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Genome-scale modeling for metabolic engineering

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Journal of Industrial Microbiology & Biotechnology

Abstract

We focus on the application of constraint-based methodologies and, more specifically, flux balance analysis in the field of metabolic engineering, and enumerate recent developments and successes of the field. We also review computational frameworks that have been developed with the express purpose of automatically selecting optimal gene deletions for achieving improved production of a chemical of interest. The application of flux balance analysis methods in rational metabolic engineering requires a metabolic network reconstruction and a corresponding in silico metabolic model for the microorganism in question. For this reason, we additionally present a brief overview of automated reconstruction techniques. Finally, we emphasize the importance of integrating metabolic networks with regulatory information—an area which we expect will become increasingly important for metabolic engineering—and present recent developments in the field of metabolic and regulatory integration.

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References

  1. Agren R, Bordel S, Mardinoglu A, Pornputtapong N, Nookaew I, Nielsen J (2012) Reconstruction of genome-scale active metabolic networks for 69 human cell types and 16 cancer types using INIT. PLoS Comput Biol 8(5):17

    Google Scholar 

  2. Agren R, Liu L, Shoaie S, Vongsangnak W, Nookaew I, Nielsen J (2013) The RAVEN toolbox and its use for generating a genome-scale metabolic model for Penicillium chrysogenum. PLoS Comput Biol 9(3):21

    Google Scholar 

  3. Ajikumar PK, Xiao WH, Tyo KE, Wang Y, Simeon F, Leonard E, Mucha O, Phon TH, Pfeifer B, Stephanopoulos G (2010) Isoprenoid pathway optimization for Taxol precursor overproduction in Escherichia coli. Science 330(6000):70–74

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Almaas E, Kovacs B, Vicsek T, Oltvai ZN, Barabasi AL (2004) Global organization of metabolic fluxes in the bacterium Escherichia coli. Nature 427(6977):839–843. doi:10.1038/nature02289

    CAS  PubMed  Google Scholar 

  5. Alper H, Jin YS, Moxley JF, Stephanopoulos G (2005) Identifying gene targets for the metabolic engineering of lycopene biosynthesis in Escherichia coli. Metab Eng 7(3):155–164

    CAS  PubMed  Google Scholar 

  6. Andersen MR, Nielsen ML, Nielsen J (2008) Metabolic model integration of the bibliome, genome, metabolome and reactome of Aspergillus niger. Mol Syst Biol 4(178):25

    Google Scholar 

  7. Asadollahi MA, Maury J, Patil KR, Schalk M, Clark A, Nielsen J (2009) Enhancing sesquiterpene production in Saccharomyces cerevisiae through in silico driven metabolic engineering. Metab Eng 11(6):328–334

    CAS  PubMed  Google Scholar 

  8. Avila-Campillo I, Drew K, Lin J, Reiss DJ, Bonneau R (2007) BioNetBuilder: automatic integration of biological networks. Bioinformatics 23(3):392–393

    CAS  PubMed  Google Scholar 

  9. Becker J, Wittmann C (2012) Bio-based production of chemicals, materials and fuels—Corynebacterium glutamicum as versatile cell factory. Curr Opin Biotechnol 23(4):631–640

    CAS  PubMed  Google Scholar 

  10. Becker SA, Feist AM, Mo ML, Hannum G, Palsson BO, Herrgard MJ (2007) Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox. Nat Protoc 2(3):727–738

    CAS  PubMed  Google Scholar 

  11. Becker SA, Palsson BO (2008) Context-specific metabolic networks are consistent with experiments. PLoS Comput Biol 4(5):e1000082

    PubMed Central  PubMed  Google Scholar 

  12. Benedict MN, Gonnerman MC, Metcalf WW, Price ND (2012) Genome-scale metabolic reconstruction and hypothesis testing in the methanogenic archaeon Methanosarcina acetivorans C2A. J Bacteriol 194(4):855–865

