A metabolite-centric view on flux distributions in genome-scale metabolic models

BMC Systems Biology

Dietmar Schomburg¹  René Rex¹  S Alexander Riemer¹ 

[1] Department of Bioinformatics and Biochemistry, Technische Universität Braunschweig, Braunschweig, Germany

关键词: iAF1260;    iJO1366;    Linear programming;    Stoichiometric matrix;    Constraint-based modelling;    Metabolic reconstruction;    Flux balance analysis;    Metabolic modelling;    Branch points;    Split ratios;   

Others  :  1142941
DOI  :  10.1186/1752-0509-7-33

 received in 2012-08-14, accepted in 2013-04-03,  发布年份 2013

【 摘 要 】

Background

Genome-scale metabolic models are important tools in systems biology. They permit the in-silico prediction of cellular phenotypes via mathematical optimisation procedures, most importantly flux balance analysis. Current studies on metabolic models mostly consider reaction fluxes in isolation. Based on a recently proposed metabolite-centric approach, we here describe a set of methods that enable the analysis and interpretation of flux distributions in an integrated metabolite-centric view. We demonstrate how this framework can be used for the refinement of genome-scale metabolic models.

Results

We applied the metabolite-centric view developed here to the most recent metabolic reconstruction of Escherichia coli. By compiling the balance sheets of a small number of currency metabolites, we were able to fully characterise the energy metabolism as predicted by the model and to identify a possibility for model refinement in NADPH metabolism. Selected branch points were examined in detail in order to demonstrate how a metabolite-centric view allows identifying functional roles of metabolites. Fructose 6-phosphate aldolase and the sedoheptulose bisphosphate bypass were identified as enzymatic reactions that can carry high fluxes in the model but are unlikely to exhibit significant activity in vivo. Performing a metabolite essentiality analysis, unconstrained import and export of iron ions could be identified as potentially problematic for the quality of model predictions.

Conclusions

The system-wide analysis of split ratios and branch points allows a much deeper insight into the metabolic network than reaction-centric analyses. Extending an earlier metabolite-centric approach, the methods introduced here establish an integrated metabolite-centric framework for the interpretation of flux distributions in genome-scale metabolic networks that can complement the classical reaction-centric framework. Analysing fluxes and their metabolic context simultaneously opens the door to systems biological interpretations that are not apparent from isolated reaction fluxes. Particularly powerful demonstrations of this are the analyses of the complete metabolic contexts of energy metabolism and the folate-dependent one-carbon pool presented in this work. Finally, a metabolite-centric view on flux distributions can guide the refinement of metabolic reconstructions for specific growth scenarios.

【 授权许可】

   
2013 Riemer et al.; licensee BioMed Central Ltd.

【 图 表 】

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