Dataset Information

The Synergetic Coupling among the Cellular Antioxidants Glutathione Peroxidase/Peroxiredoxin and Other Antioxidants and its Effect on the Concentration of H2O2

ABSTRACT: Glutathione peroxidase (GPx), peroxiredoxin (Prx), and catalase are the major antioxidants at the cellular level and protect cell compartments against hydrogen peroxide (H2O2). In addition, they affect cellular processes such as cell signaling by modulating H2O2. In this paper we demonstrate that there is a synergetic coupling between GPxs, Prxs themselves and also with other antioxidants when the GPxs and Prxs are not in their saturated reduced form. This is due to a change in the activity of glutathione peroxidases and peroxiredoxins as a result of a change in the concentrations of other antioxidants. The strength of this synergy depends on the reaction rates and the concentration of these antioxidants. We use a perturbative method to calculate the concentration of H2O2 as function of the production rate of H2O2 and the concentration of various antioxidants. This derivation shows clearly why antioxidants behave in a correlated manner and why any change in the activity of one of them translates to a change in the activity of other antioxidants. Our results show that an increase in the activity of GPxs or Prxs might not be due to a genetic switch but due to an increase in the activity of other antioxidants.

SUBMITTER: Molavian H

PROVIDER: S-EPMC4555031 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:The dual-functioning antioxidant enzyme peroxiredoxin VI (Prdx6) detoxifies lipid peroxides particularly in biological membranes, and its peroxidase function is activated by glutathione S-transferase Pi (GSTP). The GSTP gene is polymorphic in humans, with the wild-type GSTP1-1A (Ile105, Ala114) and three variants: GSTP1-1B (Ile105Val, Ala114), GSTP1-1C (Ile105Val, Ala114Val), and GSTP1-1D (Ile105, Ala114Val). The focus of this study was to determine the influence of these polymorphisms on Prdx6 peroxidase function. Using extracellular generation of OH radicals and fluorescence (DPPP dye) detection, we found a fast (~300 s) onset of lipid peroxidation in membranes of MCF-7 cells transfected with a catalytically inactive Y7F mutant of GSTP1-1 and either GSTP1-1B or GSTP1-1D. However, this effect was not detected in cells expressing either GSTP1-1A or GSTP1-1C. Imaging of DPPP-labeled MCF-7 cells showed fluorescence localized in the plasma membrane, but intensity was substantially diminished in the GSTP1-1A- and GSTP1-1C-expressing cells. Moreover, in the Y7F mutant of GSTP1-1A-, GSTP1-1B-, and GST1-1D-expressing cells ()OH generation resulted (after 36 h) in plasma membrane-permeability-related cell death, whereas GSTP1-1A- and GSTP1-1C-expressing cells had significantly better survival. We used FRET analyses to measure in vitro binding of purified GSTP1-1 allelic variant proteins to purified recombinant Prdx6. The affinities for Prdx6 binding to GSH-loaded GSTP1-1's either mirrored their observed peroxidase activities (using phospholipid hydroperoxide as a substrate), GSTP1-1A>GSTP1-1C (K(D)=51.0 vs 57.0 nM), or corresponded to inactivation, GSTP1-1B (GSTP1-1D) (K(D)=101.0 (94.0) nM). In silico modeling of the GSTP1-1-Prdx6 heterodimer revealed that the sites of GSTP1-1 polymorphism (Ile105 and Ala114) are in close proximity to the binding interface. Thus, there is a hierarchy of effectiveness for polymorphic variants of GSTP1-1 to regulate Prdx6 peroxidase function, a feature that may influence human population susceptibilities to oxidant stress.

Dataset Information

The Synergetic Coupling among the Cellular Antioxidants Glutathione Peroxidase/Peroxiredoxin and Other Antioxidants and its Effect on the Concentration of H2O2

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets