13 C-metabolic flux analysis: An accurate approach to demystify microbial metabolism for biochemical production

Bioengineering

Volumn 3, Issue 1, 2016, Pages

  Guo, Weihua ^a   Sheng, Jiayuan ^a   Feng, Xueyang ^a  

^a Virginia Polytechnic Institute and State University   (United States)

Author keywords

Biofuels; Bottleneck; Cell metabolism; Cofactor imbalance; Isotope; Synthetic biology

Indexed keywords

EID: 85043369440     PISSN: None     EISSN: 23065354     Source Type: Journal    
DOI: 10.3390/bioengineering3010003     Document Type: Review

References (186)

1. Sheng, J.; Feng, X. Metabolic engineering of yeast to produce fatty acid-derived biofuels: Bottlenecks and solutions. Front. Microbiol. 2015, 6, 554. [CrossRef] [PubMed]
2. Shin, J.H.; Kim, H.U.; Kim, D.I.; Lee, S.Y. Production of bulk chemicals via novel metabolic pathways in microorganisms. Biotechnol. Adv. 2013, 31, 925–935. [CrossRef] [PubMed]
3. Weusthuis, R.A.; Lamot, I.; van der Oost, J.; Sanders, J.P.M. Microbial production of bulk chemicals: Development of anaerobic processes. Trends Biotechnol. 2011, 29, 153–158. [CrossRef] [PubMed]
4. Hermann, B.G.; Blok, K.; Patel, M.K. Producing bio-based bulk chemicals using industrial biotechnology saves energy and combats climate change. Environ. Sci. Technol. 2007, 41, 7915–7921. [CrossRef] [PubMed]
5. Stephanopoulos, G. Challenges in engineering microbes for biofuels production. Science 2007, 315, 801–804. [CrossRef] [PubMed]
6. Peralta-Yahya, P.P.; Keasling, J.D. Advanced biofuel production in microbes. Biotechnol. J. 2010, 5, 147–162. [CrossRef] [PubMed]
7. Peralta-Yahya, P.P.; Zhang, F.; del Cardayre, S.B.; Keasling, J.D. Microbial engineering for the production of advanced biofuels. Nature 2012, 488, 320–328. [CrossRef] [PubMed]
8. Lee, S.K.; Chou, H.; Ham, T.S.; Lee, T.S.; Keasling, J.D. Metabolic engineering of microorganisms for biofuels production: From bugs to synthetic biology to fuels. Curr. Opin. Biotechnol. 2008, 19, 556–563. [CrossRef] [PubMed]
9. Stephanopoulos, G. Metabolic engineering: Enabling technology for biofuels production. Metab. Eng. 2008, 10, 293–294. [CrossRef] [PubMed]
10. Ajikumar, P.K.; Xiao, W.-H.; Tyo, K.E.J.; Wang, Y.; Simeon, F.; Leonard, E.; Mucha, O.; Phon, T.H.; Pfeifer, B.; Stephanopoulos, G. Isoprenoid pathway optimization for taxol precursor overproduction in Escherichia coli. Science 2010, 330, 70–74. [CrossRef] [PubMed]
11. Lee, S.Y.; Kim, H.U.; Park, J.H.; Park, J.M.; Kim, T.Y. Metabolic engineering of microorganisms: General strategies and drug production. Drug Discov. Today 2009, 14, 78–88. [CrossRef] [PubMed]
12. Martin, V.J.J.; Pitera, D.J.; Withers, S.T.; Newman, J.D.; Keasling, J.D. Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat. Biotech. 2003, 21, 796–802. [CrossRef] [PubMed]
13. Chang, M.C.Y.; Keasling, J.D. Production of isoprenoid pharmaceuticals by engineered microbes. Nat. Chem. Biol. 2006, 2, 674–681. [CrossRef] [PubMed]
14. Demain, A.L.; Sanchez, S. Microbial drug discovery: 80 Years of progress. J. Antibiot. 2009, 62, 5–16. [CrossRef] [PubMed]
15. Ferrer-Miralles, N.; Domingo-Espín, J.; Corchero, J.L.; Vázquez, E.; Villaverde, A. Microbial factories for recombinant pharmaceuticals. Microb. Cell Fact. 2009, 8, 1–8. [CrossRef] [PubMed]
16. Keasling, J.D. Manufacturing molecules through metabolic engineering. Science 2010, 330, 1355–1358. [CrossRef] [PubMed]
17. Atsumi, S.; Cann, A.F.; Connor, M.R.; Shen, C.R.; Smith, K.M.; Brynildsen, M.P.; Chou, K.J.Y.; Hanai, T.; Liao, J.C. Metabolic engineering of Escherichia coli for 1-butanol production. Metab. Eng. 2008, 10, 305–311. [CrossRef] [PubMed]
18. Blattner, F.R.; Plunkett, G.; Bloch, C.A.; Perna, N.T.; Burland, V.; Riley, M.; Collado-Vides, J.; Glasner, J.D.; Rode, C.K.; Mayhew, G.F.; et al. The complete genome sequence of Escherichia coli k-12. Science 1997, 277, 1453–1462. [CrossRef] [PubMed]
19. Huang, C., Jr.; Lin, H.; Yang, X. Industrial production of recombinant therapeutics in Escherichia coli and its recent advancements. J. Ind. Microbiol. Biotechnol. 2012, 39, 383–399. [CrossRef] [PubMed]
20. Alper, H.; Miyaoku, K.; Stephanopoulos, G. Construction of lycopene-overproducing E. Coli strains by combining systematic and combinatorial gene knockout targets. Nat. Biotech. 2005, 23, 612–616. [CrossRef] [PubMed]
21. Farmer, W.R.; Liao, J.C. Improving lycopene production in Escherichia coli by engineering metabolic control. Nat. Biotech. 2000, 18, 533–537.
22. Clomburg, J.; Gonzalez, R. Biofuel production in Escherichia coli: The role of metabolic engineering and synthetic biology. Appl. Microbiol. Biotechnol. 2010, 86, 419–434. [CrossRef] [PubMed]
23. Borneman, A.R.; Desany, B.A.; Riches, D.; Affourtit, J.P.; Forgan, A.H.; Pretorius, I.S.; Egholm, M.; Chambers, P.J. Whole-genome comparison reveals novel genetic elements that characterize the genome of industrial strains of Saccharomyces cerevisiae. PLoS Genet. 2011, 7, e1001287. [CrossRef] [PubMed]
24. Ostergaard, S.; Olsson, L.; Nielsen, J. Metabolic engineering of saccharomyces cerevisiae. Microbiol. Mol. Biol. Rev. 2000, 64, 34–50. [CrossRef] [PubMed]
25. Giaever, G.; Chu, A.M.; Ni, L.; Connelly, C.; Riles, L.; Veronneau, S.; Dow, S.; Lucau-Danila, A.; Anderson, K.; Andre, B.; et al. Functional profiling of the saccharomyces cerevisiae genome. Nature 2002, 418, 387–391. [CrossRef] [PubMed]
26. Nielsen, J.; Jewett, M.C. Impact of Systems Biology on Metabolic Engineering of Saccharomyces cerevisiae. FEMS Yeast Res. 2008, 8, 122–131. [CrossRef] [PubMed]
27. Chen, G.-Q. New challenges and opportunities for industrial biotechnology. Microb. Cell Fact. 2012, 11, 111. [CrossRef] [PubMed]
28. Kwok, R. Five hard truths for synthetic biology. Nature 2010, 463, 288. [CrossRef] [PubMed]
29. Antoniewicz, M. Methods and advances in metabolic flux analysis: A mini-review. J. Ind. Microbiol. Biotechnol. 2015, 42, 317–325. [CrossRef] [PubMed]
30. Young, J.D. 13c metabolic flux analysis of recombinant expression hosts. Curr. Opin. Biotechnol. 2014, 30, 238–245. [CrossRef] [PubMed]
