Applied Microbiology and Biotechnology

, Volume 97, Issue 2, pp 519–539 | Cite as

Genome-scale metabolic model in guiding metabolic engineering of microbial improvement

  • Chuan Xu
  • Lili Liu
  • Zhao Zhang
  • Danfeng Jin
  • Juanping Qiu
  • Ming Chen


In the past few decades, despite all the significant achievements in industrial microbial improvement, the approaches of traditional random mutation and selection as well as the rational metabolic engineering based on the local knowledge cannot meet today’s needs. With rapid reconstructions and accurate in silico simulations, genome-scale metabolic model (GSMM) has become an indispensable tool to study the microbial metabolism and design strain improvements. In this review, we highlight the application of GSMM in guiding microbial improvements focusing on a systematic strategy and its achievements in different industrial fields. This strategy includes a repetitive process with four steps: essential data acquisition, GSMM reconstruction, constraints-based optimizing simulation, and experimental validation, in which the second and third steps are the centerpiece. The achievements presented here belong to different industrial application fields, including food and nutrients, biopharmaceuticals, biopolymers, microbial biofuel, and bioremediation. This strategy and its achievements demonstrate a momentous guidance of GSMM for metabolic engineering breeding of industrial microbes. More efforts are required to extend this kind of study in the meantime.


Genome-scale metabolic model Systems biology Metabolic engineering Microbial improvement Industrial application 



The authors are grateful to the supports by the major special project of science and technology of Zhejiang province, China (No. 2008C12G2020010), the Fundamental Research Funds for the Central Universities, and the NSFC project, China (No. 30971743).


  1. AbuOun M, Suthers PF, Jones GI, Carter BR, Saunders MP, Maranas CD, Woodward MJ, Anjum MF (2009) Genome scale reconstruction of a Salmonella metabolic model: comparison of similarity and differences with a commensal Escherichia coli strain. J Biol Chem 284(43):29480–29488CrossRefGoogle Scholar
  2. Aggarwal S, Karimi IA, Lee DY (2011) Reconstruction of a genome-scale metabolic network of Rhodococcus erythropolis for desulfurization studies. Mol Biosyst 7(11):3122–3131CrossRefGoogle Scholar
  3. Agrawal N, Dasaradhi P, Mohmmed A, Malhotra P, Bhatnagar RK, Mukherjee SK (2003) RNA interference: biology, mechanism, and applications. Microbiol Mol Biol Rev 67(4):657–685CrossRefGoogle Scholar
  4. Åkesson M, Förster J, Nielsen J (2004) Integration of gene expression data into genome-scale metabolic models. Metab Eng 6(4):285–293CrossRefGoogle Scholar
  5. Alam MT, Merlo ME, Hodgson DA, Wellington EM, Takano E, Breitling R (2010) Metabolic modeling and analysis of the metabolic switch in Streptomyces coelicolor. BMC Genomics 11:202CrossRefGoogle Scholar
  6. Alcantara R, Axelsen KB, Morgat A, Belda E, Coudert E, Bridge A, Cao H, de Matos P, Ennis M, Turner S, Owen G, Bougueleret L, Xenarios I, Steinbeck C (2012) Rhea—a manually curated resource of biochemical reactions. Nucleic Acids Res 40:D754–D760, Database issueCrossRefGoogle Scholar
  7. Alper H, Jin YS, Moxley JF, Stephanopoulos G (2005a) Identifying gene targets for the metabolic engineering of lycopene biosynthesis in Escherichia coli. Metab Eng 7(3):155–164CrossRefGoogle Scholar
  8. Alper H, Miyaoku K, Stephanopoulos G (2005b) Construction of lycopene-overproducing E. coli strains by combining systematic and combinatorial gene knockout targets. Nat Biotechnol 23(5):612–616CrossRefGoogle Scholar
  9. Archer CT, Kim JF, Jeong H, Park JH, Vickers CE, Lee SY, Nielsen LK (2011) The genome sequence of E. coli W (ATCC 9637): comparative genome analysis and an improved genome-scale reconstruction of E. coli. BMC Genomics 12:9CrossRefGoogle Scholar
  10. 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):328–334CrossRefGoogle Scholar
  11. Baart GJ, Martens DE (2012) Genome-scale metabolic models: reconstruction and analysis. Methods Mol Biol 799:107–126CrossRefGoogle Scholar
  12. Baginsky S, Hennig L, Zimmermann P, Gruissem W (2010) Gene expression analysis, proteomics, and network discovery. Plant Physiol 152(2):402–410CrossRefGoogle Scholar
  13. Becker J, Wittmann C (2012) Systems and synthetic metabolic engineering for amino acid production—the heartbeat of industrial strain development. Curr Opin Biotechnol. doi: 10.1016/j.copbio.2011.12.025
  14. Becker J, Zelder O, Hafner S, Schroder H, Wittmann C (2011) From zero to hero–design-based systems metabolic engineering of Corynebacterium glutamicum for l-lysine production. Metab Eng 13(2):159–168CrossRefGoogle Scholar
  15. Blazeck J, Alper H (2010) Systems metabolic engineering: genome-scale models and beyond. Biotechnol J 5(7):647–659CrossRefGoogle Scholar
  16. Bochner BR (2009) Global phenotypic characterization of bacteria. FEMS Microbiol Rev 33(1):191–205CrossRefGoogle Scholar
