title: Metabolic regulation is sufficient for global and robust coordination of glucose uptake, catabolism, energy production and growth in Escherichia coli.
abstract: The metabolism of microorganisms is regulated through two main mechanisms: changes of enzyme capacities as a consequence of gene expression modulation ("hierarchical control") and changes of enzyme activities through metabolite-enzyme interactions. An increasing body of evidence indicates that hierarchical control is insufficient to explain metabolic behaviors, but the system-wide impact of metabolic regulation remains largely uncharacterized. To clarify its role, we developed and validated a detailed kinetic model of Escherichia coli central metabolism that links growth to environment. Metabolic control analyses confirm that the control is widely distributed across the network and highlight strong interconnections between all the pathways. Exploration of the model solution space reveals that several robust properties emerge from metabolic regulation, from the molecular level (e.g. homeostasis of total metabolite pool) to the overall cellular physiology (e.g. coordination of carbon uptake, catabolism, energy and redox production, and growth), while allowing a large degree of flexibility at most individual metabolic steps. These properties have important physiological implications for E. coli and significantly expand the self-regulating capacities of its metabolism.
authors.affiliation: MCISB, Manchester Institute of Biotechnology, University of Manchester, Manchester, United Kingdom.|School of Computer Science, University of Manchester, Manchester, United Kingdom.|LISBP, Université de Toulouse, CNRS, INRA, INSA, Toulouse, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Millard
authors.affiliation: MCISB, Manchester Institute of Biotechnology, University of Manchester, Manchester, United Kingdom.|School of Computer Science, University of Manchester, Manchester, United Kingdom.
authors.forename: Kieran
authors.identifier: 0000-0003-2815-7045
authors.initials: K
authors.lastname: Smallbone
authors.affiliation: MCISB, Manchester Institute of Biotechnology, University of Manchester, Manchester, United Kingdom.|School of Computer Science, University of Manchester, Manchester, United Kingdom.|Center for Quantitative Medicine and Dept. Cell Biology, UConn Health, Farmington, Connecticut, United States of America.
authors.forename: Pedro
authors.identifier: 0000-0001-6507-9168
authors.initials: P
authors.lastname: Mendes
mesh_terms: D049109:Cell Proliferation / Q000502:physiology*; D003198:Computer Simulation; D004734:Energy Metabolism / Q000502:physiology*; D004926:Escherichia coli / Q000166:cytology / Q000378:metabolism*; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005947:Glucose / Q000378:metabolism*; D064688:Metabolic Flux Analysis / Q000379:methods; D053858:Metabolic Networks and Pathways / Q000502:physiology; D008660:Metabolism; D008954:Models, Biological; D015398:Signal Transduction / Q000502:physiology
chemical_list: D005947:Glucose