Skip to main content
Log in

Genome-scale Modeling of Metabolism and Macromolecular Expression and Their Applications

  • Review Paper
  • Published:
Biotechnology and Bioprocess Engineering Aims and scope Submit manuscript

Abstract

Genome-scale models (GEMs) are predictive tools to study genotype-phenotype relationships in biological systems. Initially, genome-scale models were used for predicting the metabolic state of the organism given the nutrient condition and genetic perturbation (if any). Such metabolic (M-) models have been successfully developed for diverse organisms in both prokaryotes and eukaryotes. In this review, we focus our attention to genome-scale models of metabolism and macromolecular expression or ME-models. ME-models expand the scope of M-models by incorporating macromolecular biosynthesis pathways of transcription and translation. ME-models can predict the proteome investment in metabolism under any given condition. Therefore, ME-models significantly improve the quantitative prediction of gene expression. Unlike M-models that can predict biological properties in only nutrient-limited condition, ME-models can do so in both nutrient- and proteome-limited conditions. There are a few limitations of ME-models, many of which have now been largely overcome, making them more attractive to the broader research community. We finally discuss the applications of GEMs in general, and how they have been applied for biomedical, bioengineering and bioremediation purposes.

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

Access this article

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

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Crick, F. H. C. (1973) Project K: “The Complete Solution of E. Coli”. Perspect. Biol. Med. 17: 67–70.

    Article  Google Scholar 

  2. Bordbar, A., J. M. Monk, Z. A. King, and B. O. Palsson (2014) Constraint-based models predict metabolic and associated cellular functions. Nat. Rev. Genet. 15: 107–120.

    Article  CAS  PubMed  Google Scholar 

  3. Price, N. D., J. L. Reed, and B. O. Palsson (2004) Genome-scale models of microbial cells: evaluating the consequences of constraints. Nat. Rev. Microbiol. 2: 886–897.

    Article  CAS  PubMed  Google Scholar 

  4. Edwards, J. S. and B. O. Palsson (1999) Systems properties of the Haemophilus influenzaeRd metabolic genotype. J. Biol. Chem. 274: 17410–17416.

    Article  CAS  PubMed  Google Scholar 

  5. Edwards, J. S. and B. O. Palsson (2000) The Escherichia coli MG1655 in silico metabolic genotype: its definition, characteristics, and capabilities. Proc. Natl. Acad. Sci. USA. 97: 5528–5533.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Monk, J. M., C. J. Lloyd, E. Brunk, N. Mih, A. Sastry, Z. King, R. Takeuchi, W. Nomura, Z. Zhang, H. Mori, A. M. Feist, and B. O. Palsson (2017) iML1515, a knowledgebase that computes Escherichia coli traits. Nat. Biotechnol. 35: 904–908.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Gu, C., G. B. Kim, W. J. Kim, H. U. Kim, and S. Y. Lee (2019) Current status and applications of genome-scale metabolic models. Genome Biol. 20: 121.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Zhu, Y., T. Czauderna, J. Zhao, M. Klapperstueck, M. H. M. Maifiah, M. L. Han, J. Lu, B. Sommer, T. Velkov, T. Lithgow, J. Song, F. Schreiber, and J. Li (2018) Genome-scale metabolic modeling of responses to polymyxins in Pseudomonas aeruginosa. Gigascience. 7: giy021.

    Article  PubMed Central  CAS  Google Scholar 

  9. Huang, X. and Y. H. Lin (2019) Reconstruction and analysis of a three-compartment genome-scale metabolic model for Pseudomonas fluorescens. Biotechnol. Appl. Biochem. 67: 133–139.

    Article  CAS  Google Scholar 

  10. Nogales, J., J. Mueller, S. Gudmundsson, F. J. Canalejo, E. Duque, J. Monk, A. M. Feist, J. L. Ramos, W. Niu, and B. O. Palsson (2020) High-quality genome-scale metabolic modelling of Pseudomonas putida highlights its broad metabolic capabilities. Environ. Microbiol. 22: 255–269.

    Article  CAS  PubMed  Google Scholar 

  11. Thompson, R. A., S. Dahal, S. Garcia, I. Nookaew, and C. T. Trinh (2016) Exploring complex cellular phenotypes and model-guided strain design with a novel genome-scale metabolic model of Clostridium thermocellum DSM 1313 implementing an adjustable cellulosome. Biotechnol. Biofuels. 9: 194.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Zou, W., G. Ye, J. Zhang, C. Zhao, X. Zhao, and K. Zhang (2018) Genome-scale metabolic reconstruction and analysis for Clostridium kluyveri. Genome. 61: 605–613.

    Article  CAS  PubMed  Google Scholar 

  13. Aminian-Dehkordi, J., S. M. Mousavi, A. Jafari, I. Mijakovic, and S. A. Marashi (2019) Manually curated genome-scale reconstruction of the metabolic network of Bacillus megaterium DSM319. Sci. Rep. 9: 18762.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lu, H., F. Li, B. J. Sánchez, Z. Zhu, G. Li, I. Domenzain, S. Marcišauskas, P. M. Anton, D. Lappa, C. Lieven, M. E. Beber, N. Sonnenschein, E. J. Kerkhoven, and J. Nielsen (2019) A consensus S. cerevisiae metabolic model Yeast8 and its ecosystem for comprehensively probing cellular metabolism. Nat. Commun. 10: 3586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Witting, M., J. Hastings, N. Rodriguez, C. J. Joshi, J. P. N. Hattwell, P. R. Ebert, M. van Weeghel, A. W. Gao, M. J. O. Wakelam, R. H. Houtkooper, A. Mains, N. Le Novère, S. Sadykoff, F. Schroeder, N. E. Lewis, H. J. Schirra, C. Kaleta, and O. Casanueva (2018) Modeling meets metabolomics-the wormjam consensus model as basis for metabolic studies in the model organism Caenorhabditis elegans. Front. Mol. Biosci. 5: 96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Brunk, E., S. Sahoo, D. C. Zielinski, A. Altunkaya, A. Drager, N. Mih, F. Gatto, A. Nilsson, G. A. Preciat Gonzalez, M. K. Aurich, A. Prlic, A. Sastry, A. D. Danielsdottir, A. Heinken, A. Noronha, P. W. Rose, S. K. Burley, R. M. T. Fleming, J. Nielsen, I. Thiele, and B. O. Palsson (2018) Recon3D enables a three-dimensional view of gene variation in human metabolism. Nat. Biotechnol. 36: 272–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bauer, E. and I. Thiele (2018) From network analysis to functional metabolic modeling of the human gut microbiota. mSystems. 3: e00209–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Magnusdottir, S. and I. Thiele (2018) Modeling metabolism of the human gut microbiome. Curr. Opin. Biotechnol. 51: 90–96.

    Article  CAS  PubMed  Google Scholar 

  19. Baldini, F., A. Heinken, L. Heirendt, S. Magnusdottir, R. M. T. Fleming, and I. Thiele (2019) The Microbiome Modeling Toolbox: from microbial interactions to personalized microbial communities. Bioinformatics. 35: 2332–2334.

    Article  CAS  PubMed  Google Scholar 

  20. Koch, S., F. Kohrs, P. Lahmann, T. Bissinger, S. Wendschuh, D. Benndorf, U. Reichl, and S. Klamt (2019) RedCom: A strategy for reduced metabolic modeling of complex microbial communities and its application for analyzing experimental datasets from anaerobic digestion. PLoS Comput. Biol. 15: e1006759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Machado, D., S. Andrejev, M. Tramontano, and K. R. Patil (2018) Fast automated reconstruction of genome-scale metabolic models for microbial species and communities. Nucleic Acids Res. 46: 7542–7553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Norsigian, C. J., X. Fang, Y. Seif, J. M. Monk, and B. O. Palsson (2020) A workflow for generating multi-strain genome-scale metabolic models of prokaryotes. Nat. Protoc. 15: 1–14.

