Connecting extracellular metabolomic measurements to intracellular flux states in yeast
Open Access
- 25 March 2009
- journal article
- Published by Springer Science and Business Media LLC in BMC Systems Biology
- Vol. 3 (1), 37
- https://doi.org/10.1186/1752-0509-3-37
Abstract
Metabolomics has emerged as a powerful tool in the quantitative identification of physiological and disease-induced biological states. Extracellular metabolome or metabolic profiling data, in particular, can provide an insightful view of intracellular physiological states in a noninvasive manner. We used an updated genome-scale metabolic network model of Saccharomyces cerevisiae, i MM904, to investigate how changes in the extracellular metabolome can be used to study systemic changes in intracellular metabolic states. The i MM904 metabolic network was reconstructed based on an existing genome-scale network, i ND750, and includes 904 genes and 1,412 reactions. The network model was first validated by comparing 2,888 in silico single-gene deletion strain growth phenotype predictions to published experimental data. Extracellular metabolome data measured in response to environmental and genetic perturbations of ammonium assimilation pathways was then integrated with the i MM904 network in the form of relative overflow secretion constraints and a flux sampling approach was used to characterize candidate flux distributions allowed by these constraints. Predicted intracellular flux changes were consistent with published measurements on intracellular metabolite levels and fluxes. Patterns of predicted intracellular flux changes could also be used to correctly identify the regions of the metabolic network that were perturbed. Our results indicate that integrating quantitative extracellular metabolomic profiles in a constraint-based framework enables inferring changes in intracellular metabolic flux states. Similar methods could potentially be applied towards analyzing biofluid metabolome variations related to human physiological and disease states.Keywords
This publication has 56 references indexed in Scilit:
- Architecture of transcriptional regulatory circuits is knitted over the topology of bio-molecular interaction networksBMC Systems Biology, 2008
- Buffering of deoxyribonucleotide pool homeostasis by threonine metabolismProceedings of the National Academy of Sciences, 2007
- Global reconstruction of the human metabolic network based on genomic and bibliomic dataProceedings of the National Academy of Sciences of the United States of America, 2007
- Systematic evaluation of objective functions for predicting intracellular fluxes in Escherichia coliMolecular Systems Biology, 2007
- A genome‐scale metabolic reconstruction for Escherichia coli K‐12 MG1655 that accounts for 1260 ORFs and thermodynamic informationMolecular Systems Biology, 2007
- Systems approach to refining genome annotationProceedings of the National Academy of Sciences, 2006
- Metabolic footprinting and systems biology: the medium is the messageNature Reviews Microbiology, 2005
- Metabolic gene–deletion strains of Escherichia coli evolve to computationally predicted growth phenotypesNature Genetics, 2004
- Global organization of metabolic fluxes in the bacterium Escherichia coliNature, 2004
- Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction NetworksGenome Research, 2003