title: Optimizing metabolite production using periodic oscillations.
abstract: Methods for improving microbial strains for metabolite production remain the subject of constant research. Traditionally, metabolic tuning has been mostly limited to knockouts or overexpression of pathway genes and regulators. In this paper, we establish a new method to control metabolism by inducing optimally tuned time-oscillations in the levels of selected clusters of enzymes, as an alternative strategy to increase the production of a desired metabolite. Using an established kinetic model of the central carbon metabolism of Escherichia coli, we formulate this concept as a dynamic optimization problem over an extended, but finite time horizon. Total production of a metabolite of interest (in this case, phosphoenolpyruvate, PEP) is established as the objective function and time-varying concentrations of the cellular enzymes are used as decision variables. We observe that by varying, in an optimal fashion, levels of key enzymes in time, PEP production increases significantly compared to the unoptimized system. We demonstrate that oscillations can improve metabolic output in experimentally feasible synthetic circuits.
authors.affiliation: Microbiology Graduate Program, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Steven W
authors.initials: SW
authors.lastname: Sowa
authors.affiliation: McKetta Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Baldea
authors.affiliation: McKetta Department of Chemical Engineering, University of Texas at Austin, Austin, Texas, United States of America.
authors.forename: Lydia M
authors.initials: LM
authors.lastname: Contreras
mesh_terms: D004798:Enzymes / Q000378:metabolism* / Q000502:physiology*; D004926:Escherichia coli / Q000201:enzymology / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000502:physiology*; D008954:Models, Biological; D010728:Phosphoenolpyruvate / Q000378:metabolism; D049490:Systems Biology / Q000379:methods*
chemical_list: D004798:Enzymes; D010728:Phosphoenolpyruvate