Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks

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

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Reaction scheme representing part of monosaccharide metabolism.
Figure 2: Graphical representation of the elementary modes pertaining to the reaction scheme in Figure 1.
Figure 3

Similar content being viewed by others

References

  1. Yarmush, M.L. & Berthiaume, F. Metabolic engineering and human disease. Nat. Biotechnol. 15, 525– 528 (1997).

    Article  CAS  Google Scholar 

  2. Sauer, U. et al. Metabolic fluxes in riboflavin-producing Bacillus subtilis. Nat. Biotechnol. 15, 448– 452 (1997).

    Article  CAS  Google Scholar 

  3. 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).

    Article  CAS  Google Scholar 

  4. Bork, P. et al. Predicting function: from genes to genomes and back. J. Mol. Biol. 283, 707–725 (1998).

    Article  CAS  Google Scholar 

  5. Schilling, C.H. & Palsson, B.O. The underlying pathway structure of biochemical reaction networks. Proc. Natl. Acad. Sci. USA 95, 4193–4198 (1998).

    Article  CAS  Google Scholar 

  6. 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).

    Article  CAS  Google Scholar 

  7. Cole, S.T. et al. Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence. Nature 393, 537–544 (1998)

    Article  CAS  Google Scholar 

  8. 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).

    Article  CAS  Google Scholar 

  9. Seressiotis, A. & Bailey, J.E. MPS: an algorithm and data base for metabolic pathway synthesis. Biotechn. Lett. 8, 837–842 ( 1986).

    Article  CAS  Google Scholar 

  10. Mavrovouniotis, M.L., Stephanopoulos, G. & Stephanopoulos, G. Computer-aided synthesis of biochemical pathways. Biotechnol. Bioeng. 36, 1119– 1132 (1990).

    Article  CAS  Google Scholar 

  11. 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).

    Book  Google Scholar 

  12. 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).

    Article  CAS  Google Scholar 

  13. Clarke, B.L. Complete set of steady states for the general stoichiometric dynamical system. J. Chem. Phys. 75, 4970– 4979 (1981).

    Article  CAS  Google Scholar 

  14. Leiser, J. & Blum, J.J. On the analysis of substrate cycles in large metabolic systems. Cell Biophys. 11, 123–138 (1987).

    Article  CAS  Google Scholar 

  15. Schuster, S. & Hilgetag, C. On elementary flux modes in biochemical reaction systems at steady state. J. Biol. Syst. 2, 165–182 (1994).

    Article  Google Scholar 

  16. 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).

    Book  Google Scholar 

  17. 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).

    Article  CAS  Google Scholar 

  18. 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).

    Article  CAS  Google Scholar 

  19. 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).

    CAS  PubMed  Google Scholar 

  20. Stryer, L. Biochemistry (Freeman, New York, NY; 1995).

    Google Scholar 

  21. Hers, H.G. & Hue, L. Gluconeogenesis and related aspects of glycolysis. Annu. Rev. Biochem. 52, 617 –653 (1983).

    Article  CAS  Google Scholar 

  22. Fell, D. Understanding the control of metabolism (Portland Press, London; 1997).

    Google Scholar 

  23. Yudkin, M. & Offord, R. A guidebook to biochemistry (Cambridge University Press, Cambridge; 1980).

    Google Scholar 

  24. 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).

    Article  Google Scholar 

  25. Voet, D. & Voet, J.G. Biochemistry (John Wiley, New York, NY; 1997).

    Google Scholar 

  26. 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).

    Article  CAS  Google Scholar 

  27. Martin, J.F. New aspects of genes and enzymes for beta-lactam antibiotic biosynthesis. Appl. Microbiol. Biotechnol. 50, 1– 15 (1998).

    Article  CAS  Google Scholar 

  28. 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).

    Article  CAS  Google Scholar 

  29. Selkov, E. Jr., Grechkin, Y., Mikhailova, N. & Selkov, E. MPW: the metabolic pathways database. Nucleic Acids Res. 26, 43–45 (1998).

    Article  CAS  Google Scholar 

  30. Hartwell, L. A robust view of biochemical pathways. Nature 387, 855–857 (1997).

    Article  CAS  Google Scholar 

  31. 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).

    Google Scholar 

  32. 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).

    Article  CAS  Google Scholar 

  33. 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).

    Article  CAS  Google Scholar 

  34. Smith, E.L. et al. Principles of biochemistry. General aspects (McGraw-Hill, New York, NY; 1983).

    Google Scholar 

  35. 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).

    Article  CAS  Google Scholar 

  36. Eisenthal, R. & Panes, A. The aerobic/anaerobic transition of glucose metabolism in Trypanosoma brucei. FEBS Lett. 181, 23–27 (1985).

    Article  CAS  Google Scholar 

  37. 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).

    Article  CAS  Google Scholar 

  38. Kacser, H. & Acerenza, L. A universal method for achieving increases in metabolite production. Eur. J. Biochem. 216, 361–367 (1993).

    Article  CAS  Google Scholar 

  39. 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).

    Book  Google Scholar 

  40. 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).

    Article  CAS  Google Scholar 

  41. 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).

    Article  Google Scholar 

  42. 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)

    Article  CAS  Google Scholar 

  43. 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).

    Article  CAS  Google Scholar 

  44. Pfeiffer, T., Sánchez-Valdenebro, I., Nuño, J.C., Montero, F. & Schuster, S. METATOOL: For studying metabolic networks, Bioinformatics 15 (1999) 251–257.

    Article  CAS  Google Scholar 

Download references

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

Authors

Rights and permissions

Reprints 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

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/73786

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing