Predicting the Kinetic Properties Associated with Redox Imbalance after Oxidative Crisis in G6PD-Deficient Erythrocytes: A Simulation Study

Abstract

It is well known that G6PD-deficient individuals are highly susceptible to oxidative stress. However, the differences in the degree of metabolic alterations among patients during an oxidative crisis have not been extensively studied. In this study, we applied mathematical modeling to assess the metabolic changes in erythrocytes of various G6PD-deficient patients during hydrogen peroxide- (H2O2-) induced perturbation and predict the kinetic properties that elicit redox imbalance after exposure to an oxidative agent. Simulation results showed a discrepancy in the ability to restore regular metabolite levels and redox homeostasis among patients. Two trends were observed in the response of redox status (GSH/GSSG) to oxidative stress, a mild decrease associated with slow recovery and a drastic decline associated with rapid recovery. The former was concluded to apply to patients with severe clinical symptoms. Low V max and high K mG6P of G6PD were shown to be kinetic properties that enhance consequent redox imbalance.

Glucose 6-phosphate dehydrogenase deficiency enhances germ cell apoptosis and causes defective embryogenesis in Caenorhabditis elegans

“…5, 6, 7, 8, 9 However, during the past decade, accumulating evidence has demonstrated that G6PD deficiency also affects nucleated cells 10, 11, 12, 13, 14 and cellular pathophysiological events, including dysregulated cell proliferation, accelerated cellular senescence, enhanced susceptibility to viral infection, and impaired embryonic development. 15, 16 G6PD is essential for normal cell growth and survival.…”

Predicting plasma ascorbate levels upon infusion and biochemical implications for glucose-6-phosphate dehydrogenase deficient patients

“…Early models concentrated on defining the reaction-rate as a function of only the products and reactants (G6P, 6PGδL, NADP + , and NADPH). While these models make sense "in the test tube," they miss important important biological regulators seen in vitro and in vivo [39]. Equation 3.1 takes into account some of the biological regulation of G6PD, making it the best equation for studying in vitro and in vivo kinetics.…”

“…Initial Concentration (mM) a G6P 6 NADP + 0.067 NADPH 0 ATP 1.9 2,3-BPG 3.7 a Values for G6P, ATP and 2,3-BPG are physiologic. Physiologic values for NADPH and NADP + are 0.065 mM and 0.002 mM, respectively [39]. 64 M•s −1 a k m values are the concentration of the substrate at which the reaction proceeds at half of it's maximal activity.…”

“…V max is the maximal rate at which the reaction proceeds. From [39]. Table 3.4: Kinetic parameters used in G6PD simulations.…”

“…Intracellular NADPH to total NADP ratio under no demand. The system was simulated using equation 3.1[39] with physiologic parameters for NADP + (50 µM) and G6P concentrations(10 mM). The cell will under all circumstances reduce all of its NADP + to NADPH.…”