Abstract
Many microbes exhibit nutrient preferences, exemplified by the “hierarchical” consumption of certain carbon substrates. Here we systematically investigate under which physiological conditions hierarchical substrate utilization occurs and its mechanisms of implementation. We show utilization hierarchy of Escherichia coli to be ordered by the carbon-uptake flux rather than the identity of the substrates. A detailed study of glycerol uptake finds that it is fully suppressed if the uptake flux of another glycolytic substrate exceeds a threshold, set to the influx obtained when grown on glycerol alone. Below this threshold, limited glycerol uptake is “supplemented” such that the total carbon uptake is maintained at the threshold. This behavior results from total-flux feedback mediated by cAMP-Crp signaling, but also requires inhibition by regulator fructose-1,6-bisphosphate, which senses the upper glycolytic flux and ensures that glycerol uptake defers to other glycolytic substrates but not to gluconeogenic ones. A quantitative model reproduces all observed utilization patterns including those of key mutants. The proposed mechanism relies on differential regulation of uptake enzymes and requires a specific operon organization. This organization is found conserved across related species for several uptake systems, suggesting the deployment of similar mechanisms for hierarchical substrate utilization by a spectrum of microbes.
Accepted Version
Published Version
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