Abstract
A set of linear pathways often does not capture the full range of behaviors of a metabolic network. The concept of ‘elementary flux modes’ provides a mathematical tool to define and comprehensively describe all metabolic routes that are both stoichiometrically and thermodynamically feasible for a group of enzymes. We have used this concept to analyze the interplay between the pentose phosphate pathway (PPP) and glycolysis. The set of elementary modes for this system involves conventional glycolysis, a futile cycle, all the modes of PPP function described in biochemistry textbooks, and additional modes that are a priori equally entitled to pathway status. Applications include maximizing product yield in amino acid and antibiotic synthesis, reconstruction and consistency checks of metabolism from genome data, analysis of enzyme deficiencies, and drug target identification in metabolic networks.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Yarmush, M.L. & Berthiaume, F. Metabolic engineering and human disease. Nat. Biotechnol. 15, 525– 528 (1997).
Sauer, U. et al. Metabolic fluxes in riboflavin-producing Bacillus subtilis. Nat. Biotechnol. 15, 448– 452 (1997).
Tatusov, R.L. et al. Metabolism and evolution of Haemophilus influenzae deduced from a whole-genome comparison with Escherichia coli. Curr. Biol. 6, 279–291 ( 1996).
Bork, P. et al. Predicting function: from genes to genomes and back. J. Mol. Biol. 283, 707–725 (1998).
Schilling, C.H. & Palsson, B.O. The underlying pathway structure of biochemical reaction networks. Proc. Natl. Acad. Sci. USA 95, 4193–4198 (1998).
DeRisi, J.L., Iyer, V.R. & Brown, P.O. Exploring the metabolic and genetic control of gene expression on a genomic scale. Science 278, 680– 686 (1997).
Cole, S.T. et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544 (1998)
Dandekar, T., Schuster, S., Snel, B., Huynen, M. & Bork P. Pathway alignment: application to the comparative analysis of glycolytic enzymes, Biochem. J. 343, 115– 124 (1999).
Seressiotis, A. & Bailey, J.E. MPS: an algorithm and data base for metabolic pathway synthesis. Biotechn. Lett. 8, 837–842 ( 1986).
Mavrovouniotis, M.L., Stephanopoulos, G. & Stephanopoulos, G. Computer-aided synthesis of biochemical pathways. Biotechnol. Bioeng. 36, 1119– 1132 (1990).
Fell, D.A. in Modern trends in biothermokinetics (eds Schuster, S., Rigoulet, M., Ouhabi, R. & Mazat, J.-P.) 97–101 (Plenum, New York, NY; 1993).
Simpson, T.W., Colón, G.E. & Stephanopoulos, G. Two paradigms of metabolic engineering applied to amino acid biosynthesis. Biochem. Soc. Trans. 23, 381–387 (1995).
Clarke, B.L. Complete set of steady states for the general stoichiometric dynamical system. J. Chem. Phys. 75, 4970– 4979 (1981).
Leiser, J. & Blum, J.J. On the analysis of substrate cycles in large metabolic systems. Cell Biophys. 11, 123–138 (1987).
Schuster, S. & Hilgetag, C. On elementary flux modes in biochemical reaction systems at steady state. J. Biol. Syst. 2, 165–182 (1994).
Schuster, S., Hilgetag, C., Woods, J.H. & Fell, D.A. in Computation in cellular and molecular biological systems (eds Cuthbertson, R., Holcombe, M. & Paton, R.) 151–165 (World Scientific, Singapore, 1996).
Schuster, S., Dandekar, T. & Fell, D. Detection of elementary flux modes in biochemical networks: a promising tool for pathway analysis and metabolic engineering. Trends Biotechnol. 17, 53–60 (1999).
Schilling, C.H., Schuster, S., Palsson, B.O. & Heinrich R. Metabolic pathway analysis: basic concepts and scientific applications in the post-genomic era. Biotechnol. Prog. 15, 296–303 (1999).
Schuster, R. & Schuster, S. Refined algorithm and computer program for calculating all non-negative fluxes admissible in steady states of biochemical reaction systems with or without some flux rates fixed. Comp. Appl. Biosci. 9, 79–85 (1993).
Stryer, L. Biochemistry (Freeman, New York, NY; 1995).
Hers, H.G. & Hue, L. Gluconeogenesis and related aspects of glycolysis. Annu. Rev. Biochem. 52, 617 –653 (1983).
Fell, D. Understanding the control of metabolism (Portland Press, London; 1997).
Yudkin, M. & Offord, R. A guidebook to biochemistry (Cambridge University Press, Cambridge; 1980).
Meléndez-Hevia, E., Waddell, T.G. & Montero, F. Optimization of metabolism: the evolution of metabolic pathways toward simplicity through the game of the pentose phosphate cycle. J. Theor. Biol. 166, 201– 220 (1994).
