Skip to main content

Coupling Fluxes, Enzymes, and Regulation in Genome-Scale Metabolic Models

  • Protocol
  • First Online:
Metabolic Network Reconstruction and Modeling

Part of the book series: Methods in Molecular Biology ((MIMB,volume 1716))

Abstract

Genome-scale models have expanded beyond their metabolic origins. Multiple modeling frameworks are required to combine metabolism with enzymatic networks, transcription, translation, and regulation. Mathematical programming offers a powerful set of tools for tackling these “multi-modality” models, although special attention must be paid to the connections between modeling types. This chapter reviews common methods for combining metabolic and discrete logical models into a single mathematical programming framework. Best practices, caveats, and recommendations are presented for the most commonly used software packages. Methods for troubleshooting large sets of logical rules are also discussed.

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

Access this chapter

Institutional subscriptions

References

  1. Fell DA, Small JR (1986) Fat synthesis in adipose tissue. An examination of stoichiometric constraints. Biochem J 238:781–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Edwards JS, Palsson BO (2000) Metabolic flux balance analysis and the in silico analysis of Escherichia coli K-12 gene deletions. BMC Bioinformatics 1:1. https://doi.org/10.1186/1471-2105-1-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Kim J, Reed JL (2010) OptORF: optimal metabolic and regulatory perturbations for metabolic engineering of microbial strains. BMC Syst Biol 4:53. https://doi.org/10.1186/1752-0509-4-53

    Article  PubMed  PubMed Central  Google Scholar 

  4. Suthers PF, Zomorrodi A, Maranas CD (2009) Genome-scale gene/reaction essentiality and synthetic lethality analysis. Mol Syst Biol 5:301. https://doi.org/10.1038/msb.2009.56

    Article  PubMed  PubMed Central  Google Scholar 

  5. Shlomi T, Eisenberg Y, Sharan R, Ruppin E (2007) A genome-scale computational study of the interplay between transcriptional regulation and metabolism. Mol Syst Biol 3:101

    Article  PubMed  PubMed Central  Google Scholar 

  6. Maranas CD, Zomorrodi AR (2016) Optimization methods in metabolic networks. Wiley, Hoboken, NJ. https://doi.org/10.1002/9781119188902

    Book  Google Scholar 

  7. Becker SA, Feist AM, Mo ML et al (2007) Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox. Nat Protoc 2:727–738. https://doi.org/10.1038/nprot.2007.99

    Article  CAS  PubMed  Google Scholar 

  8. Ebrahim A, Lerman JA, Palsson BØ, Hyduke DR (2013) COBRApy: COnstraints-Based Reconstruction and Analysis for Python. BMC Syst Biol 7:74. https://doi.org/10.1186/1752-0509-7-74

    Article  PubMed  PubMed Central  Google Scholar 

  9. Bartell JA, Yen P, Varga JJ et al (2014) Comparative metabolic systems analysis of pathogenic Burkholderia. J Bacteriol 196:210–226. https://doi.org/10.1128/JB.00997-13

    Article  PubMed  PubMed Central  Google Scholar 

  10. Jensen PA, Lutz KA, Papin JA (2011) TIGER: toolbox for integrating genome-scale metabolic models, expression data, and transcriptional regulatory networks. BMC Syst Biol 5:147. https://doi.org/10.1186/1752-0509-5-147

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Covert MW, Palsson BØ (2003) Constraints-based models: regulation of gene expression reduces the steady-state solution space. J Theor Biol 221:309–325

    Article  CAS  PubMed  Google Scholar 

  12. Covert MW, Knight EM, Reed JL et al (2004) Integrating high-throughput and computational data elucidates bacterial networks. Nature 429:92–96. https://doi.org/10.1038/nature02456

    Article  CAS  PubMed  Google Scholar 

  13. Herrgård MJ, Lee B-S, Portnoy V, Palsson BØ (2006) Integrated analysis of regulatory and metabolic networks reveals novel regulatory mechanisms in Saccharomyces cerevisiae. Genome Res 16:627–635. https://doi.org/10.1101/gr.4083206

    Article  PubMed  PubMed Central  Google Scholar 

  14. Oki E (2012) GLPK (GNU linear programming kit). In: Linear programming and algorithms for communication networks. CRC Press, Boca Raton, FL, pp 25–29

    Chapter  Google Scholar 

  15. IBM ILOG CPLEX Optimizer (2010) http://www-01.ibm.com/software/integration/optimization/cplex-optimizer/

  16. Gurobi Optimization, Inc. (2016) Gurobi Optimizer Reference Manual

    Google Scholar 

  17. Duarte NC, Herrgård MJ, Palsson BØ (2004) Reconstruction and validation of Saccharomyces cerevisiae iND750, a fully compartmentalized genome-scale metabolic model. Genome Res 14:1298–1309. https://doi.org/10.1101/gr.2250904

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Burgard AP, Vaidyaraman S, Maranas CD (2001) Minimal reaction sets for Escherichia coli metabolism under different growth requirements and uptake environments. Biotechnol Prog 17:791–797. https://doi.org/10.1021/bp0100880

    Article  CAS  PubMed  Google Scholar 

  19. Zeng L, Das S, Burne RA (2010) Utilization of lactose and galactose by Streptococcus mutans: transport, toxicity, and carbon catabolite repression. J Bacteriol 192:2434–2444. https://doi.org/10.1128/JB.01624-09

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Abranches J, Chen Y-YM, Burne RA (2004) Galactose metabolism by Streptococcus mutans. Appl Environ Microbiol 70:6047–6052. https://doi.org/10.1128/AEM.70.10.6047-6052.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Becker SA, Palsson BØ (2008) Context-specific metabolic networks are consistent with experiments. PLoS Comput Biol 4:e1000082. https://doi.org/10.1371/journal.pcbi.1000082

    Article  PubMed  PubMed Central  Google Scholar 

  22. Jensen PA, Papin JA (2011) Functional integration of a metabolic network model and expression data without arbitrary thresholding. Bioinformatics 27:541–547. https://doi.org/10.1093/bioinformatics/btq702

    Article  CAS  PubMed  Google Scholar 

  23. Sun Y, Fleming RMT, Thiele I, Saunders MA (2013) Robust flux balance analysis of multiscale biochemical reaction networks. BMC Bioinformatics 14:240. https://doi.org/10.1186/1471-2105-14-240

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

The author thanks Caroline Blassick for her assistance with Fig. 1.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Paul A. Jensen .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Science+Business Media, LLC

About this protocol

Check for updates. Verify currency and authenticity via CrossMark

Cite this protocol

Jensen, P.A. (2018). Coupling Fluxes, Enzymes, and Regulation in Genome-Scale Metabolic Models. In: Fondi, M. (eds) Metabolic Network Reconstruction and Modeling. Methods in Molecular Biology, vol 1716. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7528-0_15

Download citation

  • DOI: https://doi.org/10.1007/978-1-4939-7528-0_15

  • Published:

  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7527-3

  • Online ISBN: 978-1-4939-7528-0

  • eBook Packages: Springer Protocols

Publish with us

Policies and ethics