    Article  CAS  PubMed  Google Scholar 

  23. Harcombe, W. R., N. F. Delaney, N. Leiby, N. Klitgord, and C. J. Marx (2013) The ability of flux balance analysis to predict evolution of central metabolism scales with the initial distance to the optimum. PLoS Comput. Biol. 9: e1003091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Schuetz, R., N. Zamboni, M. Zampieri, M. Heinemann, and U. Sauer (2012) Multidimensional optimality of microbial metabolism. Science. 336: 601–604.

    Article  CAS  PubMed  Google Scholar 

  25. Gianchandani, E. P., M. A. Oberhardt, A. P. Burgard, C. D. Maranas, and J. A. Papin (2008) Predicting biological system objectives de novo from internal state measurements. BMC Bioinformatics. 9: 43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Zhao, Q., A. I. Stettner, E. Reznik, I. C. Paschalidis, and D. Segre (2016) Mapping the landscape of metabolic goals of a cell. Genome Biol. 17: 109.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Lachance, J. C., C. J. Lloyd, J. M. Monk, L. Yang, A. V. Sastry, Y. Seif, B. O. Palsson, S. Rodrigue, A. M. Feist, Z. A. King, and P. É. Jacques (2019) BOFdat: Generating biomass objective functions for genome-scale metabolic models from experimental data. PLoS Comput. Biol. 15: e1006971.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Yang, L., M. A. Saunders, J. C. Lachance, B. O. Palsson, and J. Bento (2019) Estimating cellular goals from high-dimensional biological data. Proceedings of the 25th ACM SIGKDD International Conference on Knowledge Discovery & Data Mining. August 4–8. Anchorage, AK, USA.

  29. Bordbar, A., M. L. Mo, E. S. Nakayasu, A. C. Schrimpe-Rutledge, Y. M. Kim, T. O. Metz, M. B. Jones, B. C. Frank, R. D. Smith, S. N. Peterson, D. R. Hyduke, J. N. Adkins, and B. O. Palsson (2012) Model-driven multi-omic data analysis elucidates metabolic immunomodulators of macrophage activation. Mol. Syst. Biol. 8: 558.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. Sorokina, O., F. Corellou, D. Dauvillee, A. Sorokin, I. Goryanin, S. Ball, F. Y. Bouget, and A. J. Millar (2011) Microarray data can predict diurnal changes of starch content in the picoalga Ostreococcus. BMC Syst. Biol. 5: 36.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Shlomi, T., M. N. Cabili, M. J. Herrgard, B. O. Palsson, and E. Ruppin (2008) Network-based prediction of human tissue-specific metabolism. Nat. Biotechnol. 26: 1003–1010.

    Article  CAS  PubMed  Google Scholar 

  32. Agren, R., S. Bordel, A. Mardinoglu, N. Pornputtapong, I. Nookaew, and J. Nielsen (2012) Reconstruction of genome-scale active metabolic networks for 69 human cell types and 16 cancer types using INIT. PLoS Comput. Biol. 8: e1002518.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang, Y., J. A. Eddy, and N. D. Price (2012) Reconstruction of genome-scale metabolic models for 126 human tissues using mCADRE. BMC Syst. Biol. 6: 153.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Schultz, A. and A. A. Qutub (2016) Reconstruction of tissue-specific metabolic networks using CORDA. PLoS Comput. Biol. 12: e1004808.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Vivek-Ananth, R. P. and A. Samal (2016) Advances in the integration of transcriptional regulatory information into genome-scale metabolic models. Biosystems. 147: 1–10.

    Article  CAS  PubMed  Google Scholar 

  36. Opdam, S., A. Richelle, B. Kellman, S. Li, D. C. Zielinski, and N. E. Lewis (2017) A systematic evaluation of methods for tailoring genome-scale metabolic models. Cell Syst. 4: 318–329.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sanchez, B. J., C. Zhang, A. Nilsson, P. J. Lahtvee, E. J. Kerkhoven, and J. Nielsen (2017) Improving the phenotype predictions of a yeast genome-scale metabolic model by incorporating enzymatic constraints. Mol. Syst. Biol. 13: 935.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Bekiaris, P. S. and S. Klamt (2020) Automatic construction of metabolic models with enzyme constraints. BMC Bioinformatics. 21: 19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Thiele, I., N. Jamshidi, R. M. T. Fleming, and B. O. Palsson (2009) Genome-scale reconstruction of Escherichia coli’s transcriptional and translational machinery: a knowledge base, its mathematical formulation, and its functional characterization. PLoS Comput. Biol. 5: e1000312.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Wessely, F., M. Bartl, R. Guthke, P. Li, S. Schuster, and C. Kaleta (2011) Optimal regulatory strategies for metabolic pathways in Escherichia coli depending on protein costs. Mol. Syst. Biol. 7: 515.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Lerman, J. A., D. R. Hyduke, H. Latif, V. A. Portnoy, N. E. Lewis, J. D. Orth, A. C. Schrimpe-Rutledge, R. D. Smith, J. N. Adkins, K. Zengler, and B. O. Palsson (2012) In silico method for modelling metabolism and gene product expression at genome scale. Nat. Commun. 3: 929.

    Article  PubMed  CAS  Google Scholar 

  42. Thiele, I., R. M. T. Fleming, R. Que, A. Bordbar, D. Diep, and B. O. Palsson (2012) Multiscale modeling of metabolism and macromolecular synthesis in E. coli and its application to the evolution of codon usage. PLoS One. 7: e45635.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Yang, L., D. Ma, A. Ebrahim, C. J. Lloyd, M. A. Saunders, and B. O. Palsson (2016) solveME: fast and reliable solution of nonlinear ME models. BMC Bioinformatics. 17: 391.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. O’Brien, E. J., J. A. Lerman, R. L. Chang, D. R. Hyduke, and B. O. Palsson (2013) Genome-scale models of metabolism and gene expression extend and refine growth phenotype prediction. Mol. Syst. Biol. 9: 693.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Lloyd, C. J., A. Ebrahim, L. Yang, Z. A. King, E. Catoiu, E. J. O’Brien, J. K. Liu, and B. O. Palsson (2018) COBRAme: A computational framework for genome-scale models of metabolism and gene expression. PLoS Comput. Biol. 14: e1006302.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Yang, L., N. Mih, A. Anand, J. H. Park, J. Tan, J. T. Yurkovich, J. M. Monk, C. J. Lloyd, T. E. Sandberg, S. W. Seo, D. Kim, A. V. Sastry, P. Phaneuf, Y. Gao, J. T. Broddrick, K. Chen, D. Heckmann, R. Szubin, Y. Hefner, A. M. Feist, and B. O. Palsson (2019) Cellular responses to reactive oxygen species are predicted from molecular mechanisms. Proc. Natl. Acad. Sci. USA. 116: 14368–14373.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Anand, A., K. Chen, L. Yang, A. V. Sastry, C. A. Olson, S. Poudel, Y. Seif, Y. Hefner, P. V. Phaneuf, S. Xu, R. Szubin, A. M. Feist, and B. O. Palsson (2019) Adaptive evolution reveals a tradeoff between growth rate and oxidative stress during naphthoquinone-based aerobic respiration. Proc. Natl. Acad. Sci. USA. 116: 25287–25292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Barenholz, U., L. Keren, E. Segal, and R. Milo (2016) A minimalistic resource allocation model to explain ubiquitous increase in protein expression with growth rate. PLoS One. 11: e0153344.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Feist, A. M., C. S. Henry, J. L. Reed, M. Krummenacker, A. R. Joyce, P. D. Karp, L. J. Broadbelt, V. Hatzimanikatis, and B. Ø. Palsson (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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Orth, J. D., T. M. Conrad, J. Na, J. A. Lerman, H. Nam, A. M. Feist, and B. O. Palsson (2011) A comprehensive genome-scale reconstruction of Escherichia coli metabolism—2011. Mol. Syst. Biol. 7: 535.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Klumpp, S., M. Scott, S. Pedersen, and T. Hwa (2013) Molecular crowding limits translation and cell growth. Proc. Natl. Acad. Sci. USA. 110: 16754–16759.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Liu, J. K., E. J. O’Brien, J. A. Lerman, K. Zengler, B. O. Palsson, and A. M. Feist (2014) Reconstruction and modeling protein translocation and compartmentalization in Escherichia coli at the genome-scale. BMC Syst. Biol. 8: 110.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Zhuang, K., G. N. Vemuri, and R. Mahadevan (2011) Economics of membrane occupancy and respiro-fermentation. Mol. Syst. Biol. 7: 500.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Wunderling, R. (1997) SOPLEX: the sequential object-oriented simplex class library. ZIB.