31. Wang, Y.; San, K.-Y.; Bennett, G.N. Cofactor engineering for advancing chemical biotechnology. Curr. Opin. Biotechnol. 2013, 24, 994–999. [CrossRef] [PubMed]
32. Wasylenko, T.M.; Ahn, W.S.; Stephanopoulos, G. The oxidative pentose phosphate pathway is the primary source of nadph for lipid overproduction from glucose in Yarrowia lipolytica. Metab. Eng. 2015, 30, 27–39. [CrossRef] [PubMed]
33. Hollinshead, W.D.; Henson, W.R.; Abernathy, M.; Moon, T.S.; Tang, Y.J. Rapid metabolic analysis of rhodococcus opacus pd630 via parallel 13c-metabolite fingerprinting. Biotechnol. Bioeng. 2015, 113, 91–100. [CrossRef] [PubMed]
34. Hayakawa, K.; Kajihata, S.; Matsuda, F.; Shimizu, H. 13c-metabolic flux analysis in s-adenosyl-l-methionine production by saccharomyces cerevisiae. J. Biosci. Bioeng. 2015. [CrossRef] [PubMed]
35. Feng, X.; Zhao, H. Investigating xylose metabolism in recombinant saccharomyces cerevisiae via 13c metabolic flux analysis. Microb. Cell Fact. 2013, 12, 114. [CrossRef] [PubMed]
36. Lam, F.H.; Ghaderi, A.; Fink, G.R.; Stephanopoulos, G. Engineering alcohol tolerance in yeast. Science 2014, 346, 71–75. [CrossRef] [PubMed]
37. Fu, Y.; Yoon, J.; Jarboe, L.; Shanks, J. Metabolic flux analysis of Escherichia coli mg1655 under octanoic acid (c8) stress. Appl. Microbiol. Biotechnol. 2015, 99, 4397–4408. [CrossRef] [PubMed]
38. Heer, D.; Heine, D.; Sauer, U. Resistance of Saccharomyces cerevisiae to high concentrations of furfural is based on nadph-dependent reduction by at least two oxireductases. Appl. Environ. Microbiol. 2009, 75, 7631–7638. [CrossRef] [PubMed]
39. Çakar, Z.P.; Seker, U.O.S.; Tamerler, C.; Sonderegger, M.; Sauer, U. Evolutionary engineering of multiple-stress resistant Saccharomyces cerevisiae. FEMS Yeast Res. 2005, 5, 569–578. [CrossRef] [PubMed]
40. Wittmann, C.; Heinzle, E. Mass spectrometry for metabolic flux analysis. Biotechnol. Bioeng. 1999, 62, 739–750. [CrossRef]
41. Wiechert, W. 13c metabolic flux analysis. Metab. Eng. 2001, 3, 195–206. [CrossRef] [PubMed]
42. Dauner, M.; Sauer, U. Gc-ms analysis of amino acids rapidly provides rich information for isotopomer balancing. Biotechnol. Prog. 2000, 16, 642–649. [CrossRef] [PubMed]
43. 13 c labelling and nmr spectroscopy in metabolic flux analysis. In Nmr in Biotechnology: Theory and Applications; Barbotin, J.N., Portais, J.C., Eds.; Horizon Scientific Press: Norwich, UK, 2000; Chapter 4.
44. Christensen, B.; Nielsen, J. Isotopomer analysis using gc-ms. Metab. Eng. 1999, 1, 282–290. [CrossRef] [PubMed]
45. SZYPERSKI, T. 13c-nmr, ms and metabolic flux balancing in biotechnology research. Q. Rev. Biophys. 1998, 31, 41–106. [CrossRef] [PubMed]
46. Feng, X.; Zhuang, W.-Q.; Colletti, P.; Tang, Y. Metabolic pathway determination and flux analysis in nonmodel microorganisms through 13c-isotope labeling. In Microbial Systems Biology; Navid, A., Ed.; Humana Press: New York, NY, USA, 2012; Volume 881, pp. 309–330.