  17. Boghigian BA, Armando J, Salas D, Pfeifer BA (2012) Computational identification of gene over-expression targets for metabolic engineering of taxadiene production. Appl Microbiol Biotechnol 93(5):2063–2073CrossRefGoogle Scholar
  18. Borodina I, Krabben P, Nielsen J (2005) Genome-scale analysis of Streptomyces coelicolor A3(2) metabolism. Genome Res 15(6):820–829CrossRefGoogle Scholar
  19. Borodina I, Siebring J, Zhang J, Smith CP, van Keulen G, Dijkhuizen L, Nielsen J (2008) Antibiotic overproduction in Streptomyces coelicolor A3 2 mediated by phosphofructokinase deletion. J Biol Chem 283(37):25186–25199CrossRefGoogle Scholar
  20. 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):102–111CrossRefGoogle Scholar
  21. 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 9:84CrossRefGoogle Scholar
  22. 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):647–657CrossRefGoogle Scholar
  23. Burgard AP, Nikolaev EV, Schilling CH, Maranas CD (2004) Flux coupling analysis of genome-scale metabolic network reconstructions. Genome Res 14(2):301–312CrossRefGoogle Scholar
  24. Bushell ME, Sequeira SIP, Khannapho C, Zhao H, Chater KF, Butler MJ, Kierzek AM, Avignone-Rossa CA (2006) The use of genome scale metabolic flux variability analysis for process feed formulation based on an investigation of the effects of the zwf mutation on antibiotic production in Streptomyces coelicolor. Enzym Microb Technol 39(6):1347–1353CrossRefGoogle Scholar
  25. Capecchi MR (1989) Altering the genome by homologous recombination. Science 244(4910):1288–1292CrossRefGoogle Scholar
  26. Caspi R, Altman T, Dreher K, Fulcher CA, Subhraveti P, Keseler IM, Kothari A, Krummenacker M, Latendresse M, Mueller LA, Ong Q, Paley S, Pujar A, Shearer AG, Travers M, Weerasinghe D, Zhang P, Karp PD (2012) The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of pathway/genome databases. Nucleic Acids Res 40:D742–D753, Database issueCrossRefGoogle Scholar
  27. Chang RL, Ghamsari L, Manichaikul A, Hom EF, Balaji S, Fu W, Shen Y, Hao T, Palsson BO, Salehi-Ashtiani K, Papin JA (2011) Metabolic network reconstruction of Chlamydomonas offers insight into light-driven algal metabolism. Mol Syst Biol 7:518CrossRefGoogle Scholar
  28. Chavali AK, D’Auria KM, Hewlett EL, Pearson RD, Papin JA (2012) A metabolic network approach for the identification and prioritization of antimicrobial drug targets. Trends Microbiol 20(3):113–123CrossRefGoogle Scholar
  29. Chemler JA, Fowler ZL, McHugh KP, Koffas MA (2010) Improving NADPH availability for natural product biosynthesis in Escherichia coli by metabolic engineering. Metab Eng 12(2):96–104CrossRefGoogle Scholar
  30. Chen M, Hofestadt R (2004) PathAligner: metabolic pathway retrieval and alignment. Appl Bioinformatics 3(4):241–252CrossRefGoogle Scholar
  31. Chen M, Hariharaputran S, Hofestädt R, Kormeier B, Spangardt S (2011) Petri net models for the semi-automatic construction of large scale biological networks. Nat Comput 10(3):1077–1097CrossRefGoogle Scholar
  32. Choi HS, Lee SY, Kim TY, Woo HM (2010) In silico identification of gene amplification targets for improvement of lycopene production. Appl Environ Microbiol 76(10):3097–3105CrossRefGoogle Scholar
  33. Clinton SK (1998) Lycopene: chemistry, biology, and implications for human health and disease. Nutr Rev 56(2):35–51CrossRefGoogle Scholar
  34. Copeland WB, Bartley BA, Chandran D, Galdzicki M, Kim KH, Sleight SC, Maranas CD, Sauro HM (2012) Computational tools for metabolic engineering. Metab Eng. doi: 10.1016/j.ymben.2012.03.001
  35. Coppi MV, Leang C, Sandler SJ, Lovley DR (2001) Development of a genetic system for Geobacter sulfurreducens. Appl Environ Microbiol 67(7):3180–3187CrossRefGoogle Scholar
  36. Curran KA, Alper HS (2012) Expanding the chemical palate of cells by combining systems biology and metabolic engineering. Metab Eng 14(4):289–297CrossRefGoogle Scholar
  37. Cvijovic M, Olivares-Hernandez R, Agren R, Dahr N, Vongsangnak W, Nookaew I, Patil KR, Nielsen J (2010) BioMet Toolbox: genome-wide analysis of metabolism. Nucleic Acids Res 38:W144–W149, Web Server issueCrossRefGoogle Scholar
  38. de Lorenzo V (2008) Systems biology approaches to bioremediation. Curr Opin Biotechnol 19(6):579–589CrossRefGoogle Scholar
  39. de Oliveira Dal’Molin CG, Quek LE, Palfreyman RW, Brumbley SM, Nielsen LK (2010) AraGEM, a genome-scale reconstruction of the primary metabolic network in Arabidopsis. Plant Physiol 152(2):579–589CrossRefGoogle Scholar
  40. de Oliveira Dal’Molin CG, Quek LE, Palfreyman RW, Nielsen LK (2011) AlgaGEM—a genome-scale metabolic reconstruction of algae based on the Chlamydomonas reinhardtii genome. BMC Genomics 12(Suppl 4):S5CrossRefGoogle Scholar
  41. Delgado J, Liao JC (1997) Inverse flux analysis for reduction of acetate excretion in Escherichia coli. Biotechnol Prog 13(4):361–367CrossRefGoogle Scholar
  42. Duarte NC, Herrgard MJ, Palsson BO (2004) Reconstruction and validation of Saccharomyces cerevisiae iND750, a fully compartmentalized genome-scale metabolic model. Genome Res 14(7):1298–1309CrossRefGoogle Scholar
  43. 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):1777–1782CrossRefGoogle Scholar
