Quantitative modeling of pentose phosphate pathway response to oxidative stress reveals a cooperative regulatory strategy.

Living cells use signaling and regulatory mechanisms to adapt to environmental stresses. Adaptation to oxidative stress involves the regulation of many enzymes in both glycolysis and pentose phosphate pathways (PPP), so as to support PPP-driven NADPH recycling for antioxidant defense. The underlying regulatory logic is investigated by developing a kinetic modeling approach fueled with metabolomics and C-fluxomics datasets from human fibroblast cells. Bayesian parameter estimation and phenotypic analysis of models highlight complementary roles for several metabolite-enzyme regulations. Specifically, carbon flux rerouting into PPP involves a tight coordination between the upregulation of G6PD activity concomitant to a decreased NADPH/NADP ratio and the differential control of downward and upward glycolytic fluxes through the joint inhibition of PGI and GAPD enzymes. Such functional interplay between distinct regulatory feedbacks promotes efficient detoxification and homeostasis response over a broad range of stress level, but can also explain paradoxical pertubation phenotypes for instance reported for 6PGD modulation in mammalian cells.