47. You, L.; Page, L.; Feng, X.; Berla, B.; Pakrasi, H.B.; Tang, Y.J. Metabolic pathway confirmation and discovery through (13)c-labeling of proteinogenic amino acids. J. Vis. Exp. 2012, 59, e3583. [CrossRef] [PubMed]
48. Sauer, U. Metabolic Networks in Motion: 13c-Based Flux Analysis. Mol. Syst. Biol. 2006, 2, 62–72. [CrossRef] [PubMed]
49. Tang, Y.J.; Martin, H.G.; Myers, S.; Rodriguez, S.; Baidoo, E.E.K.; Keasling, J.D. Advances in analysis of microbial metabolic fluxes via 13c isotopic labeling. Mass Spectrom. Rev. 2009, 28, 362–375. [CrossRef] [PubMed]
50. Lian, J.; Si, T.; Nair, N.U.; Zhao, H. Design and construction of acetyl-coa overproducing saccharomyces cerevisiae strains. Metab. Eng. 2014, 24, 139–149. [CrossRef] [PubMed]
51. Papini, M.; Nookaew, I.; Siewers, V.; Nielsen, J. Physiological characterization of recombinant saccharomyces cerevisiae expressing the aspergillus nidulans phosphoketolase pathway: Validation of activity through 13c-based metabolic flux analysis. Appl. Microbiol. Biotechnol. 2012, 95, 1001–1010. [CrossRef] [PubMed]
52. Wang, Y.; San, K.-Y.; Bennett, G. Improvement of nadph bioavailability in Escherichia coli by replacing nad+-dependent glyceraldehyde-3-phosphate dehydrogenase gapa with nadp+-dependent gapb from bacillus subtilis and addition of nad kinase. J. Ind. Microbiol. Biotechnol. 2013, 40, 1449–1460. [CrossRef] [PubMed]
53. Bartek, T.; Blombach, B.; Lang, S.; Eikmanns, B.J.; Wiechert, W.; Oldiges, M.; Nöh, K.; Noack, S. Comparative 13c metabolic flux analysis of pyruvate dehydrogenase complex-deficient, l-valine-producing corynebacterium glutamicum. Appl. Environ. Microbiol. 2011, 77, 6644–6652. [CrossRef] [PubMed]
54. Hou, J.; Vemuri, G.; Bao, X.; Olsson, L. Impact of overexpressing nadh kinase on glucose and xylose metabolism in recombinant xylose-utilizing saccharomyces cerevisiae. Appl. Microbiol. Biotechnol. 2009, 82, 909–919. [PubMed]
55. Berríos-Rivera, S.J.; Bennett, G.N.; San, K.-Y. Metabolic engineering of Escherichia coli: Increase of nadh availability by overexpressing an nad+-dependent formate dehydrogenase. Metab. Eng. 2002, 4, 217–229.
56. He, L.; Xiao, Y.; Gebreselassie, N.; Zhang, F.; Antoniewicz, M.R.; Tang, Y.J.; Peng, L. Central metabolic responses to the overproduction of fatty acids in Escherichia coli based on 13c-metabolic flux analysis. Biotechnol. Bioeng. 2014, 111, 575–585. [CrossRef] [PubMed]
57. Ranganathan, S.; Tee, T.W.; Chowdhury, A.; Zomorrodi, A.R.; Yoon, J.M.; Fu, Y.; Shanks, J.V.; Maranas, C.D. An integrated computational and experimental study for overproducing fatty acids in Escherichia coli. Metab. Eng. 2012, 14, 687–704. [CrossRef] [PubMed]
58. Zamboni, N.; Fendt, S.-M.; Ruhl, M.; Sauer, U. 13c-based metabolic flux analysis. Nat. Protocols 2009, 4, 878–892. [CrossRef] [PubMed]