  44. Ducat DC, Way JC, Silver PA (2011) Engineering cyanobacteria to generate high-value products. Trends Biotechnol 29(2):95–103CrossRefGoogle Scholar
  45. Durot M, Le Fevre F, de Berardinis V, Kreimeyer A, Vallenet D, Combe C, Smidtas S, Salanoubat M, Weissenbach J, Schachter V (2008) Iterative reconstruction of a global metabolic model of Acinetobacter baylyi ADP1 using high-throughput growth phenotype and gene essentiality data. BMC Syst Biol 2:85CrossRefGoogle Scholar
  46. Durot M, Bourguignon PY, Schachter V (2009) Genome-scale models of bacterial metabolism: reconstruction and applications. FEMS Microbiol Rev 33(1):164–190CrossRefGoogle Scholar
  47. Edwards JS, Palsson BO (1999) Systems properties of the Haemophilus influenzae Rd metabolic genotype. J Biol Chem 274(25):17410CrossRefGoogle Scholar
  48. Edwards J, Palsson B (2000) The Escherichia coli MG1655 in silico metabolic genotype: its definition, characteristics, and capabilities. Proc Natl Acad Sci 97(10):5528–5533CrossRefGoogle Scholar
  49. Farmer WR, Liao JC (2000) Improving lycopene production in Escherichia coli by engineering metabolic control. Nat Biotechnol 18(5):533–537CrossRefGoogle Scholar
  50. Feist AM, Palsson BO (2008) The growing scope of applications of genome-scale metabolic reconstructions using Escherichia coli. Nat Biotechnol 26(6):659–667CrossRefGoogle Scholar
  51. Feist AM, Scholten JC, Palsson BO, Brockman FJ, Ideker T (2006) Modeling methanogenesis with a genome-scale metabolic reconstruction of Methanosarcina barkeri. Mol Syst Biol 2(2006):0004Google Scholar
  52. 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 3:121CrossRefGoogle Scholar
  53. Feist AM, Herrgard MJ, Thiele I, Reed JL, Palsson BO (2009) Reconstruction of biochemical networks in microorganisms. Nat Rev Microbiol 7(2):129–143Google Scholar
  54. Fleischmann RD, Adams MD, White O, Clayton RA, Kirkness EF, Kerlavage AR, Bult CJ, Tomb JF, Dougherty BA, Merrick JM (1995) Whole-genome random sequencing and assembly of Haemophilus influenzae Rd. Science 269(5223):496CrossRefGoogle Scholar
  55. 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):643–648CrossRefGoogle Scholar
  56. Forster J, Famili I, Fu P, Palsson BO, Nielsen J (2003) Genome-scale reconstruction of the Saccharomyces cerevisiae metabolic network. Genome Res 13(2):244–253CrossRefGoogle Scholar
  57. Forth T, McConkey GA, Westhead DR (2010) MetNetMaker: a free and open-source tool for the creation of novel metabolic networks in SBML format. Bioinformatics 26(18):2352–2353CrossRefGoogle Scholar
  58. Fowler ZL, Gikandi WW, Koffas MA (2009) Increased malonyl coenzyme A biosynthesis by tuning the Escherichia coli metabolic network and its application to flavanone production. Appl Environ Microbiol 75(18):5831–5839CrossRefGoogle Scholar
  59. Fu P (2009) Genome-scale modeling of Synechocystis sp. PCC 6803 and prediction of pathway insertion. J Chem Technol Biotechnol 84(4):473–483CrossRefGoogle Scholar
  60. Gerster H (1997) The potential role of lycopene for human health. J Am Coll Nutr 16(2):109–126Google Scholar
  61. Goto S, Nishioka T, Kanehisa M (1998) LIGAND: chemical database for enzyme reactions. Bioinformatics 14(7):591–599CrossRefGoogle Scholar
  62. Gowen CM, Fong SS (2011) Applications of systems biology towards microbial fuel production. Trends Microbiol 19(10):516–524CrossRefGoogle Scholar
  63. Hall N (2007) Advanced sequencing technologies and their wider impact in microbiology. J Exp Biol 210(9):1518–1525CrossRefGoogle Scholar
  64. Hansen EH, Moller BL, Kock GR, Bunner CM, Kristensen C, Jensen OR, Okkels FT, Olsen CE, Motawia MS, Hansen J (2009) De novo biosynthesis of vanillin in fission yeast (Schizosaccharomyces pombe) and baker’s yeast (Saccharomyces cerevisiae). Appl Environ Microbiol 75(9):2765–2774CrossRefGoogle Scholar
  65. Hatzimanikatis V, Li C, Ionita JA, Henry CS, Jankowski MD, Broadbelt LJ (2005) Exploring the diversity of complex metabolic networks. Bioinformatics 21(8):1603–1609CrossRefGoogle Scholar
  66. Henry CS, Zinner JF, Cohoon MP, Stevens RL (2009) iBsu1103: a new genome-scale metabolic model of Bacillus subtilis based on SEED annotations. Genome Biol 10(6):R69CrossRefGoogle Scholar
  67. 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):977–982CrossRefGoogle Scholar
  68. Hjersted JL, Henson MA, Mahadevan R (2007) Genome-scale analysis of Saccharomyces cerevisiae metabolism and ethanol production in fed-batch culture. Biotechnol Bioeng 97(5):1190–1204CrossRefGoogle Scholar
  69. Huang D, Huang Y, Bai Y, Chen D, Hofestadt R, Klukas C, Chen M (2011) MyBioNet: interactively visualize, edit and merge biological networks on the web. Bioinformatics 27(23):3321–3322CrossRefGoogle Scholar
  70. Huang D, Wen J, Wang G, Yu G, Jia X, Chen Y (2012) In silico aided metabolic engineering of Streptomyces roseosporus for daptomycin yield improvement. Appl Microbiol Biotechnol. doi: 10.1007/s00253-011-3773-6
  71. Huthmacher C, Hoppe A, Bulik S, Holzhutter HG (2010) Antimalarial drug targets in Plasmodium falciparum predicted by stage-specific metabolic network analysis. BMC Syst Biol 4:120CrossRefGoogle Scholar
