The principle of flux minimization and its application to estimate stationary fluxes in metabolic networks - PubMed (original) (raw)
The principle of flux minimization and its application to estimate stationary fluxes in metabolic networks
Hermann-Georg Holzhütter. Eur J Biochem. 2004 Jul.
Free article
Abstract
Cellular functions are ultimately linked to metabolic fluxes brought about by thousands of chemical reactions and transport processes. The synthesis of the underlying enzymes and membrane transporters causes the cell a certain 'effort' of energy and external resources. Considering that those cells should have had a selection advantage during natural evolution that enabled them to fulfil vital functions (such as growth, defence against toxic compounds, repair of DNA alterations, etc.) with minimal effort, one may postulate the principle of flux minimization, as follows: given the available external substrates and given a set of functionally important 'target' fluxes required to accomplish a specific pattern of cellular functions, the stationary metabolic fluxes have to become a minimum. To convert this principle into a mathematical method enabling the prediction of stationary metabolic fluxes, the total flux in the network is measured by a weighted linear combination of all individual fluxes whereby the thermodynamic equilibrium constants are used as weighting factors, i.e. the more the thermodynamic equilibrium lies on the right-hand side of the reaction, the larger the weighting factor for the backward reaction. A linear programming technique is applied to minimize the total flux at fixed values of the target fluxes and under the constraint of flux balance (= steady-state conditions) with respect to all metabolites. The theoretical concept is applied to two metabolic schemes: the energy and redox metabolism of erythrocytes, and the central metabolism of Methylobacterium extorquens AM1. The flux rates predicted by the flux-minimization method exhibit significant correlations with flux rates obtained by either kinetic modelling or direct experimental determination. Larger deviations occur for segments of the network composed of redundant branches where the flux-minimization method always attributes the total flux to the thermodynamically most favourable branch. Nevertheless, compared with existing methods of structural modelling, the principle of flux minimization appears to be a promising theoretical approach to assess stationary flux rates in metabolic systems in cases where a detailed kinetic model is not yet available.
Similar articles
- Computational design of reduced metabolic networks.
Holzhütter S, Holzhütter HG. Holzhütter S, et al. Chembiochem. 2004 Oct 4;5(10):1401-22. doi: 10.1002/cbic.200400128. Chembiochem. 2004. PMID: 15457535 - Composition of metabolic flux distributions by functionally interpretable minimal flux modes (MinModes).
Hoffmann S, Hoppe A, Holzhütter HG. Hoffmann S, et al. Genome Inform. 2006;17(1):195-207. Genome Inform. 2006. PMID: 17503369 - Quantification of central metabolic fluxes in the facultative methylotroph methylobacterium extorquens AM1 using 13C-label tracing and mass spectrometry.
Van Dien SJ, Strovas T, Lidstrom ME. Van Dien SJ, et al. Biotechnol Bioeng. 2003 Oct 5;84(1):45-55. doi: 10.1002/bit.10745. Biotechnol Bioeng. 2003. PMID: 12910542 - The application of flux balance analysis in systems biology.
Gianchandani EP, Chavali AK, Papin JA. Gianchandani EP, et al. Wiley Interdiscip Rev Syst Biol Med. 2010 May-Jun;2(3):372-382. doi: 10.1002/wsbm.60. Wiley Interdiscip Rev Syst Biol Med. 2010. PMID: 20836035 Review. - Metabolic flux analysis: a powerful tool for monitoring tissue function.
Lee K, Berthiaume F, Stephanopoulos GN, Yarmush ML. Lee K, et al. Tissue Eng. 1999 Aug;5(4):347-68. doi: 10.1089/ten.1999.5.347. Tissue Eng. 1999. PMID: 10477857 Review.
Cited by
- Mapping the landscape of metabolic goals of a cell.
Zhao Q, Stettner AI, Reznik E, Paschalidis ICh, Segrè D. Zhao Q, et al. Genome Biol. 2016 May 23;17(1):109. doi: 10.1186/s13059-016-0968-2. Genome Biol. 2016. PMID: 27215445 Free PMC article. - HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology.
Gille C, Bölling C, Hoppe A, Bulik S, Hoffmann S, Hübner K, Karlstädt A, Ganeshan R, König M, Rother K, Weidlich M, Behre J, Holzhütter HG. Gille C, et al. Mol Syst Biol. 2010 Sep 7;6:411. doi: 10.1038/msb.2010.62. Mol Syst Biol. 2010. PMID: 20823849 Free PMC article. - Genome-Scale Metabolic Modelling Approach to Understand the Metabolism of the Opportunistic Human Pathogen Staphylococcus epidermidis RP62A.
Díaz Calvo T, Tejera N, McNamara I, Langridge GC, Wain J, Poolman M, Singh D. Díaz Calvo T, et al. Metabolites. 2022 Feb 2;12(2):136. doi: 10.3390/metabo12020136. Metabolites. 2022. PMID: 35208211 Free PMC article. - Predicting the accumulation of storage compounds by Rhodococcus jostii RHA1 in the feast-famine growth cycles using genome-scale flux balance analysis.
Tajparast M, Frigon D. Tajparast M, et al. PLoS One. 2018 Mar 1;13(3):e0191835. doi: 10.1371/journal.pone.0191835. eCollection 2018. PLoS One. 2018. PMID: 29494607 Free PMC article. - An analytical theory of balanced cellular growth.
Dourado H, Lercher MJ. Dourado H, et al. Nat Commun. 2020 Mar 6;11(1):1226. doi: 10.1038/s41467-020-14751-w. Nat Commun. 2020. PMID: 32144263 Free PMC article.
MeSH terms
LinkOut - more resources
Full Text Sources
Other Literature Sources