Peroxynitrite reductase activity of selenoprotein glutathione peroxidase

A computational study

Rajeev Prabhakar, Keiji Morokuma, Djamaladdin G. Musaev

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The peroxynitrite reductase activity of selenoprotein glutathione peroxidase (GPx) has been investigated using density functional theory calculations for peroxynitrite/peroxynitrous acid (ONOO-/ONOOH) substrates through two different "oxidation" and "nitration" pathways. In the oxidation pathway for ONOO-, the oxidation of GPx and the subsequent formation of the selenenic acid (E-Se-OH) occur through a concerted mechanism with an energy barrier of 4.7 (3.7) kcal/mol, which is in good agreement with the computed value of 7.1 kcal/mol for the drug ebselen and the experimentally measured barrier of 8.8 kcal/mol for both ebselen and GPx. For ONOOH, the formation of the E-Se-OH prefers a stepwise mechanism with an overall barrier of 6.9 (11.3) kcal/mol, which is 10.2 (11.2) kcal/mol lower than that for hydrogen peroxide (H2O2), indicating that ONOOH is a more efficient substrate for GPx oxidation. It has been demonstrated that the active site Gln83 residue plays a critical role during the oxidation process, which is consistent with the experimental suggestions. The nitration of GPx by ONOOH produces a nitro (E-Se-NO2) product via either of two different mechanisms, isomerization and direct, having almost the same barrier heights. A comparison between the rate-determining barriers of the oxidation and nitration pathways suggests that the oxidation of GPx by ONOOH is more preferable than its nitration. It was also shown that the rate-determining barriers remain the same, 21.5 (25.5) kcal/mol, in the peroxynitrite reductase and peroxidase activities of GPx.

Original languageEnglish
Pages (from-to)6967-6977
Number of pages11
JournalBiochemistry
Volume45
Issue number22
DOIs
StatePublished - Jun 6 2006
Externally publishedYes

Fingerprint

Selenoproteins
Glutathione Peroxidase
Nitration
Oxidation
Peroxynitrous Acid
Energy barriers
Substrates
Isomerization
peroxynitrite reductase
Hydrogen Peroxide
Peroxidase
Density functional theory
Catalytic Domain
Acids

ASJC Scopus subject areas

  • Biochemistry

Cite this

Peroxynitrite reductase activity of selenoprotein glutathione peroxidase : A computational study. / Prabhakar, Rajeev; Morokuma, Keiji; Musaev, Djamaladdin G.

In: Biochemistry, Vol. 45, No. 22, 06.06.2006, p. 6967-6977.

Research output: Contribution to journalArticle

Prabhakar, Rajeev ; Morokuma, Keiji ; Musaev, Djamaladdin G. / Peroxynitrite reductase activity of selenoprotein glutathione peroxidase : A computational study. In: Biochemistry. 2006 ; Vol. 45, No. 22. pp. 6967-6977.
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