  55. Ma, D., L. Yang, R. M. T. Fleming, I. Thiele, B. O. Palsson, and M. A. Saunders (2017) Reliable and efficient solution of genome-scale models of Metabolism and macromolecular expression. Sci. Rep. 7: 40863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Chen, K., Y. Gao, N. Mih, E. J. O’Brien, L. Yang, and B. O. Palsson (2017) Thermosensitivity of growth is determined by chaperone-mediated proteome reallocation. Proc. Natl. Acad. Sci. USA. 114: 11548–11553.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Du, B., L. Yang, C. J. Lloyd, X. Fang, and B. O. Palsson (2019) Genome-scale model of metabolism and gene expression provides a multi-scale description of acid stress responses in Escherichia coli. PLoS Comput. Biol. 15: e1007525.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Liu, J. K., C. Lloyd, M. M. Al-Bassam, A. Ebrahim, J. N. Kim, C. Olson, A. Aksenov, P. Dorrestein, and K. Zengler (2019) Predicting proteome allocation, overflow metabolism, and metal requirements in a model acetogen. PLoS Comput. Biol. 15: e1006848.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Yurkovich, J. T., L. Yang, and B. O. Palsson (2019) Systemslevel physiology of the human red blood cell is computed from metabolic and macromolecular mechanisms. bioRxiv. 797258.

  60. Bryk, A. H. and J. R. Wiśniewski (2017) Quantitative analysis of human red blood cell proteome. J. Proteome Res. 16: 2752–2761.

    Article  CAS  PubMed  Google Scholar 

  61. Yang, L., A. Ebrahim, C. J. Lloyd, M. A. Saunders, and B. O. Palsson (2019) DynamicME: dynamic simulation and refinement of integrated models of metabolism and protein expression. BMC Syst. Biol. 13: 2.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  62. Klumpp, S., Z. Zhang, and T. Hwa (2009) Growth rate-dependent global effects on gene expression in bacteria. Cell. 139: 1366–1375.

    Article  PubMed  PubMed Central  Google Scholar 

  63. Grimbs, A., D. F. Klosik, S. Bornholdt, and M. T. Hutt (2019) A system-wide network reconstruction of gene regulation and metabolism in Escherichia coli. PLoS Comput. Biol. 15: e1006962.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ma, S., K. J. Minch, T. R. Rustad, S. Hobbs, S. L. Zhou, D. R. Sherman, and N. D. Price (2015) Integrated modeling of gene regulatory and metabolic networks in Mycobacterium tuberculosis. PLoS Comput. Biol. 11: e1004543.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Levering, J., C. L. Dupont, A. E. Allen, B. O. Palsson, and K. Zengler (2017) Integrated regulatory and metabolic networks of the marine diatom Phaeodactylum tricornutum predict the response to rising CO2 levels. mSystems. 2: e00142–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Covert, M. W. and B. O. Palsson (2002) Transcriptional regulation in constraints-based metabolic models of Escherichia coli. J. Biol. Chem. 277: 28058–28064.

