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Metab Eng. 2011 Jan;13(1):60-75. doi: 10.1016/j.ymben.2010.11.001. Epub 2010 Nov 12.

Reducing the allowable kinetic space by constructing ensemble of dynamic models with the same steady-state flux.

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1
Department of Chemical and Biomolecular Engineering, University of California, Los Angeles, 5531 Boelter Hall, Los Angeles, CA 90095-1592, USA.

Abstract

Dynamic models of metabolism are instrumental for gaining insight and predicting possible outcomes of perturbations. Current approaches start from the selection of lumped enzyme kinetics and determine the parameters within a large parametric space. However, kinetic parameters are often unknown and obtaining these parameters requires detailed characterization of enzyme kinetics. In many cases, only steady-state fluxes are measured or estimated, but these data have not been utilized to construct dynamic models. Here, we extend the previously developed Ensemble Modeling methodology by allowing various kinetic rate expressions and employing a more efficient solution method for steady states. We show that anchoring the dynamic models to the same flux reduces the allowable parameter space significantly such that sampling of high dimensional kinetic parameters becomes meaningful. The methodology enables examination of the properties of the model's structure, including multiple steady states. Screening of models based on limited steady-state fluxes or metabolite profiles reduces the parameter space further and the remaining models become increasingly predictive. We use both succinate overproduction and central carbon metabolism in Escherichia coli as examples to demonstrate these results.

PMID:
21075211
DOI:
10.1016/j.ymben.2010.11.001
[Indexed for MEDLINE]
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