title: A synthetic gene-metabolic oscillator.
abstract: Autonomous oscillations found in gene expression and metabolic, cardiac and neuronal systems have attracted significant attention both because of their obvious biological roles and their intriguing dynamics. In addition, de novo designed oscillators have been demonstrated, using components that are not part of the natural oscillators. Such oscillators are useful in testing the design principles and in exploring potential applications not limited by natural cellular behaviour. To achieve transcriptional and metabolic integration characteristic of natural oscillators, here we designed and constructed a synthetic circuit in Escherichia coli K12, using glycolytic flux to generate oscillation through the signalling metabolite acetyl phosphate. If two metabolite pools are interconverted by two enzymes that are placed under the transcriptional control of acetyl phosphate, the system oscillates when the glycolytic rate exceeds a critical value. We used bifurcation analysis to identify the boundaries of oscillation, and verified these experimentally. This work demonstrates the possibility of using metabolic flux as a control factor in system-wide oscillation, as well as the predictability of a de novo gene-metabolic circuit designed using nonlinear dynamic analysis.
authors.affiliation: Department of Chemical Engineering, University of California-Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Fung
authors.forename: Wilson W
authors.initials: WW
authors.lastname: Wong
authors.forename: Jason K
authors.initials: JK
authors.lastname: Suen
authors.forename: Thomas
authors.initials: T
authors.lastname: Bulter
authors.forename: Sun-gu
authors.initials: SG
authors.lastname: Lee
authors.forename: James C
authors.initials: JC
authors.lastname: Liao
mesh_terms: D001683:Biological Clocks / Q000502:physiology*; D004926:Escherichia coli / Q000235:genetics* / Q000378:metabolism*; D029968:Escherichia coli Proteins / Q000235:genetics; D015964:Gene Expression Regulation, Bacterial; D005818:Genetic Engineering; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D007700:Kinetics; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010755:Organophosphates / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D029968:Escherichia coli Proteins; D010755:Organophosphates; C011632:acetyl phosphate; D005947:Glucose