A mechanistic mathematical model for the catalytic action of glutathione peroxidase. Free Radic Res 2014 Apr;48(4):487-502
Date
01/25/2014Pubmed ID
24456207Pubmed Central ID
PMC4068149DOI
10.3109/10715762.2014.886775Scopus ID
2-s2.0-84895749936 (requires institutional sign-in at Scopus site) 23 CitationsAbstract
Glutathione peroxidase (GPx) is a well-known seleno-enzyme that protects cells from oxidative stress (e.g., lipid peroxidation and oxidation of other cellular proteins and macromolecules), by catalyzing the reduction of harmful peroxides (e.g., hydrogen peroxide: H₂O₂) with reduced glutathione (GSH). However, the catalytic mechanism of GPx kinetics is not well characterized in terms of a mathematical model. We developed here a mechanistic mathematical model of GPx kinetics by considering a unified catalytic scheme and estimated the unknown model parameters based on different experimental data from the literature on the kinetics of the enzyme. The model predictions are consistent with the consensus that GPx operates via a ping-pong mechanism. The unified catalytic scheme proposed here for GPx kinetics clarifies various anomalies, such as what are the individual steps in the catalytic scheme by estimating their associated rate constant values and a plausible rationale for the contradicting experimental results. The developed model presents a unique opportunity to understand the effects of pH and product GSSG on the GPx activity under both physiological and pathophysiological conditions. Although model parameters related to the product GSSG were not identifiable due to lack of product-inhibition data, the preliminary model simulations with the assumed range of parameters show that the inhibition by the product GSSG is negligible, consistent with what is known in the literature. In addition, the model is able to simulate the bi-modal behavior of the GPx activity with respect to pH with the pH-range for maximal GPx activity decreasing significantly as the GSH levels decrease and H₂O₂ levels increase (characteristics of oxidative stress). The model provides a key component for an integrated model of H₂O₂ balance under normal and oxidative stress conditions.
Author List
Pannala VR, Bazil JN, Camara AK, Dash RKAuthors
Amadou K. Camara PhD Professor in the Anesthesiology department at Medical College of WisconsinRanjan K. Dash PhD Professor in the Biomedical Engineering department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsCatalysis
Cattle
Glutathione Peroxidase
Humans
Hydrogen Peroxide
Lipid Peroxidation
Models, Theoretical
Reactive Oxygen Species