Limits...
Estimating the size of the solution space of metabolic networks.

Braunstein A, Mulet R, Pagnani A - BMC Bioinformatics (2008)

Bottom Line: Then we test the effect of gene knock-outs on the size of the solution space in the case of E. coli central metabolism.The method is shown to obtain, quantitatively and qualitatively compatible results with the ones of standard algorithms (where this comparison is possible) being still efficient on the analysis of large biological systems, where exact deterministic methods experience an explosion in algorithmic time.The algorithm we propose can be considered as an alternative to Monte Carlo sampling methods.

View Article: PubMed Central - HTML - PubMed

Affiliation: Politecnico di Torino, Corso Duca degli Abruzzi 34, I-10129, Torino, Italy. alfredo.braunstein@polito.it

ABSTRACT

Background: Cellular metabolism is one of the most investigated system of biological interactions. While the topological nature of individual reactions and pathways in the network is quite well understood there is still a lack of comprehension regarding the global functional behavior of the system. In the last few years flux-balance analysis (FBA) has been the most successful and widely used technique for studying metabolism at system level. This method strongly relies on the hypothesis that the organism maximizes an objective function. However only under very specific biological conditions (e.g. maximization of biomass for E. coli in reach nutrient medium) the cell seems to obey such optimization law. A more refined analysis not assuming extremization remains an elusive task for large metabolic systems due to algorithmic limitations.

Results: In this work we propose a novel algorithmic strategy that provides an efficient characterization of the whole set of stable fluxes compatible with the metabolic constraints. Using a technique derived from the fields of statistical physics and information theory we designed a message-passing algorithm to estimate the size of the affine space containing all possible steady-state flux distributions of metabolic networks. The algorithm, based on the well known Bethe approximation, can be used to approximately compute the volume of a non full-dimensional convex polytope in high dimensions. We first compare the accuracy of the predictions with an exact algorithm on small random metabolic networks. We also verify that the predictions of the algorithm match closely those of Monte Carlo based methods in the case of the Red Blood Cell metabolic network. Then we test the effect of gene knock-outs on the size of the solution space in the case of E. coli central metabolism. Finally we analyze the statistical properties of the average fluxes of the reactions in the E. coli metabolic network.

Conclusion: We propose a novel efficient distributed algorithmic strategy to estimate the size and shape of the affine space of a non full-dimensional convex polytope in high dimensions. The method is shown to obtain, quantitatively and qualitatively compatible results with the ones of standard algorithms (where this comparison is possible) being still efficient on the analysis of large biological systems, where exact deterministic methods experience an explosion in algorithmic time. The algorithm we propose can be considered as an alternative to Monte Carlo sampling methods.

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Correlation of impact and value. Change in entropy S0 - SKO after reaction knockouts and the average as a function of the average flux value ⟨ν⟩ of the unperturbed system. Red dots are relative to 75% knock-out and blue one to complete knock-out. The six red dots with average flux ~0.3 and entropy change larger than 0.15 are G1PP, GLCP, HEX1, CS, PDH, glycogen which are key check-points of central metabolism.
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Figure 10: Correlation of impact and value. Change in entropy S0 - SKO after reaction knockouts and the average as a function of the average flux value ⟨ν⟩ of the unperturbed system. Red dots are relative to 75% knock-out and blue one to complete knock-out. The six red dots with average flux ~0.3 and entropy change larger than 0.15 are G1PP, GLCP, HEX1, CS, PDH, glycogen which are key check-points of central metabolism.

Mentions: Finally in Figure 10 we display the correlations between the changes in the entropy for different reaction knock-outs and the average flux ⟨νi⟩ = ∫Pi (ν)νdν in the unperturbed network. At 75% knock-out, two kinds of regimes are divided by a clear threshold at ν ~ 0.6: (i) for ⟨νi⟩ < 0.6, S0 - SKO() has a small positive correlation with ⟨ν⟩, (ii) at larger average fluxes, correlations increase rapidly but with larger fluctuations. The presence of this threshold can be understood noting that reactions belonging to the linear (glycolysis) an circular (Krebs cycle) pathways are, in the wild cell, fast flux reactions, with average flux values larger than 0.5. An analogous scenario emerges in the case of a 100% knock-outs, but now fluctuation are wider, and also fluxes with intermediate average value start becoming important. This is the case for instance of the 6 large impact fluxes having average flux around 0.3. A closer inspection reveals that among them there is an exchange fluxes (glycogen) and 5 internal fluxes (G1PP, GLCP, HEX1, CS, PDH). The first three (G1PP, GLCP, HEX1) are the first steps of glycolysis, while PDH is the input of the Krebs cycle, and CS is a segment of the cycle strictly related to PDH. It is interesting that this peculiar behavior (large impact and relatively small average flux) are related to key check-points of central metabolism.


