Optimizing metabolite production using periodic oscillations

PLoS Comput Biol. 2014 Jun 5;10(6):e1003658. doi: 10.1371/journal.pcbi.1003658. eCollection 2014 Jun.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Enzymes / metabolism*
  • Enzymes / physiology*
  • Escherichia coli / enzymology
  • Escherichia coli / metabolism
  • Metabolic Networks and Pathways / physiology*
  • Models, Biological*
  • Phosphoenolpyruvate / metabolism
  • Systems Biology / methods*

Substances

  • Enzymes
  • Phosphoenolpyruvate

Grants and funding

We thank funding sources from the National Science Foundation (MCB 1330862 and CBET-1254754) and the Welch Foundation (F-1756) for support to LMC and MB. The funders had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.