 11p.
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  Data: <searchLink fieldCode="DE" term="%22Peroxiredoxins%22">Peroxiredoxins</searchLink><br /><searchLink fieldCode="DE" term="%22Hydroperoxides%22">Hydroperoxides</searchLink><br /><searchLink fieldCode="DE" term="%22Enzyme+specificity%22">Enzyme specificity</searchLink><br /><searchLink fieldCode="DE" term="%22Mycobacterium+tuberculosis%22">Mycobacterium tuberculosis</searchLink><br /><searchLink fieldCode="DE" term="%22Peroxynitrite%22">Peroxynitrite</searchLink><br /><searchLink fieldCode="DE" term="%22Protein+expression%22">Protein expression</searchLink>
– Name: Abstract
  Label: Abstract
  Group: Ab
  Data: 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. [ABSTRACT FROM AUTHOR]
– Name: AbstractSuppliedCopyright
  Label:
  Group: Ab
  Data: <i>Copyright of Biochemistry is the property of American Chemical Society and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.)
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      – Type: doi
        Value: 10.1021/acs.biochem.5b00758
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      – Code: eng
        Text: English
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        PageCount: 11
        StartPage: 7237
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      – SubjectFull: Peroxiredoxins
        Type: general
      – SubjectFull: Hydroperoxides
        Type: general
      – SubjectFull: Enzyme specificity
        Type: general
      – SubjectFull: Mycobacterium tuberculosis
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      – SubjectFull: Peroxynitrite
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      – SubjectFull: Protein expression
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      – TitleFull: Molecular Basis of Hydroperoxide Specificity in Peroxiredoxins: The Case of AhpE from Mycobacterium tuberculosis.
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              Text: 12/15/2015
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