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. In the case of oxidative stress due for instance to hydrogen peroxide exposure, the adaptation response relies on co-regulation of enzymes in both glycolysis and pentose phosphate pathways (PPP), so as to support PPP-dependent NADPH and redox homeostasis. To understand the regulatory logic underlying early oxidative stress response, available metabolomics and 13C fluxomics dataset are used to infer a probabilistic ensemble of kinetic models. Model ensemble properties of parameter distributions, transient dynamics, dose-response curves and loss-of-function phenotypes all highlights significant and cooperative effects of allosteric regulations of G6PD, PGI and GAPD in early oxidative response. Indeed, efficient flux rerouting into PPP is shown to require dose-dependent coordination between upregulated G6PD enzyme and increased G6P metabolite, the latter requiring fine-tuned inhibition of upper and lower glycolytic enzymes. This set of allosteric regulation also combines negative and positive feedback loops in a subtle manner prone to generate paradoxical perturbation phenotypes for instance related to 6PGD modulation.