  72. Imam S, Yilmaz S, Sohmen U, Gorzalski AS, Reed JL, Noguera DR, Donohue TJ (2011) iRsp1095: a genome-scale reconstruction of the Rhodobacter sphaeroides metabolic network. BMC Syst Biol 5:116CrossRefGoogle Scholar
  73. Islam MA, Edwards EA, Mahadevan R (2010) Characterizing the metabolism of Dehalococcoides with a constraint-based model. PLoS Comput Biol 6(8):e1000887CrossRefGoogle Scholar
  74. Izallalen M, Mahadevan R, Burgard A, Postier B, Didonato R Jr, Sun J, Schilling CH, Lovley DR (2008) Geobacter sulfurreducens strain engineered for increased rates of respiration. Metab Eng 10(5):267–275CrossRefGoogle Scholar
  75. Jang YS, Park JM, Choi S, Choi YJ, Seung DY, 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):989–1000Google Scholar
  76. Jin DF, Hu H, Liu DF, Ding HT, Jia XM, Zhao YH (2012) Optimization of a bacterial consortium for nitrobenzene degradation. Water Sci Technol 65(5):795–801CrossRefGoogle Scholar
  77. Jones CS, Mayfield SP (2012) Algae biofuels: versatility for the future of bioenergy. Curr Opin Biotechnol 23(3):346–351Google Scholar
  78. Jung YK, Kim TY, Park SJ, Lee SY (2010) Metabolic engineering of Escherichia coli for the production of polylactic acid and its copolymers. Biotechnol Bioeng 105(1):161–171CrossRefGoogle Scholar
  79. 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–D357, Database issueCrossRefGoogle Scholar
  80. Karp PD, Paley S, Romero P (2002) The pathway tools software. Bioinformatics 18(suppl 1):S225–S232CrossRefGoogle Scholar
  81. Kennedy CJ, Boyle PM, Waks Z, Silver PA (2009) Systems-level engineering of nonfermentative metabolism in yeast. Genetics 183(1):385–397CrossRefGoogle Scholar
  82. Kim J, Reed JL (2010) OptORF: optimal metabolic and regulatory perturbations for metabolic engineering of microbial strains. BMC Syst Biol 4:53CrossRefGoogle Scholar
  83. Kim PJ, Lee DY, Kim TY, Lee KH, Jeong H, Lee SY, Park S (2007) Metabolite essentiality elucidates robustness of Escherichia coli metabolism. Proc Natl Acad Sci U S A 104(34):13638–13642CrossRefGoogle Scholar
  84. Kim HU, Kim TY, Lee SY (2008a) Metabolic flux analysis and metabolic engineering of microorganisms. Mol Biosyst 4(2):113–120CrossRefGoogle Scholar
  85. Kim TY, Sohn SB, Kim HU, Lee SY (2008b) Strategies for systems-level metabolic engineering. Biotechnol J 3(5):612–623CrossRefGoogle Scholar
  86. Kim J, Reed JL, Maravelias CT (2011a) Large-scale bi-level strain design approaches and mixed-integer programming solution techniques. PLoS One 6(9):e24162CrossRefGoogle Scholar
  87. Kim TY, Sohn SB, Kim YB, Kim WJ, Lee SY (2011b) Recent advances in reconstruction and applications of genome-scale metabolic models. Curr Opin Biotechnol 23:1–7Google Scholar
  88. Kim HU, Sohn SB, Lee SY (2012a) Metabolic network modeling and simulation for drug targeting and discovery. Biotechnol J 7(3):330–342Google Scholar
  89. Kim TY, Sohn SB, Kim YB, Kim WJ, Lee SY (2012b) Recent advances in reconstruction and applications of genome-scale metabolic models. Curr Opin Biotechnol 23(4):617–623CrossRefGoogle Scholar
  90. Kjeldsen KR, Nielsen J (2009) In silico genome-scale reconstruction and validation of the Corynebacterium glutamicum metabolic network. Biotechnol Bioeng 102(2):583–597CrossRefGoogle Scholar
  91. Klinner U, Schäfer B (2004) Genetic aspects of targeted insertion mutagenesis in yeasts. FEMS Microbiol Rev 28(2):201–223CrossRefGoogle Scholar
  92. Latendresse M, Karp PD (2011) Web-based metabolic network visualization with a zooming user interface. BMC Bioinformatics 12:176CrossRefGoogle Scholar
  93. Le Borgne S (2012) Genetic engineering of industrial strains of Saccharomyces cerevisiae. Methods Mol Biol 824:451–465CrossRefGoogle Scholar
  94. Lee DY, Yun H, Park S, Lee SY (2003) MetaFluxNet: the management of metabolic reaction information and quantitative metabolic flux analysis. Bioinformatics 19(16):2144–2146CrossRefGoogle Scholar
  95. Lee SJ, Lee DY, Kim TY, Kim BH, Lee J, Lee SY (2005a) Metabolic engineering of Escherichia coli for enhanced production of succinic acid, based on genome comparison and in silico gene knockout simulation. Appl Environ Microbiol 71(12):7880–7887CrossRefGoogle Scholar
  96. Lee SY, Woo HM, Lee DY, Choi HS, Kim TY, Yun H (2005b) Systems-level analysis of genome-scalein silico metabolic models using MetaFluxNet. Biotechnol Bioproc Eng 10(5):425–431CrossRefGoogle Scholar
  97. Lee KH, Park JH, Kim TY, Kim HU, Lee SY (2007) Systems metabolic engineering of Escherichia coli for l-threonine production. Mol Syst Biol 3:149CrossRefGoogle Scholar
  98. Lee J, Yun H, Feist AM, Palsson BO, Lee SY (2008a) Genome-scale reconstruction and in silico analysis of the Clostridium acetobutylicum ATCC 824 metabolic network. Appl Microbiol Biotechnol 80(5):849–862CrossRefGoogle Scholar
  99. Lee SK, Chou H, Ham TS, Lee TS, Keasling JD (2008b) Metabolic engineering of microorganisms for biofuels production: from bugs to synthetic biology to fuels. Curr Opin Biotechnol 19(6):556–563CrossRefGoogle Scholar
