Abstract
The links between metabolic dysfunctions and various diseases or pathological conditions are being increasingly revealed. This revival of interest in cellular metabolism has pushed forward new experimental technologies enabling the characterization of metabolic phenotypes. Unfortunately, while large datasets are being collected, which encompass the concentration of many metabolites of a system under different conditions, these datasets remain largely obscure. In fact, in spite of the efforts to interpret alterations in metabolic concentrations, it is difficult to correctly ascribe them to the corresponding variations in metabolic fluxes (i.e. the rate of turnover of molecules through metabolic pathways) and thus to the up- or down-regulation of given pathways. As a first step towards a systematic procedure to connect alterations in metabolic fluxes with shifts in metabolites, we propose to exploit a Montecarlo approach to look for correlations between the variations in fluxes and in metabolites, observed when simulating the response of a metabolic network to a given perturbation. As a proof of principle, we investigate the dynamics of a simplified ODE model of yeast metabolism under different glucose abundances. We show that, although some linear correlations between shifts in metabolites and fluxes exist, those relationships are far from obvious. In particular, metabolite levels can show a low correlation with changes in the fluxes of the reactions that directly involve them, while exhibiting a strong connection with alterations in fluxes that are far apart in the network.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Agren, R., Mardinoglu, A., Asplund, A., Kampf, C., Uhlen, M., Nielsen, J.: Identification of anticancer drugs for hepatocellular carcinoma through personalized genome-scale metabolic modeling. Mol. Syst. Biol. 10(3), 721 (2014)
Canelas, A.B., van Gulik, W.M., Heijnen, J.J.: Determination of the cytosolic free nad/nadh ratio in saccharomyces cerevisiae under steady-state and highly dynamic conditions. Biotechnol. Bioeng. 100(4), 734–743 (2008)
Cazzaniga, P., Damiani, C., Besozzi, D., Colombo, R., Nobile, M.S., Gaglio, D., Pescini, D., Molinari, S., Mauri, G., Alberghina, L., et al.: Computational strategies for a system-level understanding of metabolism. Metabolites 4(4), 1034–1087 (2014)
Colombo, R., Damiani, C., Mauri, G., Pescini, D.: Ensembles of parametrizations to investigate the crabtree phenotype by constraining mechanism-based simulations. In: Proceedings of CIBB 2016 (2016)
Cumbo, F., Nobile, M., Damiani, C., Colombo, R., Mauri, G., Cazzaniga, P.: Cosys: computational systems biology infrastructure. In: Proceedings of CIBB 2016 (2016)
Damiani, C., Pescini, D., Colombo, R., Molinari, S., Alberghina, L., Vanoni, M., Mauri, G.: An ensemble evolutionary constraint-based approach to understand the emergence of metabolic phenotypes. Nat. Comput. 13(3), 321–331 (2014)
Di Filippo, M., Colombo, R., Damiani, C., Pescini, D., Gaglio, D., Vanoni, M., Alberghina, L., Mauri, G.: Zooming-in on cancer metabolic rewiring with tissue specific constraint-based models. Comput. Biol. Chem. 62, 60–69 (2016)
Holmes, E., Wilson, I.D., Nicholson, J.K.: Metabolic phenotyping in health and disease. Cell 134(5), 714–717 (2008)
Jain, M., Nilsson, R., Sharma, S., Madhusudhan, N., Kitami, T., Souza, A.L., Kafri, R., Kirschner, M.W., Clish, C.B., Mootha, V.K.: Metabolite profiling identifies a key role for glycine in rapid cancer cell proliferation. Science 336(6084), 1040–1044 (2012)
OBrien, E.J., Monk, J.M., Palsson, B.O.: Using genome-scale models to predict biological capabilities. Cell 161(5), 971–987 (2015)
Petzold, L.: Automatic selection of methods for solving stiff and nonstiff systems of ordinary differential equations. SIAM J. Sci. Stat. Comput. 4(1), 136–148 (1983). http://dx.doi.org/10.1137/0904010
Resendis-Antonio, O., Checa, A., Encarnación, S.: Modeling core metabolism in cancer cells: surveying the topology underlying the warburg effect. PloS one 5(8), e12383 (2010)
Shlomi, T., Cabili, M.N., Ruppin, E.: Predicting metabolic biomarkers of human inborn errors of metabolism. Mol. Syst. Biol. 5(1), 263 (2009)
Smallbone, K., Messiha, H.L., Carroll, K.M., Winder, C.L., Malys, N., Dunn, W.B., Murabito, E., Swainston, N., Dada, J.O., Khan, F., et al.: A model of yeast glycolysis based on a consistent kinetic characterisation of all its enzymes. FEBS Lett. 587(17), 2832–2841 (2013)
Theobald, U., Mailinger, W., Baltes, M., Rizzi, M., Reuss, M.: In vivo analysis of metabolic dynamics in saccharomyces cerevisiae: I. experimental observations. Biotechnol. Bioeng. 55(2), 305–316 (1997)
Wierling, C., Kühn, A., Hache, H., Daskalaki, A., Maschke-Dutz, E., Peycheva, S., Li, J., Herwig, R., Lehrach, H.: Prediction in the face of uncertainty: a Monte Carlo-based approach for systems biology of cancer treatment. Mutat. Res. Genet. Toxicol. Environ. Mutagen. 746(2), 163–170 (2012)
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2017 Springer International Publishing AG
About this paper
Cite this paper
Damiani, C., Colombo, R., Di Filippo, M., Pescini, D., Mauri, G. (2017). Linking Alterations in Metabolic Fluxes with Shifts in Metabolite Levels by Means of Kinetic Modeling. In: Rossi, F., Piotto, S., Concilio, S. (eds) Advances in Artificial Life, Evolutionary Computation, and Systems Chemistry. WIVACE 2016. Communications in Computer and Information Science, vol 708. Springer, Cham. https://doi.org/10.1007/978-3-319-57711-1_12
Download citation
DOI: https://doi.org/10.1007/978-3-319-57711-1_12
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-319-57710-4
Online ISBN: 978-3-319-57711-1
eBook Packages: Computer ScienceComputer Science (R0)