Peroxynitrite Reductase Activity of Selenoprotein Glutathione Peroxidase: A Computational Study
- 13 May 2006
- journal article
- Published by American Chemical Society (ACS) in Biochemistry
- Vol. 45 (22), 6967-6977
- https://doi.org/10.1021/bi060456e
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.Keywords
This publication has 19 references indexed in Scilit:
- Synthetic organoselenium compounds as antioxidants: glutathione peroxidase activityChemical Society Reviews, 2000
- Glutathione Peroxidase Protects against Peroxynitrite-mediated OxidationsJournal of Biological Chemistry, 1997
- Peroxynitrite Decomposition CatalystsJournal of the American Chemical Society, 1996
- Stopped-Flow Kinetic Study of the Reaction of Ascorbic Acid with PeroxynitriteArchives of Biochemistry and Biophysics, 1995
- Selenium in Biology and Human HealthPublished by Springer Science and Business Media LLC ,1994
- Interaction of myeloperoxidase with peroxynitriteEuropean Journal of Biochemistry, 1993
- Pathological implications of nitric oxide, superoxide and peroxynitrite formationBiochemical Society Transactions, 1993
- A novel biologically active seleno-organic compound—VIBiochemical Pharmacology, 1986
- Ebselen reduces the formation of LTB4 in human and porcine leukocytes by isomerisation to its 5S, 12R-6-trans-isomerProstaglandins, 1986
- HEMOGLOBIN CATABOLISMJournal of Biological Chemistry, 1957