title: Intracellular crowding defines the mode and sequence of substrate uptake by Escherichia coli and constrains its metabolic activity.
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 of Escherichia coli cell 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 mutant E. coli cells 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.
authors.affiliation: Department of Pathology, University of Pittsburgh, 3550 Terrace Street, Pittsburgh, PA 15261, USA.
authors.forename: Q K
authors.initials: QK
authors.lastname: Beg
authors.forename: A
authors.initials: A
authors.lastname: Vazquez
authors.forename: J
authors.initials: J
authors.lastname: Ernst
authors.forename: M A
authors.initials: MA
authors.lastname: de Menezes
authors.forename: Z
authors.initials: Z
authors.lastname: Bar-Joseph
authors.forename: A-L
authors.initials: AL
authors.lastname: Barabási
authors.forename: Z N
authors.initials: ZN
authors.lastname: Oltvai
mesh_terms: D002244:Carbon / Q000378:metabolism; D004926:Escherichia coli / Q000166:cytology / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D015964:Gene Expression Regulation, Bacterial; D050296:Microbial Viability; D020411:Oligonucleotide Array Sequence Analysis; D013379:Substrate Specificity
chemical_list: D002244:Carbon