Estimating the size of the solution space of metabolic networks.

Braunstein A, Mulet R, Pagnani A - BMC Bioinformatics (2008)

Correlation of impact and value. Change in entropy S0 - SKO after reaction knockouts and the average as a function of the average flux value ⟨ν⟩ of the unperturbed system. Red dots are relative to 75% knock-out and blue one to complete knock-out. The six red dots with average flux ~0.3 and entropy change larger than 0.15 are G1PP, GLCP, HEX1, CS, PDH, glycogen which are key check-points of central metabolism.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2483728&req=5

Figure 10: Correlation of impact and value. Change in entropy S0 - SKO after reaction knockouts and the average as a function of the average flux value ⟨ν⟩ of the unperturbed system. Red dots are relative to 75% knock-out and blue one to complete knock-out. The six red dots with average flux ~0.3 and entropy change larger than 0.15 are G1PP, GLCP, HEX1, CS, PDH, glycogen which are key check-points of central metabolism.
Mentions: Finally in Figure 10 we display the correlations between the changes in the entropy for different reaction knock-outs and the average flux ⟨νi⟩ = ∫Pi (ν)νdν in the unperturbed network. At 75% knock-out, two kinds of regimes are divided by a clear threshold at ν ~ 0.6: (i) for ⟨νi⟩ < 0.6, S0 - SKO() has a small positive correlation with ⟨ν⟩, (ii) at larger average fluxes, correlations increase rapidly but with larger fluctuations. The presence of this threshold can be understood noting that reactions belonging to the linear (glycolysis) an circular (Krebs cycle) pathways are, in the wild cell, fast flux reactions, with average flux values larger than 0.5. An analogous scenario emerges in the case of a 100% knock-outs, but now fluctuation are wider, and also fluxes with intermediate average value start becoming important. This is the case for instance of the 6 large impact fluxes having average flux around 0.3. A closer inspection reveals that among them there is an exchange fluxes (glycogen) and 5 internal fluxes (G1PP, GLCP, HEX1, CS, PDH). The first three (G1PP, GLCP, HEX1) are the first steps of glycolysis, while PDH is the input of the Krebs cycle, and CS is a segment of the cycle strictly related to PDH. It is interesting that this peculiar behavior (large impact and relatively small average flux) are related to key check-points of central metabolism.

Bottom Line: Then we test the effect of gene knock-outs on the size of the solution space in the case of E. coli central metabolism.The method is shown to obtain, quantitatively and qualitatively compatible results with the ones of standard algorithms (where this comparison is possible) being still efficient on the analysis of large biological systems, where exact deterministic methods experience an explosion in algorithmic time.The algorithm we propose can be considered as an alternative to Monte Carlo sampling methods.

View Article: PubMed Central - HTML - PubMed

Affiliation: Politecnico di Torino, Corso Duca degli Abruzzi 34, I-10129, Torino, Italy. alfredo.braunstein@polito.it

ABSTRACT

Background: Cellular metabolism is one of the most investigated system of biological interactions. While the topological nature of individual reactions and pathways in the network is quite well understood there is still a lack of comprehension regarding the global functional behavior of the system. In the last few years flux-balance analysis (FBA) has been the most successful and widely used technique for studying metabolism at system level. This method strongly relies on the hypothesis that the organism maximizes an objective function. However only under very specific biological conditions (e.g. maximization of biomass for E. coli in reach nutrient medium) the cell seems to obey such optimization law. A more refined analysis not assuming extremization remains an elusive task for large metabolic systems due to algorithmic limitations.

Results: In this work we propose a novel algorithmic strategy that provides an efficient characterization of the whole set of stable fluxes compatible with the metabolic constraints. Using a technique derived from the fields of statistical physics and information theory we designed a message-passing algorithm to estimate the size of the affine space containing all possible steady-state flux distributions of metabolic networks. The algorithm, based on the well known Bethe approximation, can be used to approximately compute the volume of a non full-dimensional convex polytope in high dimensions. We first compare the accuracy of the predictions with an exact algorithm on small random metabolic networks. We also verify that the predictions of the algorithm match closely those of Monte Carlo based methods in the case of the Red Blood Cell metabolic network. Then we test the effect of gene knock-outs on the size of the solution space in the case of E. coli central metabolism. Finally we analyze the statistical properties of the average fluxes of the reactions in the E. coli metabolic network.

Conclusion: We propose a novel efficient distributed algorithmic strategy to estimate the size and shape of the affine space of a non full-dimensional convex polytope in high dimensions. The method is shown to obtain, quantitatively and qualitatively compatible results with the ones of standard algorithms (where this comparison is possible) being still efficient on the analysis of large biological systems, where exact deterministic methods experience an explosion in algorithmic time. The algorithm we propose can be considered as an alternative to Monte Carlo sampling methods.

Show MeSH
Related in: MedlinePlus