GLUCOSE BECOMES ONE OF THE WORST CARBON SOURCES FOR E. COLI ON POOR NITROGEN SOURCES DUE TO SUBOPTIMAL LEVELS OF cAMP

In most conditions, glucose is the best carbon source for E. coli: the investment required to metabolize it is low, and it is therefore consumed first in sugar mixtures. We have identified a condition in which E. coli strains grow slower on glucose than on other sugars, namely when a single amino acid (arginine, glutamate, or proline) is the sole nitrogen source. In sugar mixtures with these nitrogen sources, E. coli still consumed glucose first, but grew faster rather than slower after exhausting glucose, generating a reversed diauxic shift. We traced this counterintuitive behavior to a metabolic imbalance: levels of TCA cycle metabolites including α-ketoglutarate are high, and levels of the key regulatory molecule cAMP are low. Growth rates were increased by replenishing cAMP, or by inhibition of glucose uptake, which increased cAMP levels. We conclude that E. coli`s metabolic strategy fails to account for the possibility of encountering both glucose and certain poor nitrogen sources– a pairing that is presumably rare in natural environments. This observation of a control strategy that is beneficial in most circumstances but potentially disastrous in rare circumstances shows the limits of the ability of biological circuits to find optimal solutions in diverse environments.