    CAS  PubMed Central  PubMed  Google Scholar 

  13. Benedict MN, Mundy MB, Henry CS, Chia N, Price ND (2014) Likelihood-based gene annotations for gap filling and quality assessment in genome-scale metabolic models. PLoS Comput Biol 10(10):e1003882

    PubMed Central  PubMed  Google Scholar 

  14. Blazeck J, Alper H (2010) Systems metabolic engineering: genome-scale models and beyond. Biotechnol J 5(7):647–659

    CAS  PubMed Central  PubMed  Google Scholar 

  15. Borodina I, Kildegaard KR, Jensen NB, Blicher TH, Maury J, Sherstyk S, Schneider K, Lamosa P, Herrgård MJ, Rosenstand I, Öberg F, Forster J, Nielsen J (2015) Establishing a synthetic pathway for high-level production of 3-hydroxypropionic acid in Saccharomyces cerevisiae via β-alanine. Metabolic Engineering 27:57–64

    CAS  PubMed  Google Scholar 

  16. Bro C, Regenberg B, Forster J, Nielsen J (2006) In silico aided metabolic engineering of Saccharomyces cerevisiae for improved bioethanol production. Metab Eng 8(2):102–111

    CAS  PubMed  Google Scholar 

  17. Brochado AR, Matos C, Moller BL, Hansen J, Mortensen UH, Patil KR (2010) Improved vanillin production in baker’s yeast through in silico design. Microb Cell Fact 9(84):1475–2859

    Google Scholar 

  18. Burgard AP, Pharkya P, Maranas CD (2003) Optknock: a bilevel programming framework for identifying gene knockout strategies for microbial strain optimization. Biotechnol Bioeng 84(6):647–657

    CAS  PubMed  Google Scholar 

  19. Burgess CM, Smid EJ, van Sinderen D (2009) Bacterial vitamin B2, B11 and B12 overproduction: an overview. Int J Food Microbiol 133(1–2):1–7

    CAS  PubMed  Google Scholar 

  20. Chandrasekaran S, Price ND (2010) Probabilistic integrative modeling of genome-scale metabolic and regulatory networks in Escherichia coli and Mycobacterium tuberculosis. Proc Natl Acad Sci U S A 107(41):17845–17850

    CAS  PubMed Central  PubMed  Google Scholar 

  21. Colijn C, Brandes A, Zucker J, Lun DS, Weiner B, Farhat MR, Cheng TY, Moody DB, Murray M, Galagan JE (2009) Interpreting expression data with metabolic flux models: predicting Mycobacterium tuberculosis mycolic acid production. PLoS Comput Biol 5(8):28

    Google Scholar 

  22. Covert MW, Schilling CH, Palsson B (2001) Regulation of gene expression in flux balance models of metabolism. J Theor Biol 213(1):73–88

    CAS  PubMed  Google Scholar 

  23. Dale JM, Popescu L, Karp PD (2010) Machine learning methods for metabolic pathway prediction. BMC Bioinform 11(15):1471–2105

    Google Scholar 

  24. Devoid S, Overbeek R, DeJongh M, Vonstein V, Best AA, Henry C (2013) Automated genome annotation and metabolic model reconstruction in the SEED and Model SEED. Methods Mol Biol 985:17–45

    CAS  PubMed  Google Scholar 

  25. Dobson PD, Smallbone K, Jameson D, Simeonidis E, Lanthaler K, Pir P, Lu C, Swainston N, Dunn WB, Fisher P, Hull D, Brown M, Oshota O, Stanford NJ, Kell DB, King RD, Oliver SG, Stevens RD, Mendes P (2010) Further developments towards a genome-scale metabolic model of yeast. BMC Syst Biol 4(145):0509–1752

