title: Peroxynitrite reductase activity of selenoprotein glutathione peroxidase: a computational study.
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.
authors.affiliation: Cherry L. Emerson Center for Scientific Computation and Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, USA.
authors.forename: Rajeev
authors.initials: R
authors.lastname: Prabhakar
authors.forename: Keiji
authors.initials: K
authors.lastname: Morokuma
authors.forename: Djamaladdin G
authors.initials: DG
authors.lastname: Musaev
mesh_terms: D019295:Computational Biology; D005979:Glutathione Peroxidase / Q000737:chemistry*; D007536:Isomerism; D008956:Models, Chemical; D009584:Nitrogen / Q000737:chemistry; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000737:chemistry*; D030421:Peroxynitrous Acid / Q000737:chemistry*; D011487:Protein Conformation; D051140:Selenoproteins / Q000737:chemistry*; D013379:Substrate Specificity
chemical_list: D051140:Selenoproteins; D030421:Peroxynitrous Acid; D010088:Oxidoreductases; D005979:Glutathione Peroxidase; C109110:peroxynitrite reductase; D009584:Nitrogen