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Network Stoichiometry

  • Nanette R. Boyle
  • Avantika A. Shastri
  • John A. Morgan
Chapter

This chapter describes approaches to modeling metabolic pathways that are based on biochemical reaction stoichiometry. These methods have some advantages over kinetic models because they do not require the determination of complicated kinetic expressions and associated kinetic parameters. Although based only upon reaction stoichiometry and mass balances, the techniques can be quite powerful in exploring the capabilities of a metabolic network. Stoichiometry-based models enable efficient calculation of theoretical yields on any nutrient [78]. The models may be used to rationally select genes for addition and/or deletion in the genome which have the most promise to significantly improve desired product yield. New targets for herbicides can be selected through a mathematical analysis of the sensitivity of inhibiting specific enzymes on growth fluxes [87]. Perhaps their greatest promise in conjunction with optimization strategies is the ability to predict metabolic fluxes to specific products or growth as a function of the environment.

Keywords

Metabolic Network Flux Distribution Flux Balance Analysis Stoichiometric Matrix Thermodynamic Constraint 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Albertsson PA (2001) A quantitative model of the domain structure of the photosynthetic membrane. Trends Plant Sci 6:349–358.PubMedCrossRefGoogle Scholar
  2. 2.
    Allen JF (2002) Photosynthesis of ATP – electrons, proton pumps, roters and poise. Cell 110:273–276.PubMedCrossRefGoogle Scholar
  3. 3.
    Arnon DI (1948) Copper enzymes in isolated chloroplasts polyphenoloxidase in Beta vulgaris. Plant Physiol 24:1–15.CrossRefGoogle Scholar
  4. 4.
    Beard DA, Babson E, Curtis E, Qian H (2004) Thermodynamic constraints for biochemical networks. J Theor Biol 228:327–333.PubMedCrossRefGoogle Scholar
  5. 5.
    Beard DA, Liang SD, Qian H (2002) Energy balance for analysis of complex metabolic networks. Biophys J 83:79–86.PubMedCrossRefGoogle Scholar
  6. 6.
    Becker S, Palsson B (2005) Genome-scale reconstruction of the metabolic network in Staphylococcus aureus N315: an initial draft to the two-dimensional annotation. BMC Microbiology 5:8.PubMedCrossRefGoogle Scholar
  7. 7.
    Bell SL, Palsson BO (2005) expa: a program for calculating extreme pathways in biochemical reaction networks. Bioinformatics 21:1739–1740.PubMedCrossRefGoogle Scholar
  8. 8.
    Borodina I, Krabben P, Nielsen J (2005) Genome-scale analysis of Streptomyces coelicolor A3(2) metabolism. Genome Res 15:820–829.PubMedCrossRefGoogle Scholar
  9. 9.
    Burgard A, Maranas C (2001) Probing the performance limits of the Escherichia coli metabolic network subject to gene additions or deletions. Biotechnnol Bioeng 74: 364–375.CrossRefGoogle Scholar
  10. 10.
    Burgard AP, Pharkya P, Maranas CD (2003) Optknock: A bilevel programming framework for identifying gene knockout strategies for microbial strain optimization. Biotechnol Bioeng 84:647–657.PubMedCrossRefGoogle Scholar
  11. 11.
    Çakir T, Kirdar B, Ülgen KÖ (2004) Metabolic pathway analysis of yeast strengthens the bridge between transcriptomics and metabolic networks. Biotechnol Bioeng 86:251–260.PubMedCrossRefGoogle Scholar
  12. 12.
    Carlson R, Srienc F (2004) Fundamental Escherichia coli biochemical pathways for biomass and energy production: Creation of overall flux states. Biotechnol Bioeng 86:149–162.PubMedCrossRefGoogle Scholar
  13. 13.
    Caspi R, Foerster H, Fulcher C, Kaipa P, Krummenacker M, Latendresse M, Paley S, Rhee S, Shearer A, Tissier C, Walk T, Zhang P, Karp P (2006) MetaCyc: A multiorganism database of metabolic pathways and enzymes. Nucleic Acids Res 34:D511–D516.PubMedCrossRefGoogle Scholar
  14. 14.
    Chvatal V (1983) Linear Programming. W. H. Freeman and Company, New York.Google Scholar
  15. 15.
    Clarke B (1988) Stoichiometric network analysis. Cell Biophy 12:237–253.Google Scholar
  16. 16.
    Cogne G, Gros JB, Dussap CG (2003) Identification of a metabolic network structure representative of Arthrospira (Spirulina) platensis metabolism. Biotechnol Bioeng 84:667–676.PubMedCrossRefGoogle Scholar
  17. 17.
    Covert MW, Schilling CH, Palsson B (2001) Regulation of gene expression in flux balance models of metabolism. J Theor Biol 213:73–88.PubMedCrossRefGoogle Scholar
  18. 18.
    DeJongh M, Formsma K, Boillot P, Gould J, Rycenga M, Best A (2007) Toward the automated generation of genome-scale metabolic networks in the SEED. BMC Bioinformatics 8:139.PubMedCrossRefGoogle Scholar
  19. 19.
    Duarte N, Herrgard MJ, Palsson BO (2007) Reconstruction and validation of Saccharomyces cerevisiae iND750, a fully compartmentalized genome-scale metabolic model. Genome Res 14:1298–1309.CrossRefGoogle Scholar
  20. 20.
    Edwards J, Palsson B (2000) The Escherichia coli MG1655 in silico metabolic genotyope: its definition, characteristics, and capabilities. Proc Natl Acad Sci USA 97:5528–5533.PubMedCrossRefGoogle Scholar
  21. 21.
    Edwards J, Ramakrishna R, Palsson B (2002) Characterizing the metabolic phenotype: a phenotype phase plane analysis. Biotechnnol Bioeng 77:27–36.CrossRefGoogle Scholar
  22. 22.
    Edwards JS, Palsson BO (1999) Systems properties of the Haemophilus influenzae Rd metabolic genotype. J Biol Chem 274:17410–17416.PubMedCrossRefGoogle Scholar
  23. 23.
    Emanuelsson O, Nielsen H, Brunak S, Heijne Gv (2000) Predicting subcellular localization of proteins based on their N-terminal amino acid sequence. J Mol Biol 300:1005–1016.PubMedCrossRefGoogle Scholar
  24. 24.
    Emmerling M, Dauner M, Ponti A, Fiaux J, Hochuli M, Szyperski T, Wuthrich K, Bailey JE, Sauer U (2002) Metabolic flux responses to pyruvate kinase knockout in Escherichia coli. J Bacteriol 184: 152–164.PubMedCrossRefGoogle Scholar
  25. 25.
    Famili I, Forster J, Nielson J, Palsson BO (2003) Saccharomyces cerevisiae phenotypes can be predicted by using constraint-based analysis of a genome-scale reconstructed metabolic network. Proc Natl Acad Sci USA 100:13134–13139.PubMedCrossRefGoogle Scholar
  26. 26.
    Feist AM, Henry CS, Reed JL, Krummenacker M, Joyce AR, Karp PD, Broadbelt LJ, Hatzimanikatis V, Palsson BO (2007) A genome-scale metabolic reconstruction for Escherichia coli K-12 MG1655 that accounts for 1260 ORFs and thermodynamic information. Mol Syst Biol 3: 121.PubMedCrossRefGoogle Scholar
  27. 27.
    Fell DA, Small JR (1986) Fat synthesis in adipose tissue – an examination of stoichiometric constraints. Biochem J 238:781–786.PubMedGoogle Scholar
  28. 28.
    Fischer E, Sauer U (2005) Large-scale in vivo flux analysis shows rigidity and suboptimal performance of Bacillus subtilis metabolism. Nature Genet 37:636–640.PubMedCrossRefGoogle Scholar
  29. 29.