    Google Scholar 

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

    CAS  PubMed Central  PubMed  Google Scholar 

  27. 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):26

    Google Scholar 

  28. Feng X, Xu Y, Chen Y, Tang YJ (2012) MicrobesFlux: a web platform for drafting metabolic models from the KEGG database. BMC Syst Biol 6:94

    PubMed Central  PubMed  Google Scholar 

  29. Fong SS, Burgard AP, Herring CD, Knight EM, Blattner FR, Maranas CD, Palsson BO (2005) In silico design and adaptive evolution of Escherichia coli for production of lactic acid. Biotechnol Bioeng 91(5):643–648

    CAS  PubMed  Google Scholar 

  30. Ghosh A, Zhao H, Price ND (2011) Genome-scale consequences of cofactor balancing in engineered pentose utilization pathways in Saccharomyces cerevisiae. PLoS One 6(11):4

    Google Scholar 

  31. Gonnerman MC, Benedict MN, Feist AM, Metcalf WW, Price ND (2013) Genomically and biochemically accurate metabolic reconstruction of Methanosarcina barkeri Fusaro, iMG746. Biotechnol J 8(9):1070–1079

    CAS  PubMed  Google Scholar 

  32. Heavner BD, Smallbone K, Price ND, Walker LP (2013) Version 6 of the consensus yeast metabolic network refines biochemical coverage and improves model performance. Database 9 (10)

  33. Henry CS, DeJongh M, Best AA, Frybarger PM, Linsay B, Stevens RL (2010) High-throughput generation, optimization and analysis of genome-scale metabolic models. Nat Biotechnol 28(9):977–982

    CAS  PubMed  Google Scholar 

  34. Herrgard MJ, Swainston N, Dobson P, Dunn WB, Arga KY, Arvas M, Bluthgen N, Borger S, Costenoble R, Heinemann M, Hucka M, Le Novere N, Li P, Liebermeister W, Mo ML, Oliveira AP, Petranovic D, Pettifer S, Simeonidis E, Smallbone K, Spasic I, Weichart D, Brent R, Broomhead DS, Westerhoff HV, Kirdar B, Penttila M, Klipp E, Palsson BO, Sauer U, Oliver SG, Mendes P, Nielsen J, Kell DB (2008) A consensus yeast metabolic network reconstruction obtained from a community approach to systems biology. Nat Biotechnol 26(10):1155–1160

    CAS  PubMed Central  PubMed  Google Scholar 

  35. Hong KK, Nielsen J (2012) Metabolic engineering of Saccharomyces cerevisiae: a key cell factory platform for future biorefineries. Cell Mol Life Sci 69(16):2671–2690

    CAS  PubMed  Google Scholar 

  36. Hucka M, Finney A, Sauro HM, Bolouri H, Doyle JC, Kitano H, Arkin AP, Bornstein BJ, Bray D, Cornish-Bowden A, Cuellar AA, Dronov S, Gilles ED, Ginkel M, Gor V, Goryanin II, Hedley WJ, Hodgman TC, Hofmeyr JH, Hunter PJ, Juty NS, Kasberger JL, Kremling A, Kummer U, Le Novere N, Loew LM, Lucio D, Mendes P, Minch E, Mjolsness ED, Nakayama Y, Nelson MR, Nielsen PF, Sakurada T, Schaff JC, Shapiro BE, Shimizu TS, Spence HD, Stelling J, Takahashi K, Tomita M, Wagner J, Wang J (2003) The systems biology markup language (SBML): a medium for representation and exchange of biochemical network models. Bioinformatics 19(4):524–531

    CAS  PubMed  Google Scholar 

  37. Jang YS, Park JM, Choi S, Choi YJ, Seung do Y, Cho JH, Lee SY (2012) Engineering of microorganisms for the production of biofuels and perspectives based on systems metabolic engineering approaches. Biotechnol Adv 30(5):989–1000

    CAS  PubMed  Google Scholar 

  38. Jensen PA, Papin JA (2011) Functional integration of a metabolic network model and expression data without arbitrary thresholding. Bioinformatics 27(4):541–547

