Intracellular crowding defines the mode and sequence of substrate uptake byEscherichia coliand constrains its metabolic activity

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Abstract
The influence of the high intracellular concentration of macromolecules on cell physiology is increasingly appreciated, but its impact on system-level cellular functions remains poorly quantified. To assess its potential effect, here we develop a flux balance model ofEscherichia colicell metabolism that takes into account a systems-level constraint for the concentration of enzymes catalyzing the various metabolic reactions in the crowded cytoplasm. We demonstrate that the model's predictions for the relative maximum growth rate of wild-type and mutantE. colicells in single substrate-limited media, and the sequence and mode of substrate uptake and utilization from a complex medium are in good agreement with subsequent experimental observations. These results suggest that molecular crowding represents a bound on the achievable functional states of a metabolic network, and they indicate that models incorporating this constraint can systematically identify alterations in cellular metabolism activated in response to environmental change.