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Flux sampling is a powerful tool to study metabolism under changing environmental conditions.

ABSTRACT: The development of high-throughput 'omic techniques has sparked a rising interest in genome-scale metabolic models, with applications ranging from disease diagnostics to crop adaptation. Efficient and accurate methods are required to analyze large metabolic networks. Flux sampling can be used to explore the feasible flux solutions in metabolic networks by generating probability distributions of steady-state reaction fluxes. Unlike other methods, flux sampling can be used without assuming a particular cellular objective. We have undertaken a rigorous comparison of several sampling algorithms and concluded that the coordinate hit-and-run with rounding (CHRR) algorithm is the most efficient based on both run-time and multiple convergence diagnostics. We demonstrate the power of CHRR by using it to study the metabolic changes that underlie photosynthetic acclimation to cold of Arabidopsis thaliana plant leaves. In combination with experimental measurements, we show how the regulated interplay between diurnal starch and organic acid accumulation defines the plant acclimation process. We confirm fumarate accumulation as a requirement for cold acclimation and further predict ?-aminobutyric acid to have a key role in metabolic signaling under cold conditions. These results demonstrate how flux sampling can be used to analyze the feasible flux solutions across changing environmental conditions, whereas eliminating the need to make assumptions which introduce observer bias.

SUBMITTER: Herrmann HA

PROVIDER: S-EPMC6718391 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Flux sampling is a powerful tool to study metabolism under changing environmental conditions.

Herrmann Helena A HA Dyson Beth C BC Vass Lucy L Johnson Giles N GN Schwartz Jean-Marc JM

NPJ systems biology and applications 20190902

The development of high-throughput 'omic techniques has sparked a rising interest in genome-scale metabolic models, with applications ranging from disease diagnostics to crop adaptation. Efficient and accurate methods are required to analyze large metabolic networks. Flux sampling can be used to explore the feasible flux solutions in metabolic networks by generating probability distributions of steady-state reaction fluxes. Unlike other methods, flux sampling can be used without assuming a parti ...[more]

PMID: 31482008

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Project description:BackgroundBiological systems adapt to changing environments by reorganizing their cellular and physiological program with metabolites representing one important response level. Different stresses lead to both conserved and specific responses on the metabolite level which should be reflected in the underlying metabolic network.Methodology/principal findingsStarting from experimental data obtained by a GC-MS based high-throughput metabolic profiling technology we here develop an approach that: (1) extracts network representations from metabolic condition-dependent data by using pairwise correlations, (2) determines the sets of stable and condition-dependent correlations based on a combination of statistical significance and homogeneity tests, and (3) can identify metabolites related to the stress response, which goes beyond simple observations about the changes of metabolic concentrations. The approach was tested with Escherichia coli as a model organism observed under four different environmental stress conditions (cold stress, heat stress, oxidative stress, lactose diauxie) and control unperturbed conditions. By constructing the stable network component, which displays a scale free topology and small-world characteristics, we demonstrated that: (1) metabolite hubs in this reconstructed correlation networks are significantly enriched for those contained in biochemical networks such as EcoCyc, (2) particular components of the stable network are enriched for functionally related biochemical pathways, and (3) independently of the response scale, based on their importance in the reorganization of the correlation network a set of metabolites can be identified which represent hypothetical candidates for adjusting to a stress-specific response.Conclusions/significanceNetwork-based tools allowed the identification of stress-dependent and general metabolic correlation networks. This correlation-network-based approach does not rely on major changes in concentration to identify metabolites important for stress adaptation, but rather on the changes in network properties with respect to metabolites. This should represent a useful complementary technique in addition to more classical approaches.

Dataset Information

Flux sampling is a powerful tool to study metabolism under changing environmental conditions.

Publications

Flux sampling is a powerful tool to study metabolism under changing environmental conditions.

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