Skip to main content
SpringerLink
Log in

Combining flux balance analysis and model checking for metabolic network validation and analysis

  • Published:
Natural Computing Aims and scope Submit manuscript

Abstract

Several human diseases are caused by metabolism defects. Discovering the mechanisms that govern the onset and progression of human metabolism-related diseases is not a straightforward process. Computational approaches, such as the flux balance analysis, have been successfully used to extract useful knowledge on the metabolic dysregulation processes from genome-scale network models. In this work, we propose a novel approach which integrates constraint-based techniques with model checking methods, with the aim to extract relevant qualitative information from a metabolic network model. As a case study, we applied our methodology to the simulation and analysis of the primary hyperoxaluria type I, an inherited disease in which the lack of a particular liver enzyme causes the kidney to accumulate excessive amounts of oxalate.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Promela code snippet 1
Fig. 5
Fig. 6
Fig. 7
Fig. 8

Similar content being viewed by others

References

  • Altshuler D, Daly MJ, Lander ES (2008) Genetic mapping in human disease. Science (New York, N.Y.) 322(5903):881–888

    Article  Google Scholar 

  • Baier C, Katoen J (2008) Principles of Model Checking. The MIT Press,  Cambridge

    MATH  Google Scholar 

  • Balsara Z, Roach S (2005) Prediction of inherited and genetic mutations using the software model checker SPIN. In: Haddad H, Liebrock LM, Omicini A, Wainwright RL (eds) SAC. ACM, New York, pp 208–209

  • Bordbar A, Feist AM, Usaite-Black R, Woodcock J, Palsson BO, Famili I (2011) A multi-tissue type genome-scale metabolic network for analysis of whole-body systems physiology. BMC Syst Biol 5(1):180+

    Article  Google Scholar 

  • Brim L, Češka M, Šafránek D (2013) Model checking of biological systems. Formal methods for dynamical systems, Springer, pp 63–112

  • Cerami EG, Gross BE, Demir E, Rodchenkov I, Babur Ö, Anwar N, Schultz N, Bader GD, Sander C (2011) Pathway commons, a web resource for biological pathway data. Nucleic Acids Res 39(Suppl 1):D685–D690

    Article  Google Scholar 

  • Cimatti A, Clarke E, Giunchiglia E, Giunchiglia F, Pistore M, Roveri M, Sebastiani R, Tacchella A (2002) Nusmv 2: an opensource tool for symbolic model checking. In: Computer aided verification,Springer, pp 359–364

  • Clarke EM, Grumberg O, Peled DA (1999) Model checking. MIT Press,  Cambridge

    Google Scholar 

  • Cochat P, Rumsby G (2013) Primary hyperoxaluria. N Engl J Med 369(7):649–658

    Article  Google Scholar 

  • Crawhall JC, Scowen EF, De Mowbray RR, Watts RWE (1959) Conversion of glycine to oxalate in normal subject. The Lancet, 274(7107):810 Originally published as Volume 2, Issue 7107

    Article  Google Scholar 

  • Danpure CJ (2006) Primary hyperoxaluria type 1: Agt mistargeting highlights the fundamental differences between the peroxisomal and mitochondrial protein import pathways. Biochimica et Biophysica Acta (BBA) - Mol Cell Res 1763(12):1776–1784

    Article  Google Scholar 

  • Danpure CJ, Jennings PR (1986) Peroxisomal alanine:glyoxylate aminotransferase deficiency in primary hyperoxaluria type i. FEBS Lett 201(1):20–34

    Article  Google Scholar 

  • Duarte NC, Becker SA, Jamshidi N, Thiele I, Mo ML, Vo TD, Srivas R, Palsson B (2007) Global reconstruction of the human metabolic network based on genomic and bibliomic data. Proc Natl Acad Sci 104(6):1777–1782

    Article  Google Scholar 

  • Elder TD, Wyngaarden JB (1960) The biosynthesis and turnover of oxalate in normal and hyperoxaluric subjects *. J Clin Investig 39(8):1337–1344 8

    Article  Google Scholar 

  • Emerson EA (2008) The beginning of model checking: a personal perspective. In: 25 Years of Model Checking, Springer, pp 27–45

  • Emerson EA, Clarke EM (1982) Using branching time temporal logic to synthesize synchronization skeletons. Sci Comput Progr, 2(3):241–266, 1982. cited By (since 1996)188.

    Google Scholar 

  • Folger O, Jerby L, Frezza C, Gottlieb E, Ruppin E, Shlomi T (2011) Predicting selective drug targets in cancer through metabolic networks. Mol Syst Biol 7:501

    Google Scholar 

  • Gille C, Bolling C, Hoppe A, Bulik S, Hoffmann S, Hubner K, Karlstadt A, Ganeshan R, Konig M, Rother K, Weidlich M, Behre J, Holzhutter H (2010) HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology. Mol Syst Biol 6(1)

  • Glazier AM, Nadeau JH, Aitman TJ (2002) Finding genes that underlie complex traits. Science 298(5602):2345–2349

    Article  Google Scholar 

  • Ross PH, Dean GA (1998) Glyoxylate synthesis, and its modulation and influence on oxalate synthesis. J Urol 160(5):1617–1624

    Article  Google Scholar 

  • Holmes RP, Knight J, Assimos DG (2007) Origin of urinary oxalate. In: AIP Conference proceedings, vol 900(1)

  • Holzhütter HG (2004) The principle of flux minimization and its application to estimate stationary fluxes in metabolic networks. Eur J Biochem 271(14):2905–2922