    Article  CAS  PubMed  Google Scholar 

  67. Covert, M. W., E. M. Knight, J. L. Reed, M. J. Herrgard, and B. O. Palsson (2004) Integrating high-throughput and computational data elucidates bacterial networks. Nature. 429: 92–96.

    Article  CAS  PubMed  Google Scholar 

  68. Shlomi, T., Y. Eisenberg, R. Sharan, and E. Ruppin (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 

  69. Chandrasekaran, S. and N. D. Price (2010) Probabilistic integrative modeling of genome-scale metabolic and regulatory networks in Escherichia coli and Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA. 107: 17845–17850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Goelzer, A. and V. Fromion (2017) Resource allocation in living organisms. Biochem. Soc. Trans. 45: 945–952.

    Article  CAS  PubMed  Google Scholar 

  71. Bonneau, R., M. T. Facciotti, D. J. Reiss, A. K. Schmid, M. Pan, A. Kaur, V. Thorsson, P. Shannon, M. H. Johnson, J. C. Bare, W. Longabaugh, M. Vuthoori, K. Whitehead, A. Madar, L. Suzuki, T. Mori, D. E. Chang, J. Diruggiero, C. H. Johnson, L. Hood, and N. S. Baliga (2007) A predictive model for transcriptional control of physiology in a free living cell. Cell. 131: 1354–1365.

    Article  CAS  PubMed  Google Scholar 

  72. Wang, Z., S. A. Danziger, B. D. Heavner, S. Ma, J. J. Smith, S. Li, T. Herricks, E. Simeonidis, N. S. Baliga, J. D. Aitchison, and N. D. Price (2017) Combining inferred regulatory and reconstructed metabolic networks enhances phenotype prediction in yeast. PLoS Comput. Biol. 13: e1005489.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  73. Sastry, A. V., Y. Gao, R. Szubin, Y. Hefner, S. Xu, D. Kim, K. S. Choudhary, L. Yang, Z. A. King, and B. O. Palsson (2019) The Escherichia coli transcriptome mostly consists of independently regulated modules. Nat. Commun. 10: 5536.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. O’Brien, E. J. and B. O. Palsson (2015) Computing the functional proteome: recent progress and future prospects for genome-scale models. Curr. Opin. Biotechnol. 34: 125–134.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  75. Heckmann, D., C. J. Lloyd, N. Mih, Y. Ha, D. C. Zielinski, Z. B. Haiman, A. A. Desouki, M. J. Lercher, and B. O. Palsson (2018) Machine learning applied to enzyme turnover numbers reveals protein structural correlates and improves metabolic models. Nat. Commun. 9: 5252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Nilsson, A., J. Nielsen, and B. O. Palsson (2017) Metabolic models of protein allocation call for the kinetome. Cell Syst. 5: 538–541.

    Article  CAS  PubMed  Google Scholar 

  77. Heckmann, D., A. Campeau, C. J. Lloyd, P. V. Phaneuf, Y. Hefner, M. Carrillo-Terrazas, A. M. Feist, D. J. Gonzalez, and B. O. Palsson (2020) Kinetic profiling of metabolic specialists demonstrates stability and consistency of in vivo enzyme turnover numbers. Proc. Natl. Acad. Sci. USA. 117: 23182–23190.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Salvy, P. and V. Hatzimanikatis (2020) The ETFL formulation allows multi-omics integration in thermodynamics-compliant metabolism and expression models. Nat. Commun. 11: 30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Ataman, M., D. F. Hernandez Gardiol, G. Fengos, and V. Hatzimanikatis (2017) redGEM: Systematic reduction and analysis of genome-scale metabolic reconstructions for development of consistent core metabolic models. PLoS Comput. Biol. 13: e1005444.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Erdrich, P., R. Steuer, and S. Klamt (2015) An algorithm for the reduction of genome-scale metabolic network models to meaningful core models. BMC Syst. Biol. 9: 48.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Rohl, A. and A. Bockmayr (2017) A mixed-integer linear programming approach to the reduction of genome-scale metabolic networks. BMC Bioinformatics. 18: 2.

