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A key challenge for living systems is balancing utilization of multiple elemental nutrients, such as carbon, nitrogen, and oxygen, whose availability is subject to environmental fluctuations. As growth can be limited by the scarcity of any one nutrient, the rate at which each nutrient is assimilated must be sensitive not only to its own availability, but also to that of other nutrients. Remarkably, across diverse nutrient conditions, E. coli grows nearly optimally, balancing effectively the conversion of carbon into energy versus biomass. To investigate the link between the metabolism of different nutrients, we quantified metabolic responses to nutrient perturbations using LC-MS based metabolomics and built differential equation models that bridge multiple nutrient systems. We discovered that the carbonaceous substrate of nitrogen assimilation, ÃÂ±-ketoglutarate, directly inhibits glucose uptake and that the upstream glycolytic metabolite, fructose-1,6-bisphosphate, ultrasensitively regulates anaplerosis to allow rapid adaptation to changing carbon availability. We also showed that NADH controls the metabolic response to changing oxygen levels. Our findings support a general mechanism for nutrient integration: limitation for a nutrient other than carbon leads to build-up of the most closely related product of carbon metabolism, which in turn feedback inhibits further carbon uptake

Integration of Carbon, Nitrogen, and Oxygen Metabolism in Escherichia coli--Final Report