  100. Lee JY, Jang YS, Lee J, Papoutsakis ET, Lee SY (2009a) Metabolic engineering of Clostridium acetobutylicum M5 for highly selective butanol production. Biotechnol J 4(10):1432–1440CrossRefGoogle Scholar
  101. Lee SY, Kim HU, Park JH, Park JM, Kim TY (2009b) Metabolic engineering of microorganisms: general strategies and drug production. Drug Discov Today 14(1–2):78–88CrossRefGoogle Scholar
  102. Lee KY, Park JM, Kim TY, Yun H, Lee SY (2010) The genome-scale metabolic network analysis of Zymomonas mobilis ZM4 explains physiological features and suggests ethanol and succinic acid production strategies. Microb Cell Fact 9:94CrossRefGoogle Scholar
  103. Lee JW, Kim HU, Choi S, Yi J, Lee SY (2011a) Microbial production of building block chemicals and polymers. Curr Opin Biotechnol 22(6):758–767CrossRefGoogle Scholar
  104. Lee JW, Kim TY, Jang YS, Choi S, Lee SY (2011b) Systems metabolic engineering for chemicals and materials. Trends Biotechnol 29(8):370–378CrossRefGoogle Scholar
  105. 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):536–546CrossRefGoogle Scholar
  106. Letunic I, Bork P (2011) Interactive tree of life v2: online annotation and display of phylogenetic trees made easy. Nucleic Acids Res 39:W475–W478, Web Server issueCrossRefGoogle Scholar
  107. Lewis NE, Nagarajan H, Palsson BO (2012) Constraining the metabolic genotype-phenotype relationship using a phylogeny of in silico methods. Nat Rev Microbiol. doi: 10.1038/nrmicro2737
  108. Li S, Huang D, Li Y, Wen J, Jia X (2012) Rational improvement of the engineered isobutanol-producing Bacillus subtilis by elementary mode analysis. Microb Cell Fact 11(1):101CrossRefGoogle Scholar
  109. Liao YC, Huang TW, Chen FC, Charusanti P, Hong JS, Chang HY, Tsai SF, Palsson BO, Hsiung CA (2011) An experimentally validated genome-scale metabolic reconstruction of Klebsiella pneumoniae MGH 78578, iYL1228. J Bacteriol 193(7):1710–1717CrossRefGoogle Scholar
  110. Liu L, Agren R, Bordel S, Nielsen J (2010) Use of genome-scale metabolic models for understanding microbial physiology. FEBS Lett 584(12):2556–2564CrossRefGoogle Scholar
  111. Lovley DR, Holmes DE, Nevin KP (2004) Dissimilatory Fe ((III)) and Mn (IV) reduction. Adv Microb Physiol 49:219–286CrossRefGoogle Scholar
  112. Lun DS, Rockwell G, Guido NJ, Baym M, Kelner JA, Berger B, Galagan JE, Church GM (2009) Large-scale identification of genetic design strategies using local search. Mol Syst Biol 5:296CrossRefGoogle Scholar
  113. 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 3:135CrossRefGoogle Scholar
  114. Mahadevan R, Bond DR, Butler JE, Esteve-Nunez A, Coppi MV, Palsson BO, Schilling CH, Lovley DR (2006) Characterization of metabolism in the Fe(III)-reducing organism Geobacter sulfurreducens by constraint-based modeling. Appl Environ Microbiol 72(2):1558–1568CrossRefGoogle Scholar
  115. Mardis ER (2008) Next-generation DNA sequencing methods. Annu Rev Genomics Hum Genet 9:387–402CrossRefGoogle Scholar
  116. Meng H, Wang Y, Hua Q, Zhang S, Wang X (2011) In silico analysis and experimental improvement of taxadiene heterologous biosynthesis in Escherichia coli. Biotechnol Bioproc Eng 16(2):205–215CrossRefGoogle Scholar
  117. Methe B, Nelson K, Eisen J, Paulsen I, Nelson W, Heidelberg J, Wu D, Wu M, Ward N, Beanan M (2003) Genome of Geobacter sulfurreducens: metal reduction in subsurface environments. Science 302(5652):1967CrossRefGoogle Scholar
  118. Milne CB, Kim PJ, Eddy JA, Price ND (2009) Accomplishments in genome-scale in silico modeling for industrial and medical biotechnology. Biotechnol J 4(12):1653–1670CrossRefGoogle Scholar
  119. 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 beijerinckiiNCIMB 8052. BMC Syst Biol 5:130CrossRefGoogle Scholar
  120. Mintz-Oron S, Meir S, Malitsky S, Ruppin E, Aharoni A, Shlomi T (2012) Reconstruction of Arabidopsis metabolic network models accounting for subcellular compartmentalization and tissue-specificity. Proc Natl Acad Sci U S A 109(1):339–344CrossRefGoogle Scholar
  121. Montagud A, Navarro E, Fernandez de Cordoba P, Urchueguia JF, Patil KR (2010) Reconstruction and analysis of genome-scale metabolic model of a photosynthetic bacterium. BMC Syst Biol 4:156CrossRefGoogle Scholar
  122. Montagud A, Zelezniak A, Navarro E, de Córdoba PF, Urchueguía JF, Patil KR (2011) Flux coupling and transcriptional regulation within the metabolic network of the photosynthetic bacterium Synechocystis sp. PCC6803. Biotechnol J 6(3):330–342CrossRefGoogle Scholar
  123. Moon SY, Hong SH, Kim TY, Lee SY (2008) Metabolic engineering of Escherichia coli for the production of malic acid. Biochem Eng J 40(2):312–320CrossRefGoogle Scholar
  124. Mukhopadhyay A, Redding AM, Rutherford BJ, Keasling JD (2008) Importance of systems biology in engineering microbes for biofuel production. Curr Opin Biotechnol 19(3):228–234CrossRefGoogle Scholar
  125. Ng CY, Jung MY, Lee J, Oh MK (2012) Production of 2,3-butanediol in Saccharomyces cerevisiae by in silico aided metabolic engineering. Microb Cell Fact 11:68CrossRefGoogle Scholar
  126. Nielsen LK (2008) On the reconstruction of the Mus musculus genome-scale metabolic network model. Genome Inform 21:253Google Scholar
