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Biophys. J. BioFAST: First Published October 1, 2004. doi:10.1529/biophysj.104.048090
© 2004 by the Biophysical Society.

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BIOPHYSICAL THEORY AND MODELING

Metabolic Control Analysis under Uncertainty: Framework Development and Case Studies

Liqing Wang 1, Inanc Birol 1 and Vassily Hatzimanikatis 1*

1 Northwestern University

* To whom correspondence should be addressed. E-mail: vassily{at}northwestern.edu.

Submitted on June 21, 2004
Revised on August 27, 2004
Accepted on 22 September 2004


  Abstract
Information about the enzyme kinetics in a metabolic network will enable understanding of the function of the network and quantitative prediction of the network responses to genetic and environmental perturbations. Despite recent advances in experimental techniques, such information is limited and existing experimental data show extensive variation and they are based on in vitro experiments. In this paper, we present a computational framework based on the well-established (log)linear formalism of Metabolic Control Analysis. The framework employs a Monte Carlo sampling procedure to simulate the uncertainty in the kinetic data and applies statistical tools for the identification of the rate limiting steps in metabolic networks. We applied the proposed framework to a branched biosynthetic pathway and the yeast glycolysis pathway. Analysis of the results allowed us to interpret and predict the responses of metabolic networks to genetic and environmental changes, and to gain insights on how uncertainty in the kinetic mechanisms and kinetic parameters propagate into the uncertainty in predicting network responses. Some of the practical applications of the proposed approach include the identification of drug targets for metabolic diseases and the guidance for design strategies in metabolic engineering for the purposeful manipulation of the metabolism of industrial organisms.

Key Words: (Log)linear, Conserved moiety, Glycolysis, Kinetic modeling, Metabolic networks, Monte-Carlo




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Copyright © 2004 by the Biophysical Society.