Voet, D. & Voet, J.G. Biochemistry (John Wiley, New York, NY; 1997).
Liao, J.C., Hou, S.-Y. & Chao, Y.-P. Pathway analysis, engineering, and physiological considerations for redirecting central metabolism. Biotechnol. Bioeng. 52, 129–140 (1996).
Martin, J.F. New aspects of genes and enzymes for beta-lactam antibiotic biosynthesis. Appl. Microbiol. Biotechnol. 50, 1– 15 (1998).
Frost, J.W. & Draths, K.M. Biocatalytic syntheses of aromatics from D-glucose: renewable microbial sources of aromatic compounds. Annu. Rev. Microbiol. 49, 557–579 (1995).
Selkov, E. Jr., Grechkin, Y., Mikhailova, N. & Selkov, E. MPW: the metabolic pathways database. Nucleic Acids Res. 26, 43–45 (1998).
Hartwell, L. A robust view of biochemical pathways. Nature 387, 855–857 (1997).
Cronan Jr., J.E. & LaPorte, D. in Escherichia coli and Salmonella. Cellular and molecular biology, Vol. I (ed. Neidhardt, F.C.) 206–215 (ASM Press, Washington, DC; 1996).
Bonarius, H.P.J. et al. Metabolic flux analysis of hybridoma cells in different culture media using mass balances. Biotechn. Bioeng. 50, 299–318 (1996).
Boros, L.G. et al. Nonoxidative pentose phosphate pathways and their direct role in ribose synthesis in tumors: is cancer a disease of cellular glucose metabolism? Med. Hypoth. 50, 55–59 (1998).
Smith, E.L. et al. Principles of biochemistry. General aspects (McGraw-Hill, New York, NY; 1983).
Bakker, B.M., Michels, P.A.M., Opperdoes, F.R. & Westerhoff, H.V. Glycolysis in bloodstream form Trypanosoma brucei can be understood in terms of the kinetics of the glycolytic enzymes. J. Biol. Chem. 272, 3207–3215 ( 1997).
Eisenthal, R. & Panes, A. The aerobic/anaerobic transition of glucose metabolism in Trypanosoma brucei. FEBS Lett. 181, 23–27 (1985).
Kiaira, J.K. & Njogu, M.R. Oligomycin-sensitivity of hexose-sugar catabolism in the bloodstream form of Trypanosoma brucei brucei. Biotechnol. Appl. Biochem. 20, 347– 356 (1994).
Kacser, H. & Acerenza, L. A universal method for achieving increases in metabolite production. Eur. J. Biochem. 216, 361–367 (1993).
Rohwer, J.M. & Hofmeyr, J.-H.S. in Technological and medical implications of metabolic control analysis (eds Cornish-Bowden, A. & Cárdenas, M.L.) 73–79 (Kluwer Academic Publishers Dordrecht; 2000).
Bonarius, H.P.J., Schmid, G. & Tramper, J. Flux analysis of underdetermined metabolic networks: the quest for the missing constraints. Trends Biotechn. 15, 308–314 (1997).
Nuño, J.C., Sánchez-Valdenebro, I., Pérez-Iratxeta, C., Meléndez-Hevia, E. & Montero, F. Network organization of cell metabolism: monosaccharide interconversion. Biochem. J. 324, 103–111 (1997).
Ruwende, C. et al. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature 376 , 246–249 (1995)
Pandolfi, P.P. et al. Targeted disruption of the housekeeping gene encoding glucose 6-phosphate dehydrogenase (G6PD): G6PD is dispensable for pentose synthesis but essential for defense against oxidative stress. EMBO J. 14, 5209–5215 (1995).
Pfeiffer, T., Sánchez-Valdenebro, I., Nuño, J.C., Montero, F. & Schuster, S. METATOOL: For studying metabolic networks, Bioinformatics 15 (1999) 251–257.
Acknowledgements
The authors are indebted to the anonymous referees for very helpful comments. We would like to thank Dr. Peer Bork (Heidelberg) and Thomas Pfeiffer (Berlin) for stimulating discussions and the DFG and BMBF (Germany) for generous support.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Schuster, S., Fell, D. & Dandekar, T. A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks. Nat Biotechnol 18, 326–332 (2000). https://doi.org/10.1038/73786
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/73786
This article is cited by
-
Soil pseudotargeted metabolomics reveals that planting years of masson pine (Pinus massoniana) affect soil metabolite profiles and metabolic pathways
Plant and Soil (2024)
-
Local flux coordination and global gene expression regulation in metabolic modeling
Nature Communications (2023)
-
Biology, geometry and information
Theory in Biosciences (2022)
-
Understanding and mathematical modelling of cellular resource allocation in microorganisms: a comparative synthesis
BMC Bioinformatics (2021)
-
EFMlrs: a Python package for elementary flux mode enumeration via lexicographic reverse search
BMC Bioinformatics (2021)