    CAS  PubMed  Google Scholar 

  39. Jerby L, Shlomi T, Ruppin E (2010) Computational reconstruction of tissue-specific metabolic models: application to human liver metabolism. Mol Syst Biol 6(401):56

    Google Scholar 

  40. Joyce AR, Palsson BO (2008) Predicting gene essentiality using genome-scale in silico models. Methods Mol Biol 416:433–457

    CAS  PubMed  Google Scholar 

  41. Kanehisa M, Araki M, Goto S, Hattori M, Hirakawa M, Itoh M, Katayama T, Kawashima S, Okuda S, Tokimatsu T, Yamanishi Y (2008) KEGG for linking genomes to life and the environment. Nucleic Acids Res 36:12 (Database issue)

    Google Scholar 

  42. Karp PD, Ouzounis CA, Moore-Kochlacs C, Goldovsky L, Kaipa P, Ahren D, Tsoka S, Darzentas N, Kunin V, Lopez-Bigas N (2005) Expansion of the BioCyc collection of pathway/genome databases to 160 genomes. Nucleic Acids Res 33(19):6083–6089

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Karr JR, Sanghvi JC, Macklin DN, Gutschow MV, Jacobs JM, Bolival B Jr, Assad-Garcia N, Glass JI, Covert MW (2012) A whole-cell computational model predicts phenotype from genotype. Cell 150(2):389–401

    CAS  PubMed Central  PubMed  Google Scholar 

  44. King ZA, Feist AM (2014) Optimal cofactor swapping can increase the theoretical yield for chemical production in Escherichia coli and Saccharomyces cerevisiae. Metab Eng 24:117–128

    CAS  PubMed  Google Scholar 

  45. Klamt S, Saez-Rodriguez J, Gilles ED (2007) Structural and functional analysis of cellular networks with Cell NetAnalyzer. BMC Syst Biol 1:2

    PubMed Central  PubMed  Google Scholar 

  46. Lang M, Stelzer M, Schomburg D (2011) BKM-react, an integrated biochemical reaction database. BMC Biochem 12(42):1471–2091

    Google Scholar 

  47. Lee JW, Na D, Park JM, Lee J, Choi S, Lee SY (2012) Systems metabolic engineering of microorganisms for natural and non-natural chemicals. Nat Chem Biol 8(6):536–546

    CAS  PubMed  Google Scholar 

  48. Lee KH, Park JH, Kim TY, Kim HU, Lee SY (2007) Systems metabolic engineering of Escherichia coli for l-threonine production. Mol Syst Biol 3(149):4

    Google Scholar 

  49. Lee SY, Hong SH, Moon SY (2002) In silico metabolic pathway analysis and design: succinic acid production by metabolically engineered Escherichia coli as an example. Genome Inform 13:214–223

    CAS  PubMed  Google Scholar 

  50. Lee SY, Lee DY, Kim TY (2005) Systems biotechnology for strain improvement. Trends Biotechnol 23(7):349–358

    CAS  PubMed  Google Scholar 

  51. Lerman JA, Hyduke DR, Latif H, Portnoy VA, Lewis NE, Orth JD, Schrimpe-Rutledge AC, Smith RD, Adkins JN, Zengler K, Palsson BO (2012) In silico method for modelling metabolism and gene product expression at genome scale. Nat Commun 3:929

    PubMed  Google Scholar 

  52. Liu L, Redden H, Alper HS (2013) Frontiers of yeast metabolic engineering: diversifying beyond ethanol and Saccharomyces. Curr Opin Biotechnol 24(6):1023–1030

    CAS  PubMed  Google Scholar 

  53. Ma F, Hanna MA (1999) Biodiesel production: a review. Bioresour Technol 70(1):1–15

    CAS  Google Scholar 

  54. Machado D, Herrgard M (2014) Systematic evaluation of methods for integration of transcriptomic data into constraint-based models of metabolism. PLoS Comput Biol 10(4):e1003580

