Metabolic design based on a coupled gene expression - Metabolic network model of tryptophan production in Escherichia coli

Joachim W. Schmid, Klaus Mauch, Matthias Reuss, Ernst D. Gilles, Andreas Kremling

Research output: Contribution to journalArticlepeer-review

60 Scopus citations

Abstract

The presumably high potential of a holistic design approach for complex biochemical reaction networks is exemplified here for the network of tryptophan biosynthesis from glucose, a system whose components have been investigated thoroughly before. A dynamic model that combines the behavior of the trp operon gene expression with the metabolic network of central carbon metabolism and tryptophan biosynthesis is investigated. This model is analyzed in terms of metabolic fluxes, metabolic control, and nonlinear optimization. We compare two models for a wild-type strain and another model for a tryptophan producer. An integrated optimization of the whole network leads to a significant increase in tryptophan production rate for all systems under study. This enhancement is well above the increase that can be achieved by an optimization of subsystems. A constant ratio of control coefficients on tryptophan synthesis rate has been identified for the models regarding or disregarding trp operon expression. Although we found some examples where flux control coefficients even contradict the trends of enzyme activity changes in an optimized profile, flux control can be used as an indication for enzymes that have to be taken into account in optimization.

Original languageEnglish
Pages (from-to)364-377
Number of pages14
JournalMetabolic Engineering
Volume6
Issue number4
DOIs
StatePublished - Oct 2004
Externally publishedYes

Keywords

  • Central carbon metabolism
  • Gene expression
  • Nonlinear optimization
  • Tryptophan synthesis

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