59. Pingitore, F.; Tang, Y.; Kruppa, G.H.; Keasling, J.D. Analysis of amino acid isotopomers using ft-icr ms. Anal. Chem. 2007, 79, 2483–2490. [CrossRef] [PubMed]
60. Guo, W.; Luo, S.; He, Z.; Feng, X. 13c pathway analysis of biofilm metabolism of shewanella oneidensis mr-1. RSC Adv. 2015, 5, 39840–39843. [CrossRef]
61. Iwatani, S.; Van Dien, S.; Shimbo, K.; Kubota, K.; Kageyama, N.; Iwahata, D.; Miyano, H.; Hirayama, K.; Usuda, Y.; Shimizu, K.; et al. Determination of metabolic flux changes during fed-batch cultivation from measurements of intracellular amino acids by lc-ms/ms. J. Biotechnol. 2007, 128, 93–111. [CrossRef] [PubMed]
62. Millard, P.; Letisse, F.; Sokol, S.; Portais, J.-C. Isocor: Correcting ms data in isotope labeling experiments. Bioinformatics 2012, 28, 1294–1296. [CrossRef] [PubMed]
63. Wahl, S.A.; Dauner, M.; Wiechert, W. New tools for mass isotopomer data evaluation in 13c flux analysis: Mass isotope correction, data consistency checking, and precursor relationships. Biotechnol. Bioeng. 2004, 85, 259–268. [CrossRef] [PubMed]
64. Zhang, Z.; Shen, T.; Rui, B.; Zhou, W.; Zhou, X.; Shang, C.; Xin, C.; Liu, X.; Li, G.; Jiang, J.; et al. Cecafdb: A curated database for the documentation, visualization and comparative analysis of central carbon metabolic flux distributions explored by 13c-fluxomics. Nucleic Acids Res. 2014. [CrossRef] [PubMed]
65. (13) c-mfa modeling software package adjusted for the comprehensive analysis of single and parallel labeling experiments. Microb. Cell Fact. 2014, 13, 152. [CrossRef] [PubMed]
66. Weitzel, M.; Nöh, K.; Dalman, T.; Niedenführ, S.; Stute, B.; Wiechert, W. 13cflux2—high-performance software suite for 13c-metabolic flux analysis. Bioinformatics 2013, 29, 143–145. [CrossRef] [PubMed]
67. Antoniewicz, M.R.; Kelleher, J.K.; Stephanopoulos, G. Elementary metabolite units (emu): A novel framework for modeling isotopic distributions. Metab. Eng. 2007, 9, 68–86. [CrossRef] [PubMed]
68. Young, J.D. Inca: A computational platform for isotopically non-stationary metabolic flux analysis. Bioinformatics 2014, 30, 1333–1335. [CrossRef] [PubMed]
69. Zamboni, N.; Fischer, E.; Sauer, U. Fiatflux—A software for metabolic flux analysis from (13)c-glucose experiments. BMC Bioinf. 2005, 6, 209. [CrossRef] [PubMed]
70. Garcia-Albornoz, M.; Thankaswamy-Kosalai, S.; Nilsson, A.; Väremo, L.; Nookaew, I.; Nielsen, J. Biomet toolbox 2.0: Genome-wide analysis of metabolism and omics data. Nucleic Acids Res. 2014, 42, W175–W181. [CrossRef] [PubMed]
71. Young, J.D.; Walther, J.L.; Antoniewicz, M.R.; Yoo, H.; Stephanopoulos, G. An elementary metabolite unit (emu) based method of isotopically nonstationary flux analysis. Biotechnol. Bioeng. 2008, 99, 686–699. [CrossRef] [PubMed]