    PubMed Central  PubMed  Google Scholar 

  55. Mahadevan R, Schilling CH (2003) The effects of alternate optimal solutions in constraint-based genome-scale metabolic models. Metab Eng 5(4):264–276

    CAS  PubMed  Google Scholar 

  56. Meijer S, Nielsen ML, Olsson L, Nielsen J (2009) Gene deletion of cytosolic ATP: citrate lyase leads to altered organic acid production in Aspergillus niger. J Ind Microbiol Biotechnol 36(10):1275–1280

    CAS  PubMed  Google Scholar 

  57. Milne CB, Eddy JA, Raju R, Ardekani S, Kim PJ, Senger RS, Jin YS, Blaschek HP, Price ND (2011) Metabolic network reconstruction and genome-scale model of butanol-producing strain Clostridium beijerinckii NCIMB 8052. BMC Syst Biol 5:130

    CAS  PubMed Central  PubMed  Google Scholar 

  58. Monk J, Nogales J, Palsson BO (2014) Optimizing genome-scale network reconstructions. Nat Biotechnol 32(5):447–452

    CAS  PubMed  Google Scholar 

  59. Nevoigt E (2008) Progress in metabolic engineering of Saccharomyces cerevisiae. Microbiol Mol Biol Rev 72(3):379–412

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Nogales J, Gudmundsson S, Knight EM, Palsson BO, Thiele I (2012) Detailing the optimality of photosynthesis in cyanobacteria through systems biology analysis. Proc Natl Acad Sci U S A 109(7):2678–2683

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Oberhardt MA, Palsson BO, Papin JA (2009) Applications of genome-scale metabolic reconstructions. Mol Syst Biol 5(320):3

    Google Scholar 

  62. Ohno S, Furusawa C, Shimizu H (2013) In silico screening of triple reaction knockout Escherichia coli strains for overproduction of useful metabolites. J Biosci Bioeng 115(2):221–228

    CAS  PubMed  Google Scholar 

  63. Orth JD, Conrad TM, Na J, Lerman JA, Nam H, Feist AM, Palsson BO (2011) A comprehensive genome-scale reconstruction of Escherichia coli metabolism–2011. Mol Syst Biol 7(535):65

    Google Scholar 

  64. Papin JA, Price ND, Palsson BO (2002) Extreme pathway lengths and reaction participation in genome-scale metabolic networks. Genome Res 12(12):1889–1900

    CAS  PubMed Central  PubMed  Google Scholar 

  65. Parekh S, Vinci VA, Strobel RJ (2000) Improvement of microbial strains and fermentation processes. Appl Microbiol Biotechnol 54(3):287–301

    CAS  PubMed  Google Scholar 

  66. Park JH, Lee KH, Kim TY, Lee SY (2007) Metabolic engineering of Escherichia coli for the production of l-valine based on transcriptome analysis and in silico gene knockout simulation. Proc Natl Acad Sci U S A 104(19):7797–7802

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Patil KR, Rocha I, Forster J, Nielsen J (2005) Evolutionary programming as a platform for in silico metabolic engineering. BMC Bioinform 6:308

    Google Scholar 

  68. Pharkya P, Burgard AP, Maranas CD (2004) OptStrain: a computational framework for redesign of microbial production systems. Genome Res 14(11):2367–2376

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Pharkya P, Maranas CD (2006) An optimization framework for identifying reaction activation/inhibition or elimination candidates for overproduction in microbial systems. Metab Eng 8(1):1–13

    CAS  PubMed  Google Scholar 

  70. Philp JC, Ritchie RJ, Allan JE (2013) Biobased chemicals: the convergence of green chemistry with industrial biotechnology. Trends Biotechnol 31(4):219–222