    Article  PubMed  PubMed Central  Google Scholar 

  82. Hyduke, D. R., N. E. Lewis, and B. O. Palsson (2013) Analysis of omics data with genome-scale models of metabolism. Mol. Biosyst. 9: 167–174.

    Article  CAS  PubMed  Google Scholar 

  83. Ben Guebila, M. and I. Thiele (2019) Predicting gastrointestinal drug effects using contextualized metabolic models. PLoS Comput. Biol. 15: e1007100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Pusa, T., M. G. Ferrarini, R. Andrade, A. Mary, A. Marchetti-Spaccamela, L. Stougie, and M. F. Sagot (2020) MOOMIN — Mathematical explOration of ‘Omics data on a MetabolIc Network. Bioinformatics. 36: 514–523.

    CAS  PubMed  Google Scholar 

  85. Ebrahim, A., E. Brunk, J. Tan, E. J. O’Brien, D. Kim, R. Szubin, J. A. Lerman, A. Lechner, A. Sastry, A. Bordbar, A. M. Feist, and B. O. Palsson (2016) Multi-omic data integration enables discovery of hidden biological regularities. Nat. Commun. 7: 13091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Dos Santos, F. B., B. G. Olivier, J. Boele, V. Smessaert, P. De Rop, P. Krumpochova, G. W. Klau, M. Giera, P. Dehottay, B. Teusink, and P. Goffin (2017) Probing the genome-scale metabolic landscape of Bordetella pertussis, the causative agent of whooping cough. Appl. Environ. Microbiol. 83: e01528–17.

    Google Scholar 

  87. Brynildsen, M. P., J. A. Winkler, C. S. Spina, I. C. MacDonald, and J. J. Collins (2013) Potentiating antibacterial activity by predictably enhancing endogenous microbial ROS production. Nat. Biotechnol. 31: 160–165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Greenhalgh, K., J. Ramiro-Garcia, A. Heinken, P. Ullmann, T. Bintener, M. P. Pacheco, J. Baginska, P. Shah, A. Frachet, R. Halder, J. V. Fritz, T. Sauter, I. Thiele, S. Haan, E. Letellier, and P. Wilmes (2019) Integrated in vitro and in silico modeling delineates the molecular effects of a synbiotic regimen on colorectal-cancer-derived cells. Cell Rep. 27: 1621–1632.e9.

    Article  CAS  PubMed  Google Scholar 

  89. Cesur, M. F., B. Siraj, R. Uddin, S. Durmuş, and T. Çakır (2020) Network-based metabolism-centered screening of potential drug targets in Klebsiella pneumoniae at genome scale. Front. Cell Infect. Microbiol. 9: 447.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Wu, H. Q., M. L. Cheng, J. M. Lai, H. H. Wu, M. C. Chen, W. H. Liu, W. H. Wu, P. M. H. Chang, C. Y. F. Huang, A. P. Tsou, M. S. Shiao, and F. S. Wang (2017) Flux balance analysis predicts Warburg-like effects of mouse hepatocyte deficient in miR-122a. PLoS Comput. Biol. 13: e1005618.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. King, Z. A., E. J. O’Brien, A. M. Feist, and B. O. Palsson (2017) Literature mining supports a next-generation modeling approach to predict cellular byproduct secretion. Metab. Eng. 39: 220–227.

