Control Analysis of Cooperativity and Complementarity in Metabolic Regulations: The Case of NADPH Homeostasis

Complex feedback regulation patterns shape the cellular metabolic response to external or internal perturbations. We propose here a framework consisting of a sampling-based metabolic control analysis of kinetic models to investigate the modes of regulatory interplay in metabolic functions. NADPH homeostasis, for instance in a context of oxidative stress, is an example of metabolic function that involves multiple feedback regulations which raises the issue of their concerted action. Our computational framework allows us to characterize both respective and combined effects of regulations, distinguishing between synergistic versus complementary modes of regulatory crosstalk. Synergistic regulation of G6PD enzymes and PGI enzymes is mediated by congruent effects between concentration sensitivities and reaction elasticities. Complementary regulation of pentose phosphate pathway and lower glycolysis relates to metabolic state-dependent range of regulation efficiency. These cooperative effects are shown to significantly improve metabolic flux response to support NADPH homeostasis, providing a rationale for the complex feedback regulation pattern at work.