    Forster J, Famili I, Fu P, Palsson BO, Nielsen J (2003) Genome-scale reconstruction of the Saccharomyces cerevisiae metabolic network. Genome Res 13:244–253.PubMedCrossRefGoogle Scholar
  30. 30.
    Gibaldi M, Perrier D (1983) Pharmacokinetics. Marcel Dekker, New York.Google Scholar
  31. 31.
    Harary F (1994) Graph Theory. Perseus Books, Reading Westview Press, Boulder, CO.Google Scholar
  32. 32.
    Heinemann M, Kümmel A, Ruinatscha R, Panke S (2005) In silico genome-scale reconstruction and validation of the Staphylococcus aureus metabolic network. Biotechnol Bioeng 92:850–864.PubMedCrossRefGoogle Scholar
  33. 33.
    Henriksen CM, Christensen LH, Nielsen J, Villadsen J (1996) Growth energetics and metabolic fluxes in continuous cultures of Penicillium chrysogenum. J Biotechnol 45: 149–164.PubMedCrossRefGoogle Scholar
  34. 34.
    Henry CS, Broadbelt LJ, Hatzimanikatis V (2007) Thermodynamics-based metabolic flux analysis. Biophys J 92:1792–1805.PubMedCrossRefGoogle Scholar
  35. 35.
    Henry CS, Jankowski MD, Broadbelt LJ, Hatzimanikatis V (2006) Genome-scale thermodynamic analysis of Escherichia coli metabolism. Biophys J 90:1453–1461.PubMedCrossRefGoogle Scholar
  36. 36.
    Hjersted JL, Henson MA (2006) Optimization of fed-batch Saccharomyces cerevisiae fermentation using dynamic flux balance models. Biotechnol Prog 22:1239–1248.PubMedCrossRefGoogle Scholar
  37. 37.
    Hjersted JL, Henson MA, Mahadevan R (2007) Genome-scale analysis of Saccharomyces cerevisiae metabolism and ethanol production in fed-batch culture. Biotechnol Bioeng 97:1190–1204.PubMedCrossRefGoogle Scholar
  38. 38.
    Ibarra RU, Edwards JS, Palsson BO (2002) Escherichia coli K-12 undergoes adaptive evolution to achieve in silico predicted optimal growth. Nature 420:186–189.PubMedCrossRefGoogle Scholar
  39. 39.
    Jorgensen H, Nielsen J, Villadsen J, Mollgaard H (1995) Metabolic flux distributions in Penicillium chrysogenum during fed-batch cultivations. Biotechnol Bioeng 46:117–131.PubMedCrossRefGoogle Scholar
  40. 40.
    Kanehisa M, Goto S, Hattori M, Aoki-Kinoshita KF, Itoh M, Kawashima S, Katayama T, Araki M, Hirakawa M (2006) From genomics to chemical genomics: new developments in KEGG. Nucleic Acids Res 34:D354–357.PubMedCrossRefGoogle Scholar
  41. 41.
    Karp PD, Paley S, Romero P (2002) The pathway tools software. Bioinformatics 18: S225–232.PubMedGoogle Scholar
  42. 42.
    Kelly GJ, Latzko E (1977) Chloroplast phosphofructokinase .1. Proof of phosphofructokinase activity in chloroplasts. Plant Physiol 60:290–294.PubMedCrossRefGoogle Scholar
  43. 43.
    Kim HU, Kim TY, Lee SY (2008) Metabolic flux analysis and metabolic engineering of microorganisms. Mol BioSyst 4:113–120.PubMedCrossRefGoogle Scholar
  44. 44.
    Klamt S, Stelling J. 2003. Stoichiometric analysis of metabolic networks. in: Proceedings of the Tutorial at the 4th International Conference on Systems Biology, Heidelberg, Germany.Google Scholar
  45. 45.
    Klamt S, Stelling J (2003) Two approaches for metabolic pathway analysis? Trends Biotechnol 21:64–69.PubMedCrossRefGoogle Scholar
  46. 46.
