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Metabolic network structure determines key aspects of functionality and regulation

Abstract

The relationship between structure, function and regulation in complex cellular networks is a still largely open question1,2,3. Systems biology aims to explain this relationship by combining experimental and theoretical approaches4. Current theories have various strengths and shortcomings in providing an integrated, predictive description of cellular networks. Specifically, dynamic mathematical modelling of large-scale networks meets difficulties because the necessary mechanistic detail and kinetic parameters are rarely available. In contrast, structure-oriented analyses only require network topology, which is well known in many cases. Previous approaches of this type focus on network robustness5 or metabolic phenotype2,6, but do not give predictions on cellular regulation. Here, we devise a theoretical method for simultaneously predicting key aspects of network functionality, robustness and gene regulation from network structure alone. This is achieved by determining and analysing the non-decomposable pathways able to operate coherently at steady state (elementary flux modes). We use the example of Escherichia coli central metabolism to illustrate the method.

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Figure 1: Example network.
Figure 2: Metabolic network topology and phenotype.
Figure 3: Prediction of gene expression patterns.

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Acknowledgements

We thank M. Ginkel for software optimization, J. Liao for providing us with data before publication, U. Sauer, S. Bonhoeffer and A. Cornish-Bowden for critical reading of the manuscript and suggestions. S.S. gratefully acknowledges financial support by the Deutsche Forschungsgemeinschaft.

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Correspondence to Jörg Stelling.

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Stelling, J., Klamt, S., Bettenbrock, K. et al. Metabolic network structure determines key aspects of functionality and regulation. Nature 420, 190–193 (2002). https://doi.org/10.1038/nature01166

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