Analyzing the Function of Catalase and the Ascorbate-Glutathione Pathway in H2O2 Processing: Insights from an Experimentally Constrained Kinetic Model

Recent Advances: Based on emerging data and concepts, we introduce a new experimentally constrained kinetic model to analyze interactions between H2O2, CAT, ascorbate, glutathione, and NADPH. The sensitivity points required for accurate simulation of experimental observations are analyzed, and the implications for H2O2-linked redox signaling are discussed. Critical Issues: We discuss several implications of the modeled results, in particular the following. (i) CAT and ascorbate peroxidase can share the load in H2O2 processing even in optimal conditions. (ii) Intracellular H2O2 concentrations more than the low mu M range may rarely occur. (iii) Ascorbate redox turnover is largely independent of glutathione until ascorbate peroxidation exceeds a certain value. (iv) NADPH availability may determine glutathione redox status through its influence on monodehydroascorbate reduction. (v) The sensitivity of glutathione status to oxidative stress emphasizes its potential suitability as a sensor of increased H2O2. Future Directions: Important future questions include the roles of other antioxidative systems in interacting with CAT and the ascorbate-glutathione pathway as well as the nature and significance of processes that achieve redox exchange between different subcellular compartments. Progress in these areas is likely to be favored by integrating kinetic modeling analyses into experimentally based programs, allowing each approach to inform the other.