  127. Nogales J, Palsson BO, Thiele I (2008) A genome-scale metabolic reconstruction of Pseudomonas putida KT2440: iJN746 as a cell factory. BMC Syst Biol 2:79CrossRefGoogle Scholar
  128. 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):2678–2683CrossRefGoogle Scholar
  129. Notebaart RA, van Enckevort FH, Francke C, Siezen RJ, Teusink B (2006) Accelerating the reconstruction of genome-scale metabolic networks. BMC Bioinformatics 7:296CrossRefGoogle Scholar
  130. Oberhardt MA, Palsson BO, Papin JA (2009) Applications of genome-scale metabolic reconstructions. Mol Syst Biol 5:320CrossRefGoogle Scholar
  131. Oberhardt MA, Puchalka J, Martins dos Santos VA, Papin JA (2011) Reconciliation of genome-scale metabolic reconstructions for comparative systems analysis. PLoS Comput Biol 7(3):e1001116CrossRefGoogle Scholar
  132. Oddone GM, Mills DA, Block DE (2009) A dynamic, genome-scale flux model of Lactococcus lactis to increase specific recombinant protein expression. Metab Eng 11(6):367–381CrossRefGoogle Scholar
  133. Oh YK, Palsson BO, Park SM, Schilling CH, Mahadevan R (2007) Genome-scale reconstruction of metabolic network in Bacillus subtilis based on high-throughput phenotyping and gene essentiality data. J Biol Chem 282(39):28791–28799CrossRefGoogle Scholar
  134. Oliveira AP, Nielsen J, Forster J (2005) Modeling Lactococcus lactis using a genome-scale flux model. BMC Microbiol 5:39CrossRefGoogle Scholar
  135. Orth JD, Thiele I, Palsson BO (2010) What is flux balance analysis? Nat Biotechnol 28(3):245–248CrossRefGoogle Scholar
  136. 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 7:535CrossRefGoogle Scholar
  137. Osterlund T, Nookaew I, Nielsen J (2012) Fifteen years of large scale metabolic modeling of yeast: developments and impacts. Biotechnol Adv 30(5):979–988Google Scholar
  138. Palsson B (2006) Systems biology: properties of reconstructed networks. Cambridge University Press, New York, NYGoogle Scholar
  139. Palsson B (2009) Metabolic systems biology. FEBS Lett 583(24):3900–3904CrossRefGoogle Scholar
  140. Papp B, Szappanos B, Notebaart RA (2011) Use of genome-scale metabolic models in evolutionary systems biology. Methods Mol Biol 759:483–497CrossRefGoogle Scholar
  141. Park JH, Lee SY (2008) Towards systems metabolic engineering of microorganisms for amino acid production. Curr Opin Biotechnol 19(5):454–460CrossRefGoogle Scholar
  142. 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):7797–7802CrossRefGoogle Scholar
  143. Park JM, Kim TY, Lee SY (2009) Constraints-based genome-scale metabolic simulation for systems metabolic engineering. Biotechnol Adv 27(6):979–988CrossRefGoogle Scholar
  144. Park JM, Kim TY, Lee SY (2010) Prediction of metabolic fluxes by incorporating genomic context and flux-converging pattern analyses. Proc Natl Acad Sci U S A 107(33):14931–14936CrossRefGoogle Scholar
  145. Park JH, Kim TY, Lee KH, Lee SY (2011) Fed-batch culture of Escherichia coli for l-valine production based on in silico flux response analysis. Biotechnol Bioeng 108(4):934–946CrossRefGoogle Scholar
  146. Pastink MI, Teusink B, Hols P, Visser S, de Vos WM, Hugenholtz J (2009) Genome-scale model of Streptococcus thermophilus LMG18311 for metabolic comparison of lactic acid bacteria. Appl Environ Microbiol 75(11):3627–3633CrossRefGoogle Scholar
  147. Patil KR, Akesson M, Nielsen J (2004) Use of genome-scale microbial models for metabolic engineering. Curr Opin Biotechnol 15(1):64–69CrossRefGoogle Scholar
  148. Patil KR, Rocha I, Forster J, Nielsen J (2005) Evolutionary programming as a platform for in silico metabolic engineering. BMC Bioinformatics 6:308CrossRefGoogle Scholar
  149. 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):1–13CrossRefGoogle Scholar
  150. Pharkya P, Burgard AP, Maranas CD (2004) OptStrain: a computational framework for redesign of microbial production systems. Genome Res 14(11):2367–2376CrossRefGoogle Scholar
  151. Pinchuk GE, Hill EA, Geydebrekht OV, De Ingeniis J, Zhang X, Osterman A, Scott JH, Reed SB, Romine MF, Konopka AE, Beliaev AS, Fredrickson JK, Reed JL (2010) Constraint-based model of Shewanella oneidensis MR-1 metabolism: a tool for data analysis and hypothesis generation. PLoS Comput Biol 6(6):e1000822CrossRefGoogle Scholar
  152. Pinney JW, Shirley MW, McConkey GA, Westhead DR (2005) metaSHARK: software for automated metabolic network prediction from DNA sequence and its application to the genomes of Plasmodium falciparum and Eimeria tenella. Nucleic Acids Res 33(4):1399–1409CrossRefGoogle Scholar
  153. Pitkanen E, Rousu J, Ukkonen E (2010) Computational methods for metabolic reconstruction. Curr Opin Biotechnol 21(1):70–77CrossRefGoogle Scholar
  154. Plata G, Hsiao TL, Olszewski KL, Llinas M, Vitkup D (2010) Reconstruction and flux-balance analysis of the Plasmodium falciparum metabolic network. Mol Syst Biol 6:408CrossRefGoogle Scholar
  155. Poolman MG, Miguet L, Sweetlove LJ, Fell DA (2009) A genome-scale metabolic model of Arabidopsis and some of its properties. Plant Physiol 151(3):1570–1581CrossRefGoogle Scholar