72. Chopra, P.; Kamma, A. Engineering life through synthetic biology. Silico Biol. 2006, 6, 401–410.
73. Hong, K.-K.; Nielsen, J. Metabolic engineering of saccharomyces cerevisiae: A key cell factory platform for future biorefineries. Cell. Mol. Life Sci. 2012, 69, 2671–2690. [CrossRef] [PubMed]
74. Nielsen, J.; Jewett, M.C. Impact of systems biology on metabolic engineering of saccharomyces cerevisiae. FEMS Yeast Res. 2008, 8, 122–131. [CrossRef] [PubMed]
75. Bro, C.; Regenberg, B.; Förster, J.; Nielsen, J. In silico aided metabolic engineering of saccharomyces cerevisiae for improved bioethanol production. Metab. Eng. 2006, 8, 102–111. [CrossRef] [PubMed]
76. Overkamp, K.M.; Bakker, B.M.; Kötter, P.; Luttik, M.A.H.; van Dijken, J.P.; Pronk, J.T. Metabolic engineering of glycerol production in saccharomyces cerevisiae. Appl. Environ. Microbiol. 2002, 68, 2814–2821. [CrossRef] [PubMed]
77. Feng, X.; Lian, J.; Zhao, H. Metabolic engineering of saccharomyces cerevisiae to improve 1-hexadecanol production. Metab. Eng. 2015, 27, 10–19. [CrossRef] [PubMed]
78. Runguphan, W.; Keasling, J.D. Metabolic engineering of saccharomyces cerevisiae for production of fatty acid-derived biofuels and chemicals. Metab. Eng. 2014, 21, 103–113. [CrossRef] [PubMed]
79. DeJong, J.M.; Liu, Y.; Bollon, A.P.; Long, R.M.; Jennewein, S.; Williams, D.; Croteau, R.B. Genetic engineering of taxol biosynthetic genes in saccharomyces cerevisiae. Biotechnol. Bioeng. 2006, 93, 212–224. [CrossRef] [PubMed]
80. Ro, D.-K.; Paradise, E.M.; Ouellet, M.; Fisher, K.J.; Newman, K.L.; Ndungu, J.M.; Ho, K.A.; Eachus, R.A.; Ham, T.S.; Kirby, J.; et al. Production of the antimalarial drug precursor artemisinic acid in engineered yeast. Nature 2006, 440, 940–943. [CrossRef] [PubMed]
81. Yamano, S.; Ishii, T.; Nakagawa, M.; Ikenaga, H.; Misawa, N. Metabolic engineering for production of β-carotene and lycopene in saccharomyces cerevisiae. Biosci. Biotechnol. Biochem. 1994, 58, 1112–1114. [CrossRef] [PubMed]
82. Curran, K.A.; Leavitt, J.M.; Karim, A.S.; Alper, H.S. Metabolic engineering of muconic acid production in saccharomyces cerevisiae. Metab. Eng. 2013, 15, 55–66. [CrossRef] [PubMed]
83. Jiang, H.; Wood, K.V.; Morgan, J.A. Metabolic engineering of the phenylpropanoid pathway in saccharomyces cerevisiae. Appl. Environ. Microbiol. 2005, 71, 2962–2969. [CrossRef] [PubMed]
84. Frick, O.; Wittmann, C. Characterization of the metabolic shift between oxidative and fermentative growth in saccharomyces cerevisiae by comparative 13c flux analysis. Microb. Cell Fact. 2005, 4, 30. [CrossRef] [PubMed]
85. Zaidi, N.; Swinnen, J.V.; Smans, K. Atp-citrate lyase: A key player in cancer metabolism. Cancer Res. 2012, 72, 3709–3714. [CrossRef] [PubMed]
86. Meile, L.; Rohr, L.M.; Geissmann, T.A.; Herensperger, M.; Teuber, M. Characterization of the d-xylulose 5-phosphate/d-fructose 6-phosphate phosphoketolase gene (xfp) from bifidobacterium lactis. J. Bacteriol. 2001, 183, 2929–2936. [CrossRef] [PubMed]
87. Panagiotou, G.; Andersen, M.R.; Grotkjaer, T.; Regueira, T.B.; Hofmann, G.; Nielsen, J.; Olsson, L. Systems analysis unfolds the relationship between the phosphoketolase pathway and growth in Aspergillus nidulans. PLoS ONE 2008, 3, e3847. [CrossRef] [PubMed]