    Klamt S, Stelling J, Ginkel M, Gilles ED (2003) FluxAnalyzer: exploring structure, pathways, flux distributions in metabolic networks on interactive flux maps. Bioinformatics 19: 261–269.PubMedCrossRefGoogle Scholar
  47. 47.
    Kummel A, Panke S, Heinemann M (2006) Systematic assignment of thermodynamic constraints in metabolic network models. BMC Bioinformatics 7.Google Scholar
  48. 48.
    Lee S, Palakornkule C, Domach MM, Grossmann IE (2000) Recursive MILP model for finding all the alternate optima in LP models for metabolic networks. Comput Chem Eng 24: 711–716.CrossRefGoogle Scholar
  49. 49.
    Li K, Frost JW (1998) Synthesis of vanillin from glucose. J Am Chem Soc 120:10545–10546.CrossRefGoogle Scholar
  50. 50.
    Mahadevan R, Edwards JS, Doyle FJ, III (2002) Dynamic flux balance analysis of diauxic growth in Escherichia coli. Biophys J 83:1331–1340.PubMedCrossRefGoogle Scholar
  51. 51.
    Mahadevan R, Schilling CH (2003) The effects of alternate optimal solutions in constraint-based genome-scale metabolic models. Metabol Eng 5:264–276.CrossRefGoogle Scholar
  52. 52.
    Majewski RA, Domach MM (1990) Simple constrained optimization view of acetate overflow in Escherichia coli. Biotechnol Bioeng 35:732–738.PubMedCrossRefGoogle Scholar
  53. 53.
    Mavrovouniotis ML (1990) Group contributions for estimating standard Gibbs energies of formation of biochemical compounds in aqueous solution. Biotechnol Bioeng 36: 1070–1082.PubMedCrossRefGoogle Scholar
  54. 54.
    Nelson DL, Cox MM (2005) Lehninger Principles of Biochemistry. W.H. Freeman and Company, New York.Google Scholar
  55. 55.
    Oliveira A, Nielsen J, Forster J (2005) Modeling Lactococcus lactis using a genome-scale flux model. BMC Microbiology 5:39.PubMedCrossRefGoogle Scholar
  56. 56.
    Papin JA, Stelling J, Price ND, Klamt S, Schuster S, Palsson BO (2004) Comparison of network-based pathway analysis methods. Trends Biotechnol 22:400–405.PubMedCrossRefGoogle Scholar
  57. 57.
    Park SM, Sinskey AJ, Stephanopoulos G (1997) Metabolic and physiological studies of Corynebacterium glutamicum mutants. Biotechnol Bioeng 55:864–879.PubMedCrossRefGoogle Scholar
  58. 58.
    Pharkya P, Burgard AP, Maranas CD (2003) Exploring the overproduction of amino acids using the bilevel optimization framework OptKnock. Biotechnol Bioeng 84:887–899.PubMedCrossRefGoogle Scholar
  59. 59.
    Plaxton WC (1996) The organization and regulation of plant glycolysis. Annu Rev Plant Physiol Plant Mol Biol 47:185–214.PubMedCrossRefGoogle Scholar
  60. 60.
    Poolman MG, Fell DA, Raines CA (2003) Elementary modes analysis of photosynthate metabolism in the chloroplast stroma. Eur J Biochem 270:430–439.PubMedCrossRefGoogle Scholar
  61. 61.
    Pramanik J, Keasling JD (1997) Stoichiometric model of Escherichia coli metabolism: Incorporation of growth-rate dependent biomass composition and mechanistic energy requirements. Biotechnol Bioeng 56:398–421.PubMedCrossRefGoogle Scholar
  62. 62.
    Price ND, Famili I, Beard DA, Palsson BO (2002) Extreme Pathways and Kirchhoff’s Second Law. Biophys J 83:2879–2882.PubMedCrossRefGoogle Scholar
  63. 63.
    Price ND, Papin JA, Palsson BO (2002) Determination of redundancy and systems properties of the metabolic network of Helicobacter pylori using genome-scale extreme pathway analysis. Genome Res 12:760–769.PubMedGoogle Scholar
  64. 64.