    Article  CAS  PubMed  Google Scholar 

  92. Niu, W., L. Kramer, J. Mueller, K. Liu, and J. Guo (2019) Metabolic engineering of Escherichia coli for the de novo stereospecific biosynthesis of 1,2-propanediol through lactic acid. Metab. Eng. Commun. 8: e00082.

    Article  PubMed  Google Scholar 

  93. Zheng, Y., Q. Yuan, X. Yang, and H. Ma (2017) Engineering Escherichia coli for poly-(3-hydroxybutyrate) production guided by genome-scale metabolic network analysis. Enzyme Microb. Technol. 106: 60–66.

    Article  CAS  PubMed  Google Scholar 

  94. Mohite, O. S., T. Weber, H. U. Kim, and S. Y. Lee (2019) Genome-scale metabolic reconstruction of actinomycetes for antibiotics production. Biotechnol. J. 14: e1800377.

    Article  PubMed  CAS  Google Scholar 

  95. Dahal, S., S. Poudel, and R. A. Thompson (2016) Genome-scale modeling of thermophilic microorganisms. pp. 103–119. In: I. Nookaew (ed.). Network Biology. Springer, Cham, Switzerland.

    Chapter  Google Scholar 

  96. Zhuang, K., M. Izallalen, P. Mouser, H. Richter, C. Risso, R. Mahadevan, and D. R. Lovley (2011) Genome-scale dynamic modeling of the competition between Rhodoferax and Geobacter in anoxic subsurface environments. ISME J. 5: 305–316.

    Article  PubMed  Google Scholar 

  97. Zhuang, K., E. Ma, D. R. Lovley, and R. Mahadevan (2012) The design of long-term effective uranium bioremediation strategy using a community metabolic model. Biotechnol. Bioeng. 109: 2475–2483.

    Article  CAS  PubMed  Google Scholar 

  98. Scheibe, T. D., R. Mahadevan, Y. Fang, S. Garg, P. E. Long, and D. R. Lovley (2009) Coupling a genome-scale metabolic model with a reactive transport model to describe in situ uranium bioremediation. Microb. Biotechnol. 2: 274–286.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Tobalina, L., R. Bargiela, J. Pey, F. A. Herbst, I. Lores, D. Rojo, C. Barbas, A. I. Peláez, J. Sánchez, M. von Bergen, J. Seifert, M. Ferrer, and F. J. Planes (2015) Context-specific metabolic network reconstruction of a naphthalene-degrading bacterial community guided by metaproteomic data. Bioinformatics. 31: 1771–1779.

    Article  CAS  PubMed  Google Scholar 

  100. Lloyd, C. J., Z. A. King, T. E. Sandberg, Y. Hefner, C. A. Olson, P. V. Phaneuf, E. J. O’Brien, J. G. Sanders, R. A. Salido, K. Sanders, C. Brennan, G. Humphrey, R. Knight, and A. M. Feist (2019) The genetic basis for adaptation of model-designed syntrophic co-cultures. PLoS Comput. Biol. 15: e1006213.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Hanemaaijer, M., B. G. Olivier, W. F. M. Roling, F. J. Bruggeman, and B. Teusink (2017) Model-based quantification of metabolic interactions from dynamic microbial-community data. PLoS One. 12: e0173183.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Pacheco, A. R., M. Moel, and D. Segre (2019) Costless metabolic secretions as drivers of interspecies interactions in microbial ecosystems. Nat. Commun. 10: 103.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Queen’s University and the Natural Sciences and Engineering Research Council of Canada (NSERC) [RGPIN-2020-06325].

The authors declare no conflict of interest. No ethical approval was required. No informed consent was required.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Laurence Yang.

Additional information

Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dahal, S., Zhao, J. & Yang, L. Genome-scale Modeling of Metabolism and Macromolecular Expression and Their Applications. Biotechnol Bioproc E 25, 931–943 (2020). https://doi.org/10.1007/s12257-020-0061-2

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12257-020-0061-2

Keywords

Navigation