88. de Jong, B.W.; Shi, S.; Siewers, V.; Nielsen, J. Improved production of fatty acid ethyl esters in saccharomyces cerevisiae through up-regulation of the ethanol degradation pathway and expression of the heterologous phosphoketolase pathway. Microb. Cell Fact. 2014, 13, 39. [CrossRef] [PubMed]
89. Jeppsson, M.; Johansson, B.; Hahn-Hägerdal, B.; Gorwa-Grauslund, M.F. Reduced oxidative pentose phosphate pathway flux in recombinant xylose-utilizing saccharomyces cerevisiae strains improves the ethanol yield from xylose. Appl. Environ. Microbiol. 2002, 68, 1604–1609. [CrossRef] [PubMed]
90. Watanabe, S.; Abu Saleh, A.; Pack, S.P.; Annaluru, N.; Kodaki, T.; Makino, K. Ethanol production from xylose by recombinant saccharomyces cerevisiae expressing protein-engineered nadh-preferring xylose reductase from pichia stipitis. Microbiology 2007, 153, 3044–3054. [CrossRef] [PubMed]
91. Jeppsson, M.; Bengtsson, O.; Franke, K.; Lee, H.; Hahn-Hägerdal, B.; Gorwa-Grauslund, M.F. The expression of a pichia stipitis xylose reductase mutant with higher km for nadph increases ethanol production from xylose in recombinant saccharomyces cerevisiae. Biotechnol. Bioeng. 2006, 93, 665–673. [CrossRef] [PubMed]
92. Watanabe, S.; Pack, S.P.; Saleh, A.A.; Annaluru, N.; Kodaki, T.; Makino, K. The positive effect of the decreased nadph-preferring activity of xylose reductase from pichia stipitis on ethanol production using xylose-fermenting recombinant saccharomyces cerevisiae. Biosci. Biotechnol. Biochem. 2007, 71, 1365–1369. [CrossRef] [PubMed]
93. Runquist, D.; Hahn-Hägerdal, B.; Bettiga, M. Increased expression of the oxidative pentose phosphate pathway and gluconeogenesis in anaerobically growing xylose-utilizing saccharomyces cerevisiae. Microb. Cell Fact. 2009, 8, 49. [CrossRef] [PubMed]
94. Petschacher, B.; Nidetzky, B. Altering the coenzyme preference of xylose reductase to favor utilization of nadh enhances ethanol yield from xylose in a metabolically engineered strain of saccharomyces cerevisiae. Microb. Cell Fact. 2008, 7, 9. [CrossRef] [PubMed]
95. Bengtsson, O.; Hahn-Hägerdal, B.; Gorwa-Grauslund, M.F. Xylose reductase from pichia stipitis with altered coenzyme preference improves ethanolic xylose fermentation by recombinant saccharomyces cerevisiae. Biotechnol. Biofuels 2009, 2, 9. [CrossRef] [PubMed]
96. Runquist, D.; Hahn-Hägerdal, B.; Bettiga, M. Increased ethanol productivity in xylose-utilizing saccharomyces cerevisiae via a randomly mutagenized xylose reductase. Appl. Environ. Microbiol. 2010, 76, 7796–7802. [CrossRef] [PubMed]
97. Watanabe, S.; Saleh, A.A.; Pack, S.P.; Annaluru, N.; Kodaki, T.; Makino, K. Ethanol production from xylose by recombinant saccharomyces cerevisiae expressing protein engineered nadp+-dependent xylitol dehydrogenase. J. Biotechnol. 2007, 130, 316–319. [CrossRef] [PubMed]
98. Matsushika, A.; Watanabe, S.; Kodaki, T.; Makino, K.; Inoue, H.; Murakami, K.; Takimura, O.; Sawayama, S. Expression of protein engineered nadp+-dependent xylitol dehydrogenase increases ethanol production from xylose in recombinant saccharomyces cerevisiae. Appl. Microbiol. Biotechnol. 2008, 81, 243–255. [CrossRef] [PubMed]
99. Krahulec, S.; Klimacek, M.; Nidetzky, B. Engineering of a matched pair of xylose reductase and xylitol dehydrogenase for xylose fermentation by saccharomyces cerevisiae. Biotechnol. J. 2009, 4, 684–694. [CrossRef] [PubMed]