    CAS  PubMed  Google Scholar 

  71. Pitkanen E, Akerlund A, Rantanen A, Jouhten P, Ukkonen E (2008) ReMatch: a web-based tool to construct, store and share stoichiometric metabolic models with carbon maps for metabolic flux analysis. J Integr Bioinform 5(2):2008–2102

    Google Scholar 

  72. 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(5):760–769

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Price ND, Schellenberger J, Palsson BO (2004) Uniform sampling of steady-state flux spaces: means to design experiments and to interpret enzymopathies. Biophys J 87(4):2172–2186

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Ranganathan S, Suthers PF, Maranas CD (2010) OptForce: an optimization procedure for identifying all genetic manipulations leading to targeted overproductions. PLoS Comput Biol 6(4):1000744

    Google Scholar 

  75. Reed JL, Patel TR, Chen KH, Joyce AR, Applebee MK, Herring CD, Bui OT, Knight EM, Fong SS, Palsson BO (2006) Systems approach to refining genome annotation. Proc Natl Acad Sci U S A 103(46):17480–17484

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Reed JL, Vo TD, Schilling CH, Palsson BO (2003) An expanded genome-scale model of Escherichia coli K-12 (iJR904 GSM/GPR). Genome Biol 4(9):28

    Google Scholar 

  77. Reyes R, Gamermann D, Montagud A, Fuente D, Triana J, Urchueguia JF, de Cordoba PF (2012) Automation on the generation of genome-scale metabolic models. J Comput Biol 19(12):1295–1306

    CAS  PubMed  Google Scholar 

  78. Rocha I, Maia P, Evangelista P, Vilaca P, Soares S, Pinto JP, Nielsen J, Patil KR, Ferreira EC, Rocha M (2010) OptFlux: an open-source software platform for in silico metabolic engineering. BMC Syst Biol 4(45):0509–1752

    Google Scholar 

  79. Savile CK, Janey JM, Mundorff EC, Moore JC, Tam S, Jarvis WR, Colbeck JC, Krebber A, Fleitz FJ, Brands J, Devine PN, Huisman GW, Hughes GJ (2010) Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture. Science 329(5989):305–309

    CAS  PubMed  Google Scholar 

  80. Savinell JM, Palsson BO (1992) Optimal selection of metabolic fluxes for in vivo measurement. I. Development of mathematical methods. J Theor Biol 155(2):201–214

    CAS  PubMed  Google Scholar 

  81. Savinell JM, Palsson BO (1992) Optimal selection of metabolic fluxes for in vivo measurement. II. Application to Escherichia coli and hybridoma cell metabolism. J Theor Biol 155(2):215–242

    CAS  PubMed  Google Scholar 

  82. Schellenberger J, Park JO, Conrad TM, Palsson BO (2010) BiGG: a Biochemical Genetic and Genomic knowledgebase of large scale metabolic reconstructions. BMC Bioinform 11(213):1471–2105

    Google Scholar 

  83. Schilling CH, Schuster S, Palsson BO, Heinrich R (1999) Metabolic pathway analysis: basic concepts and scientific applications in the post-genomic era. Biotechnol Prog 15(3):296–303

    CAS  PubMed  Google Scholar 

  84. Schomburg I, Chang A, Ebeling C, Gremse M, Heldt C, Huhn G, Schomburg D (2004) BRENDA, the enzyme database: updates and major new developments. Nucleic Acids Res 32:D431–D433 (Database issue)

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Shapiro HM (1969) Input-output models of biological systems: formulation and applicability. Comput Biomed Res 2(5):430–445

    CAS  PubMed  Google Scholar 

  86. Shinfuku Y, Sorpitiporn N, Sono M, Furusawa C, Hirasawa T, Shimizu H (2009) Development and experimental verification of a genome-scale metabolic model for Corynebacterium glutamicum. Microb Cell Fact 8(43):1475–2859