    Article  Google Scholar 

  • Holzmann GJ (2003) The SPIN model checker: Primer and reference manual. Addison-Wesley Professional, 1 edn

  • Holzmann GJ, Joshi R, Groce A (2011) Swarm verification techniques. IEEE Trans Softw Eng 37(6):845–857

    Article  Google Scholar 

  • Ideker T, Galitski T, Hood L (2001) A new approach to decoding life: systems biology. Annu Rev Genomics Hum Genet 2(1):343–372

    Article  Google Scholar 

  • Jerby L, Shlomi T, Ruppin E (2010) Computational reconstruction of tissue-specific metabolic models: application to human liver metabolism. Mol Syst Biol 6(1)

  • Kanehisa M, Goto S (2000) KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28(1):27–30

    Article  Google Scholar 

  • Kitano H (2002) Systems biology: a brief overview. Science 295(5560):1662–1664

    Article  Google Scholar 

  • Lanpher B, Brunetti-Pierri N, Lee B (2006) Inborn errors of metabolism: the flux from mendelian to complex diseases. Nat Rev Genet 7(6):449–459

    Article  Google Scholar 

  • Larsen KG, Pettersson P, Yi W (1997) Uppaal in a nutshell. Int J Softw Tools Technol Transf (STTT) 1(1):134–152

    Article  MATH  Google Scholar 

  • Lewis NE, Nagarajan H, Palsson BO (2012) Constraining the metabolic genotype-phenotype relationship using a phylogeny of in silico methods. Nat Rev Micro 10(4):291–305

    Google Scholar 

  • Ma H, Sorokin A, Mazein A, Selkov A, Selkov E, Demin O, Goryanin I (2007). The edinburgh human metabolic network reconstruction and its functional analysis. Mol Syst Biol, 3(1)

  • Matthews L, Gopinath G, Gillespie M, Caudy M, Croft D, de Bono B, Garapati P, Hemish J, Hermjakob H, Jassal B, Kanapin A, Lewis S, Mahajan S, May B, Schmidt E, Vastrik I, Wu G, Birney E, Stein L, D’Eustachio P (2009) Reactome knowledgebase of human biological pathways and processes. Nucleic Acids Res 37(Suppl 1):D619–D622

    Article  Google Scholar 

  • Melham T (2012) Modelling, abstraction, and computation in systems biology: a view from computer science, Prog Biophys Mol Biol 111(2):129–136

    Google Scholar 

  • Mysore V, Mishra B (2007) Algorithmic algebraic model checking iv: Characterization of metabolic networks. In Hirokazu Anai, Katsuhisa Horimoto, Temur Kutsia (eds) AB, volume 4545 of Lecture notes in computer science. Springer, New York, pp 170–184

  • Oberhardt MA, Palsson BO, Papin JA (2009) Applications of genome-scale metabolic reconstructions. Mol Syst Biol 5:320

    Google Scholar 

  • Orth JD, Thiele I, Palsson BO (2010) What is flux balance analysis? Nat Biotechnol 28(3):245–248

    Article  Google Scholar 

  • Pagliarini R, di Bernardo D (2013) A genome-scale modeling approach to study inborn errors of liver metabolism: toward an in silico patient. J Comput Biol 20(5):383–397

    Article  MathSciNet  Google Scholar 

  • Pnueli A (1977) The temporal logic of programs. In Foundations of computer science, 1977, 18th Annual symposium on, pp 46–57

  • Shlomi T, Benyamini T, Gottlieb E, Sharan R, Ruppin E (2011) Genome-Scale metabolic modeling elucidates the role of proliferative adaptation in causing the warburg effect. PLoS Comput Biol 7(3):e1002018+

    Google Scholar 

  • Shlomi T, Cabili MN, Ruppin E (2009) Predicting metabolic biomarkers of human inborn errors of metabolism. Mol Syst Biol 5(1)

  • Thiele I, Swainston N, Fleming RMT, Hoppe A, Sahoo S, Aurich MK, Haraldsdottir H, Mo ML, Or Rolfsson, Stobbe MD, Thorleifsson SG, Agren R, Bolling C, Bordel S, Chavali AK, Dobson P, Dunn WB, Endler L, Hala D, Hucka M, Hull D, Jameson D, Jamshidi N, Jonsson JJ, Juty N, Keating S, Nookaew I, Le Novere N, Malys N, Mazein A, Papin JA, Price ND, Selkov E, Sigurdsson MI, Simeonidis E, Sonnenschein N, Smallbone K, Sorokin A, van Beek JHGM, Weichart D, Goryanin I, Nielsen J, Westerhoff HV, Kell DB, Mendes P, Palsson BO (2013) A community-driven global reconstruction of human metabolism. Nat Biotechnol 31(5):419–425

Download references

Author information

Authors and Affiliations

  1. Telethon Institute of Genetics and Medicine, Via P. Castellino 111, Naples, Italy

    Roberto Pagliarini & Diego di Bernardo

  2. Department of Electrical Engineering and Information Technology, Federico II University, Via Claudio 21, Naples, Italy

    Mara Sangiovanni, Adriano Peron & Diego di Bernardo

Authors
  1. Roberto Pagliarini
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mara Sangiovanni
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Adriano Peron
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Diego di Bernardo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Roberto Pagliarini.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pagliarini, R., Sangiovanni, M., Peron, A. et al. Combining flux balance analysis and model checking for metabolic network validation and analysis. Nat Comput 14, 341–354 (2015). https://doi.org/10.1007/s11047-014-9419-8

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11047-014-9419-8

Keywords

Search

Navigation