On the design principles of metabolic flux sensing

Metabolism is precisely coordinated, with the goal of balancing fluxes to maintain robust growth. However, coordinating fluxes requires information about rates, which can only be inferred through concentrations. While flux-sensitive metabolites have been reported, the design principles underlying such sensing have not been clearly elucidated. Here we use kinetic modeling to show that substrate concentrations of thermodynamically constrained reactions reflect upstream flux and therefore carry information about rates. Then we use untargeted multi-omic data from Escherichia coli and Saccharomyces cerevisiae to show that the concentrations of some metabolites in central carbon metabolism reflect fluxes as a result of thermodynamic constraints. We then establish, using 37 real concentration-flux relationships across both organisms, that in vivo ΔG^∘≥-4 kJ/mol is the threshold above which substrates are likely to be sensitive to upstream flux(es).