    Google Scholar 

  87. Shlomi T, Cabili MN, Herrgard MJ, Palsson BO, Ruppin E (2008) Network-based prediction of human tissue-specific metabolism. Nat Biotechnol 26(9):1003–1010

    CAS  PubMed  Google Scholar 

  88. Shlomi T, Eisenberg Y, Sharan R (2007) Ruppin E A genome-scale computational study of the interplay between transcriptional regulation and metabolism. Mol Syst Biol. 3:101 Epub 2007 Apr 17

    PubMed Central  PubMed  Google Scholar 

  89. Simeonidis E, Chandrasekaran S, Price ND (2013) A guide to integrating transcriptional regulatory and metabolic networks using PROM (probabilistic regulation of metabolism). Methods Mol Biol 985:103–112

    PubMed  Google Scholar 

  90. Song H, Kim TY, Choi BK, Choi SJ, Nielsen LK, Chang HN, Lee SY (2008) Development of chemically defined medium for Mannheimia succiniciproducens based on its genome sequence. Appl Microbiol Biotechnol 79(2):263–272

    CAS  PubMed  Google Scholar 

  91. Stephanopoulos G (1999) Metabolic fluxes and metabolic engineering. Metab Eng 1(1):1–11

    CAS  PubMed  Google Scholar 

  92. Sun Z, Meng H, Li J, Wang J, Li Q, Wang Y, Zhang Y (2014) Identification of Novel Knockout Targets for Improving Terpenoids Biosynthesis in Saccharomyces cerevisiae. PLoS One 9(11):e112615

    PubMed Central  PubMed  Google Scholar 

  93. Swainston N, Smallbone K, Mendes P, Kell D, Paton N (2011) The SuBliMinaL Toolbox: automating steps in the reconstruction of metabolic networks. J Integr Bioinform 8(2):2011–2186

    Google Scholar 

  94. Tepper N, Shlomi T (2010) Predicting metabolic engineering knockout strategies for chemical production: accounting for competing pathways. Bioinformatics 26(4):536–543

    CAS  PubMed  Google Scholar 

  95. Thiele I, Palsson BO (2010) A protocol for generating a high-quality genome-scale metabolic reconstruction. Nat Protoc 5(1):93–121

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Trinh CT, Carlson R, Wlaschin A, Srienc F (2006) Design, construction and performance of the most efficient biomass producing E. coli bacterium. Metab Eng 8(6):628–638

    CAS  PubMed  Google Scholar 

  97. Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S, Wernerus H, Bjorling L (2010) Ponten F Towards a knowledge-based Human Protein Atlas. Nat Biotechnol. 28(12):1248–1250. doi:10.1038/nbt1210-1248

    CAS  PubMed  Google Scholar 

  98. Varma A, Palsson BO (1993) Metabolic capabilities of Escherichia coli: I. synthesis of biosynthetic precursors and cofactors. J Theor Biol 165(4):477–502

    CAS  PubMed  Google Scholar 

  99. Varma A, Palsson BO (1993) Metabolic capabilities of Escherichia coli: II. optimal growth patterns. J Theor Biol 165(4):503–522

    CAS  Google Scholar 

  100. 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(10):3724–3731

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Wang Y, Eddy JA, Price ND (2012) Reconstruction of genome-scale metabolic models for 126 human tissues using mCADRE. BMC Syst Biol 6(153):0509–1752

    Google Scholar 

  102. Watson MR (1984) Metabolic maps for the Apple II. Biochem Soc Trans 12:1093–1094

    CAS  Google Scholar 

  103. Wendisch VF, Bott M, Eikmanns BJ (2006) Metabolic engineering of Escherichia coli and Corynebacterium glutamicum for biotechnological production of organic acids and amino acids. Curr Opin Microbiol 9(3):268–274