    Price ND, Thiele I, Palsson BO (2006) Candidate states of Helicobacter pylori’s genome-scale metabolic network upon application of “loop law” thermodynamic constraints. Biophys J 90:3919–3928.PubMedCrossRefGoogle Scholar
  65. 65.
    Ramakrishna R, Edwards J, McCulloch A, Palsson B (2001) Flux balance analysis of mitochondrial energy metabolism: consequences of systemic stoichiometry constraints. Am J Physiolo Regul Integr Comp Physiol 280:R695–R704.Google Scholar
  66. 66.
    Reed J, Vo T, Schilling C, Palsson B (2003) An expanded genome-scale model of Escherichia coli K-12 (iJR904 GSM/GPR). Genome Biol 4:R54.PubMedCrossRefGoogle Scholar
  67. 67.
    Rockafellar RT (1970) Convex Analysis. Princeton University Press, Princeton, NJ.Google Scholar
  68. 68.
    Sainz J, Pizarro F, Perez-Correa JR, Agosin E (2003) Modeling of yeast metabolism and process dynamics in batch fermentation. Biotechnol Bioeng 81:818–828.PubMedCrossRefGoogle Scholar
  69. 69.
    Savinell JM, Palsson BO (1992) Optimal selection of metabolic fluxes for in vivo measurement .1. Development of mathematical methods. J Theor Biol 155:201–214.PubMedCrossRefGoogle Scholar
  70. 70.
    Schilling CH, Covert MW, Famili I, Church GM, Edwards JS, Palsson BO (2002) Genome-scale metabolic model of Helicobacter pylori 26695. J Bacteriol 184:4582–4593.PubMedCrossRefGoogle Scholar
  71. 71.
    Schilling CH, Letscher D, Palsson BO (2000) Theory for the systemic definition of metabolic pathways and their use in interpreting metabolic function from a pathway-oriented perspective. J Theor Biol 203:229–248.PubMedCrossRefGoogle Scholar
  72. 72.
    Schuster S, Dandekar T, Fell DA (1999) Detection of elementary flux modes in biochemical networks: a promising tool for pathway analysis and metabolic engineering. Trends Biotechnol 17:53–60.PubMedCrossRefGoogle Scholar
  73. 73.
    Schuster S, Fell DA, Dandekar T (2000) A general definition of metabolic pathways useful for systematic organization and analysis of complex metabolic networks. Nat Biotech 18:326–332.CrossRefGoogle Scholar
  74. 74.
    Schuster S, Hilgetag C (1994) On elementary flux modes in biochemical reaction systems at steady state. J Biol Syst 2:165–182.CrossRefGoogle Scholar
  75. 75.
    Schuster S, Kenanov D (2005) Adenine and adenosine salvage pathways in erythrocytes and the role of S-adenosylhomocysteine hydrolase. A theoretical study using elementary flux modes. FEBS Journal 272:5278–5290.PubMedCrossRefGoogle Scholar
  76. 76.
    Schwender J, Goffman F, Ohlrogge JB, Shachar-Hill Y (2004) Rubisco without the Calvin cycle improves the carbon efficiency of developing green seeds. Nature 432:779–782.PubMedCrossRefGoogle Scholar
  77. 77.
    Segre D, Vitkup D, Church GM (2002) Analysis of optimality in natural and perturbed metabolic networks. Proc Natl Acad Sci USA 99:15112–15117.PubMedCrossRefGoogle Scholar
  78. 78.
    Shastri A, Morgan J (2004) Calculation of theoretical yields in metabolic networks. Biochem Mol Biol Educ 32:314–318.CrossRefGoogle Scholar
  79. 79.
    Shastri AA, Morgan JA (2005) Flux balance analysis of photoautotrophic metabolism. Biotechnol Prog 21:1617–1626.PubMedCrossRefGoogle Scholar
  80. 80.
