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 Delta G degrees >= 4 kJ/mol is the threshold above which substrates are likely to be sensitive to upstream flux(es). SIGNIFICANCE Some metabolites naturally have concentrations that are dependent on local metabolic fluxes. The relationship between fructose-1,6-bisphosphate (FBP) concentration and glycolytic flux is a well-characterized example of this phenomenon. These so-called flux sensors provide a mechanism for cells to measure fluxes and perform control action in response to perturbations. However, the underlying mechanism(s) that lead to such concentration-flux relationships is/are not understood, so engineers have no principles to guide their search for existing unknown flux sensors and/or to build flux-sensing controllers. This study outlines a thermodynamic constraint hypothesis explaining the emergence of flux sensors. Multi-omics data from both Escherichia coli and Saccharomyces cerevisiae are analyzed to show that natural concentration-flux relationships are associated with thermodynamically constrained reactions.

Automated summary

This study demonstrates that substrate concentrations of thermodynamically constrained reactions can serve as indicators of upstream flux and carry information about rates. The research also reveals concentration-flux relationships in central carbon metabolism and establishes a threshold for substrate sensitivity to upstream flux. These findings provide insights into the understanding of concentration-flux relationships and their cellular functions.