    CAS  PubMed  Google Scholar 

  104. Wijffels RH, Kruse O, Hellingwerf KJ (2013) Potential of industrial biotechnology with cyanobacteria and eukaryotic microalgae. Curr Opin Biotechnol 24(3):405–413

    CAS  PubMed  Google Scholar 

  105. Wishart DS, Tzur D, Knox C, Eisner R, Guo AC, Young N, Cheng D, Jewell K, Arndt D, Sawhney S, Fung C, Nikolai L, Lewis M, Coutouly MA, Forsythe I, Tang P, Shrivastava S, Jeroncic K, Stothard P, Amegbey G, Block D, Hau DD, Wagner J, Miniaci J, Clements M, Gebremedhin M, Guo N, Zhang Y, Duggan GE, Macinnis GD, Weljie AM, Dowlatabadi R, Bamforth F, Clive D, Greiner R, Li L, Marrie T, Sykes BD, Vogel HJ, Querengesser L (2007) HMDB: the Human Metabolome Database. Nucleic Acids Res 35:D521–D526 (Database issue)

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Wright J, Wagner A (2008) The Systems Biology Research Tool: evolvable open-source software. BMC Syst Biol 2(55):0509–1752

    Google Scholar 

  107. Yadav VG, De Mey M, Lim CG, Ajikumar PK, Stephanopoulos G (2012) The future of metabolic engineering and synthetic biology: towards a systematic practice. Metab Eng 14(3):233–241

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Yang L, Cluett WR, Mahadevan R (2011) EMILiO: a fast algorithm for genome-scale strain design. Metab Eng 13(3):272–281

    CAS  PubMed  Google Scholar 

  109. Yin J, Chen J-C, Wu Q, Chen G-Q (2014) Halophiles, coming stars for industrial biotechnology. Biotechnology Advances (in press)

  110. Yoshikawa K, Kojima Y, Nakajima T, Furusawa C, Hirasawa T, Shimizu H (2011) Reconstruction and verification of a genome-scale metabolic model for Synechocystis sp. PCC6803. Appl Microbiol Biotechnol 92(2):347–358

    CAS  PubMed  Google Scholar 

  111. Zhou H, Cheng JS, Wang BL, Fink GR, Stephanopoulos G (2012) Xylose isomerase overexpression along with engineering of the pentose phosphate pathway and evolutionary engineering enable rapid xylose utilization and ethanol production by Saccharomyces cerevisiae. Metab Eng 14(6):611–622

    CAS  PubMed  Google Scholar 

  112. Zhou T (2013) Computational reconstruction of metabolic networks from KEGG. Methods Mol Biol 930:235–249

    CAS  PubMed  Google Scholar 

  113. Zhuang K, Bakshi BR, Herrgard MJ (2013) Multi-scale modeling for sustainable chemical production. Biotechnol J 8(9):973–984

    CAS  PubMed  Google Scholar 

  114. Zomorrodi AR, Suthers PF, Ranganathan S, Maranas CD (2012) Mathematical optimization applications in metabolic networks. Metab Eng 14(6):672–686

    CAS  PubMed  Google Scholar 

  115. Zur H, Ruppin E, Shlomi T (2010) iMAT: an integrative metabolic analysis tool. Bioinformatics 26(24):3140–3142

    CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The authors gratefully acknowledge funding from the Luxembourg Centre for Systems Biomedicine (ES), and the DOE ARPA-E program (DE-AR0000426), an NIH Center for Systems Biology (2P50 GM076547) and the Camille Dreyfus Teacher-Scholar Program (NDP). We also thank Julie Bletz and Ben Heavner for critical readings of the manuscript, and James Eddy for assistance with the illustrations.

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Correspondence to Nathan D. Price.

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Special Issue: Metabolic Engineering.

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Simeonidis, E., Price, N.D. Genome-scale modeling for metabolic engineering. J Ind Microbiol Biotechnol 42, 327–338 (2015). https://doi.org/10.1007/s10295-014-1576-3

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