    Shlomi T, Berkman O, Ruppin E (2005) Regulatory on/off minimization of metabolic flux changes after genetic perturbations. Proc Natl Acad Sci USA 102:7695–7700.PubMedCrossRefGoogle Scholar
  81. 81.
    Stelling J, Klamt S, Bettenbrock K, Schuster S, Gilles ED (2002) Metabolic network structure determines key aspects of functionality and regulation. Nature 420:190–193.PubMedCrossRefGoogle Scholar
  82. 82.
    Stephanopoulos G, Vallino JJ (1991) Network rigidity and metabolic engineering in metabolite overproduction. Science 252:1675–1681.PubMedCrossRefGoogle Scholar
  83. 83.
    Stephanopoulos GN, Aristidou AA, Nielsen J (1998) Metabolic Engineering Principles and Methodologies. Academic Press, San Diego.Google Scholar
  84. 84.
    Stitt M, Heldt HW (1981) Physiological rates of starch breakdown in isolated intact spinach chloroplasts. Plant Physiol 68:755–761.PubMedCrossRefGoogle Scholar
  85. 85.
    Teusink B, Wiersma A, Molenaar D, Francke C, Vos WMd, Siezen RJ, Smid EJ (2006) Analysis of growth of Lactobacillus plantarum WCFS1 on a complex medium using genome-scale metabolic model. J Biol Chem 281:40041–40048.PubMedCrossRefGoogle Scholar
  86. 86.
    Thiele I, Vo TD, Price ND, Palsson BO (2005) Expanded metabolic reconstruction of Helicobacter pylori (iIT341 GSM/GPR): an in silico genome-scale characterization of single- and double-deletion mutants J Bacteriol 187:5818–5830.PubMedCrossRefGoogle Scholar
  87. 87.
    Trawick JD, Schilling CH (2006) Use of constraint-based modeling for the prediction and validation of antimicrobial targets. Biochem Pharmacol 71:1026–1035.PubMedCrossRefGoogle Scholar
  88. 88.
    Trinh CT, Carlson R, Wlaschin A, Srienc F (2006) Design, construction and performance of the most efficient biomass producing E. coli bacterium. Metabol Eng 8:628–638.CrossRefGoogle Scholar
  89. 89.
    Varma A, Boesch BW, Palsson BO (1993) Biochemical production capabilities of Escherichia coli. Biotechnol Bioeng 42:59–73.PubMedCrossRefGoogle Scholar
  90. 90.
    Varma A, Palsson BO (1993) Metabolic capabilities of Escherichia coli. 1. Synthesis of biosynthetic precursors and cofactors. J Theor Biol 165:477–502.PubMedCrossRefGoogle Scholar
  91. 91.
    Varma A, Palsson BO (1993) Metabolic capabilities of Escherichia coli. 2. Optimal-growth patterns. J Theor Biol 165:503–522.CrossRefGoogle Scholar
  92. 92.
    Varma A, Palsson BO (1994) Stoichiometric flux balance models quantitatively predict growth and metabolic by-product secretion in wild-type Escherichia coli W3110. Appl Environ Microbiol 60:3724–3731.PubMedGoogle Scholar
  93. 93.
    von Kamp A, Schuster S (2006) Metatool 5.0: fast and flexible elementary modes analysis. Bioinformatics 22:1930–1931.CrossRefGoogle Scholar
  94. 94.
    Watson MR (1986) A discrete model of bacterial metabolism. Comput Appl Biosci 2:23–27.PubMedGoogle Scholar
  95. 95.
    Yang C, Hua Q, Shimizu K (2000) Energetics and carbon metabolism during growth of microalgal cells under photoautotrophic, mixotrophic and cyclic light-autotrophic/dark-heterotrophic conditions. Biochem Eng J 6:87–102.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Nanette R. Boyle
    • 1
  • Avantika A. Shastri
    • 1
  • John A. Morgan
    • 1
  1. 1.School of Chemical Engineering, 480 Stadium Mall Dr., Purdue UniversityWest LafayetteUSA

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