  156. Price ND, Reed JL, Palsson BO (2004) Genome-scale models of microbial cells: evaluating the consequences of constraints. Nat Rev Microbiol 2(11):886–897CrossRefGoogle Scholar
  157. Puchalka J, Oberhardt MA, Godinho M, Bielecka A, Regenhardt D, Timmis KN, Papin JA, Martins dos Santos VA (2008) Genome-scale reconstruction and analysis of the Pseudomonas putida KT2440 metabolic network facilitates applications in biotechnology. PLoS Comput Biol 4(10):e1000210CrossRefGoogle Scholar
  158. Ranganathan S, Maranas CD (2010) Microbial 1-butanol production: identification of non-native production routes and in silico engineering interventions. Biotechnol J 5(7):716–725CrossRefGoogle Scholar
  159. 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):e1000744CrossRefGoogle Scholar
  160. 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):R54CrossRefGoogle Scholar
  161. Risso C, Sun J, Zhuang K, Mahadevan R, DeBoy R, Ismail W, Shrivastava S, Huot H, Kothari S, Daugherty S, Bui O, Schilling CH, Lovley DR, Methe BA (2009) Genome-scale comparison and constraint-based metabolic reconstruction of the facultative anaerobic Fe(III)-reducer Rhodoferax ferrireducens. BMC Genomics 10:447CrossRefGoogle Scholar
  162. Roberts SB, Gowen CM, Brooks JP, Fong SS (2010) Genome-scale metabolic analysis of Clostridium thermocellum for bioethanol production. BMC Syst Biol 4:31CrossRefGoogle Scholar
  163. Rocha I, Forster J, Nielsen J (2008) Design and application of genome-scale reconstructed metabolic models. Methods Mol Biol 416:409–431CrossRefGoogle Scholar
  164. 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 4:45CrossRefGoogle Scholar
  165. Rokem JS, Vongsangnak W, Nielsen J (2011) Comparative metabolic capabilities for Micrococcus luteus NCTC 2665, the “Fleming” strain, and actinobacteria. Biotechnol Bioeng 108(11):2770–2775CrossRefGoogle Scholar
  166. Saha R, Suthers PF, Maranas CD (2011) Zea mays iRS1563: a comprehensive genome-scale metabolic reconstruction of maize metabolism. PLoS One 6(7):e21784CrossRefGoogle Scholar
  167. Santala S, Efimova E, Kivinen V, Larjo A, Aho T, Karp M, Santala V (2011) Improved triacylglycerol production in Acinetobacter baylyi ADP1 by metabolic engineering. Microb Cell Fact 10:36CrossRefGoogle Scholar
  168. Satish Kumar V, Dasika MS, Maranas CD (2007) Optimization based automated curation of metabolic reconstructions. BMC Bioinformatics 8:212CrossRefGoogle Scholar
  169. Satish Kumar V, Ferry JG, Maranas CD (2011) Metabolic reconstruction of the archaeon methanogen Methanosarcina Acetivorans. BMC Syst Biol 5:28CrossRefGoogle Scholar
  170. Sayers EW, Barrett T, Benson DA, Bolton E, Bryant SH, Canese K, Chetvernin V, Church DM, DiCuccio M, Federhen S, Feolo M, Fingerman IM, Geer LY, Helmberg W, Kapustin Y, Landsman D, Lipman DJ, Lu Z, Madden TL, Madej T, Maglott DR, Marchler-Bauer A, Miller V, Mizrachi I, Ostell J, Panchenko A, Phan L, Pruitt KD, Schuler GD, Sequeira E, Sherry ST, Shumway M, Sirotkin K, Slotta D, Souvorov A, Starchenko G, Tatusova TA, Wagner L, Wang Y, Wilbur WJ, Yaschenko E, Ye J (2010) Database resources of the National Center for Biotechnology Information. Nucleic Acids Res 39:D38–D51, DatabaseCrossRefGoogle Scholar
  171. Scheer M, Grote A, Chang A, Schomburg I, Munaretto C, Rother M, Sohngen C, Stelzer M, Thiele J, Schomburg D (2011) BRENDA, the enzyme information system in 2011. Nucleic Acids Res 39:D670–D676, Database issueCrossRefGoogle Scholar
  172. Schellenberger J, Que R, Fleming RMT, Thiele I, Orth JD, Feist AM, Zielinski DC, Bordbar A, Lewis NE, Rahmanian S, Kang J, Hyduke DR, Palsson BØ (2011) Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox v2.0. Nat Protoc 6(9):1290–1307CrossRefGoogle Scholar
  173. Schuster SC (2008) Next-generation sequencing transforms today’s biology. Nat Methods 5:16–18Google Scholar
  174. Segre D, Vitkup D, Church GM (2002) Analysis of optimality in natural and perturbed metabolic networks. Proc Natl Acad Sci U S A 99(23):15112–15117CrossRefGoogle Scholar
  175. Selvarasu S, Karimi IA, Ghim GH, Lee DY (2010) Genome-scale modeling and in silico analysis of mouse cell metabolic network. Mol Biosyst 6(1):152–161CrossRefGoogle Scholar
  176. Senger RS, Papoutsakis ET (2008) Genome-scale model for Clostridium acetobutylicum: part I. Metabolic network resolution and analysis. Biotechnol Bioeng 101(5):1036–1052CrossRefGoogle Scholar
  177. Sheikh K, Förster J, Nielsen LK (2005) Modeling hybridoma cell metabolism using a generic genome–scale metabolic model of Mus musculus. Biotechnol Prog 21(1):112–121CrossRefGoogle Scholar
  178. 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 8:43CrossRefGoogle Scholar
  179. Shlomi T, Berkman O, Ruppin E (2005) Regulatory on/off minimization of metabolic flux changes after genetic perturbations. Proc Natl Acad Sci U S A 102(21):7695–7700CrossRefGoogle Scholar
  180. Sigurdsson MI, Jamshidi N, Steingrimsson E, Thiele I, Palsson BO (2010) A detailed genome-wide reconstruction of mouse metabolism based on human Recon 1. BMC Syst Biol 4:140CrossRefGoogle Scholar
