Thermodynamic constraints are sufficient for the emergence of flux sensors in metabolism

Abstract

Metabolism is a precisely coordinated phenomenon, the apparent goal of which is to balance fluxes to maintain robust growth. However, coordinating fluxes requires information about rates, which is not obviously reconcilable with known regulatory mechanisms in which concentrations are sensed through metabolite binding. While flux sensor examples have been characterized, the fundamental principles underlying the phenomenon in general are not well understood. Specifically, the questions of which fluxes can be sensed, and the mechanism by which they are remain open. We address this by showing that the concentrations of substrates of thermodynamically constrained reactions reflect upstream flux and therefore carry information about rates which can be propagated through regulatory interactions to control other fluxes in the network. Using fluxomic, metabolomic, and thermodynamic data in E coli, we show that the concentrations of a few metabolites in central carbon metabolism reflect their producing fluxes and demonstrate that they can transmit information about these rates because of their positions in the network and their roles as effectors.