RESUMEN
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.
Asunto(s)
Glutatión Peroxidasa/metabolismo , Animales , Catálisis , Bovinos , Humanos , Peróxido de Hidrógeno/farmacología , Peroxidación de Lípido , Modelos Teóricos , Especies Reactivas de OxígenoRESUMEN
The genetic regulatory network responds dynamically to perturbations in the intracellular and extracellular environments of an organism. The GAL system in the yeast Saccharomyces cerevisiae has evolved to utilise galactose as an alternative carbon and energy source, in the absence of glucose in the environment. This work contains a modified dynamic model for GAL system in S. cerevisiae, which includes a novel mechanism for Gal3p activation upon induction with galactose. The modification enables the model to simulate the experimental observation that in absence of galactose, oversynthesis of Gal3p can also induce the GAL system. Subsequently, the model is related to growth on galactose and glucose in a structured manner. The growth-related models are validated with experimental data for growth on individual substrates as well as mixed substrates. Finally, the model is tested for its prediction of a variety of known mutant behaviours. The exercise shows that the authors' model with a single set of parameters is able to capture the rich behaviour of the GAL system in S. cerevisiae. [Includes supplementary material].