  181. Sohn SB, Kim TY, Park JM, Lee SY (2010) In silico genome-scale metabolic analysis of Pseudomonas putida KT2440 for polyhydroxyalkanoate synthesis, degradation of aromatics and anaerobic survival. Biotechnol J 5(7):739–750CrossRefGoogle Scholar
  182. Stephanopoulos G (2007) Challenges in engineering microbes for biofuels production. Science 315(5813):801–804CrossRefGoogle Scholar
  183. Sun J, Sayyar B, Butler JE, Pharkya P, Fahland TR, Famili I, Schilling CH, Lovley DR, Mahadevan R (2009) Genome-scale constraint-based modeling of Geobacter metallireducens. BMC Syst Biol 3:15CrossRefGoogle Scholar
  184. Sun J, Haveman SA, Bui O, Fahland TR, Lovley DR (2010) Constraint-based modeling analysis of the metabolism of two Pelobacter species. BMC Syst Biol 4:174CrossRefGoogle Scholar
  185. Teusink B, Wiersma A, Molenaar D, Francke C, de Vos WM, Siezen RJ, Smid EJ (2006) Analysis of growth of Lactobacillus plantarum WCFS1 on a complex medium using a genome-scale metabolic model. J Biol Chem 281(52):40041–40048CrossRefGoogle Scholar
  186. Teusink B, Bachmann H, Molenaar D (2011) Systems biology of lactic acid bacteria: a critical review. Microb Cell Fact 10(Suppl 1):S11CrossRefGoogle Scholar
  187. Thiele I, Palsson BO (2010) A protocol for generating a high-quality genome-scale metabolic reconstruction. Nat Protoc 5(1):93–121CrossRefGoogle Scholar
  188. Tsoka S, Simon D, Ouzounis CA (2004) Automated metabolic reconstruction for Methanococcus jannaschii. Archaea 1:223–229CrossRefGoogle Scholar
  189. Tyo KE, Kocharin K, Nielsen J (2010) Toward design-based engineering of industrial microbes. Curr Opin Microbiol 13(3):255–262CrossRefGoogle Scholar
  190. van Ooyen J, Noack S, Bott M, Reth A, Eggeling L (2012) Improved l-lysine production with Corynebacterium glutamicum and systemic insight into citrate synthase flux and activity. Biotechnol Bioeng. doi: 10.1002/bit.24486
  191. Vongsangnak W, Figueiredo LF, Forster J, Weber T, Thykaer J, Stegmann E, Wohlleben W, Nielsen J (2012) Genome-scale metabolic representation of Amycolatopsis balhimycina. Biotechnol Bioeng. doi: 10.1002/bit.24436
  192. Wang Q, Chen X, Yang Y, Zhao X (2006) Genome-scale in silico aided metabolic analysis and flux comparisons of Escherichia coli to improve succinate production. Appl Microbiol Biotechnol 73(4):887–894CrossRefGoogle Scholar
  193. Widiastuti H, Kim JY, Selvarasu S, Karimi IA, Kim H, Seo JS, Lee DY (2011) Genome-scale modeling and in silico analysis of ethanologenic bacteria Zymomonas mobilis. Biotechnol Bioeng 108(3):655–665CrossRefGoogle Scholar
  194. Wiechert W (2002) Modeling and simulation: tools for metabolic engineering. J Biotechnol 94(1):37–63CrossRefGoogle Scholar
  195. Xu P, Ranganathan S, Fowler ZL, Maranas CD, Koffas MA (2011) Genome-scale metabolic network modeling results in minimal interventions that cooperatively force carbon flux towards malonyl-CoA. Metab Eng 13(5):578–587CrossRefGoogle Scholar
  196. Yan HD, Xu PY, Huang HC, Qiu JP (2009) Analysis of spectinomycin in fermentation broth by reversed-phase chromatography. Chem Pap 63(6):635–640CrossRefGoogle Scholar
  197. Yang TH, Kim TW, Kang HO, Lee SH, Lee EJ, Lim SC, Oh SO, Song AJ, Park SJ, Lee SY (2010) Biosynthesis of polylactic acid and its copolymers using evolved propionate CoA transferase and PHA synthase. Biotechnol Bioeng 105(1):150–160CrossRefGoogle Scholar
  198. Yang L, Cluett WR, Mahadevan R (2011) EMILiO: a fast algorithm for genome-scale strain design. Metab Eng 13(3):272–281CrossRefGoogle Scholar
  199. Yim H, Haselbeck R, Niu W, Pujol-Baxley C, Burgard A, Boldt J, Khandurina J, Trawick JD, Osterhout RE, Stephen R (2011) Metabolic engineering of Escherichia coli for direct production of 1, 4-butanediol. Nat Chem Biol 7(7):445–452CrossRefGoogle Scholar
  200. 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):347–358CrossRefGoogle Scholar
  201. Zelle RM, de Hulster E, van Winden WA, de Waard P, Dijkema C, Winkler AA, Geertman JM, van Dijken JP, Pronk JT, van Maris AJ (2008) Malic acid production by Saccharomyces cerevisiae: engineering of pyruvate carboxylation, oxaloacetate reduction, and malate export. Appl Environ Microbiol 74(9):2766–2777CrossRefGoogle Scholar
  202. Zhu Y, Zhang Y, Li Y (2009) Understanding the industrial application potential of lactic acid bacteria through genomics. Appl Microbiol Biotechnol 83(4):597–610CrossRefGoogle Scholar
  203. Ziegler A, Zaia J (2006) Size-exclusion chromatography of heparin oligosaccharides at high and low pressure. J Chromatogr B Analyt Technol Biomed Life Sci 837(1–2):76–863Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2012

Authors and Affiliations

  • Chuan Xu
    • 1
    • 2
  • Lili Liu
    • 2
  • Zhao Zhang
    • 2
    • 3
  • Danfeng Jin
    • 2
    • 4
  • Juanping Qiu
    • 1
  • Ming Chen
    • 2
    • 3
  1. 1.College of Biological and Environmental EngineeringZhejiang University of TechnologyHangzhouChina
  2. 2.Department of Bioinformatics, College of Life SciencesZhejiang UniversityHangzhouChina
  3. 3.Watson Institute of Genome SciencesZhejiang UniversityHangzhouChina
  4. 4.Institute of MicrobiologyZhejiang UniversityHangzhouChina

Personalised recommendations