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.
Highlights
Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-chromosome linked genetic disorder, is the most prevalent mutation in humans affecting more than 400 million people worldwide [1,2,3,4]
Substantial differences in the behavior of GSH/GSSG, nicotine adenine dinucleotide phosphate (NADPH)/NADP, and G6PD activity in response to the input of H2O2 were observed among the patients
We examined the metabolic changes in G6PD-deficient RBCs during exposure to H2O2 using a model that reproduced the oxidative-stress removal mechanism and evaluated how the alterations in redox homeostasis depend on the combination of kinetic parameters for enzymatic reactions in a patient’s RBCs
Summary
Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-chromosome linked genetic disorder, is the most prevalent mutation in humans affecting more than 400 million people worldwide [1,2,3,4]. It is characterized by the decreased activity of the G6PD enzyme, which is the central factor of the antioxidant defense system in erythrocytes (or RBCs). As RBCs are unable to generate NADPH through other pathways [5, 6], G6PD-deficient RBCs lack the ability to tolerate excessive amounts of oxidative stress [7,8,9]. The defect can result in complications such as kidney failure, severe neonatal jaundice, gallstones, and may require blood transfusion [2, 9,10,11]
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