Journal
BIOTECHNOLOGY AND BIOENGINEERING
Volume 86, Issue 3, Pages 317-331Publisher
WILEY
DOI: 10.1002/bit.20011
Keywords
constraint-based modeling; extreme pathways; metabolic flux analysis
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Funding
- NIGMS NIH HHS [GM 068837, GM 062791] Funding Source: Medline
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Constraint-based metabolic modeling has been used to capture the genome-scale, systems properties of an organism's metabolism. The first generation of these models has been built on annotated gene sequence. To further this field, we now need to develop methods to incorporate additional omic data types including transcriptomics, metabolomics, and fluxomics to further facilitate the construction, validation, and predictive capabilities of these models. The work herein combines metabolic flux data with an in silico model of central metabolism of Escherichia coli for model centric integration of the flux data. The extreme pathways for this network, which define the allowable solution space for all possible flux distributions, are analyzed using the alpha-spectrum. The alpha-spectrum determines which extreme pathways can and cannot contribute to the metabolic flux distribution for a given condition and gives the allowable range of weightings on each extreme pathway that can contribute. Since many extreme pathways cannot be used under certain conditions, the result is a condition-specific solution space that is a subset of the original solution space. The alpha-spectrum results are used to create a condition-specific extreme pathway matrix that can be analyzed using singular value decomposition (SVD). The first mode of the SVD analysis characterizes the solution space for a given condition. We show that SVD analysis of the alpha-spectrum extreme pathway matrix that incorporates measured uptake and by-product secretion rates, can predict internal flux trends for different experimental conditions. These predicted internal flux trends are, in general, consistent with the flux trends measured using experimental metabolic flux analysis techniques. (C) 2004 Wiley Periodicals, Inc.
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