100. Matsushika, A.; Inoue, H.; Watanabe, S.; Kodaki, T.; Makino, K.; Sawayama, S. Efficient bioethanol production by a recombinant flocculent saccharomyces cerevisiae strain with a genome-integrated nadp(+)-dependent xylitol dehydrogenase gene. Appl. Environ. Microbiol. 2009, 75, 3818–3822. [CrossRef] [PubMed]
101. Verho, R.; Londesborough, J.; Penttilä, M.; Richard, P. Engineering redox cofactor regeneration for improved pentose fermentation in saccharomyces cerevisiae. Appl. Environ. Microbiol. 2003, 69, 5892–5897. [CrossRef] [PubMed]
102. Zhang, G.-C.; Liu, J.-J.; Ding, W.-T. Decreased xylitol formation during xylose fermentation in saccharomyces cerevisiae due to overexpression of water-forming nadh oxidase. Appl. Environ. Microbiol. 2012, 78, 1081–1086. [CrossRef] [PubMed]
103. Wasylenko, T.M.; Stephanopoulos, G. Metabolomic and 13c-metabolic flux analysis of a xylose-consuming saccharomyces cerevisiae strain expressing xylose isomerase. Biotechnol. Bioeng. 2015, 112, 470–483. [CrossRef] [PubMed]
104. Birnbaum, S.; Bailey, J.E. Plasmid presence changes the relative levels of many host cell proteins and ribosome components in recombinant Escherichia coli. Biotechnol. Bioeng. 1991, 37, 736–745. [CrossRef] [PubMed]
105. Guyot, S.; Gervais, P.; Young, M.; Winckler, P.; Dumont, J.; Davey, H.M. Surviving the heat: Heterogeneity of response in saccharomyces cerevisiae provides insight into thermal damage to the membrane. Environ. Microbiol. 2015, 17, 2982–2992. [CrossRef] [PubMed]
106. Nugroho, R.H.; Yoshikawa, K.; Shimizu, H. Metabolomic analysis of acid stress response in saccharomyces cerevisiae. J. Biosci. Bioeng. 2015, 120, 396–404. [CrossRef] [PubMed]
107. Parawira, W.; Tekere, M. Biotechnological strategies to overcome inhibitors in lignocellulose hydrolysates for ethanol production: Review. Crit. Rev. Biotechnol. 2011, 31, 20–31. [CrossRef] [PubMed]
108. Fillet, S.; Gibert, J.; Suárez, B.; Lara, A.; Ronchel, C.; Adrio, J. Fatty alcohols production by oleaginous yeast. J. Ind. Microbiol. Biotechnol. 2015, 42, 1463–1472. [CrossRef] [PubMed]
109. Feng, Y.; Cronan, J.E. Escherichia coli unsaturated fatty acid synthesis: Complex transcription of the faba gene and in vivo identification of the essential reaction catalyzed by fabb. J. Biol. Chem. 2009, 284, 29526–29535. [CrossRef] [PubMed]
110. Davis, M.S.; Solbiati, J.; Cronan, J.E., Jr. Overproduction of acetyl-coa carboxylase activity increases the rate of fatty acid biosynthesis in Escherichia coli. J. Biol. Chem. 2000, 275, 28593–28598. [CrossRef] [PubMed]
111. Lu, X.; Vora, H.; Khosla, C. Overproduction of free fatty acids in E. Coli: Implications for biodiesel production. Metab. Eng. 2008, 10, 333–339. [CrossRef] [PubMed]
112. Zhang, F.; Ouellet, M.; Batth, T.S.; Adams, P.D.; Petzold, C.J.; Mukhopadhyay, A.; Keasling, J.D. Enhancing fatty acid production by the expression of the regulatory transcription factor fadr. Metab. Eng. 2012, 14, 653–660. [CrossRef] [PubMed]
113. Subrahmanyam, S.; Cronan, J.E., Jr. Overproduction of a functional fatty acid biosynthetic enzyme blocks fatty acid synthesis in Escherichia coli. J. Bacteriol. 1998, 180, 4596–4602. [PubMed]
114. Kim, Y.M.; Cho, H.-S.; Jung, G.Y.; Park, J.M. Engineering the pentose phosphate pathway to improve hydrogen yield in recombinant Escherichia coli. Biotechnol. Bioeng. 2011, 108, 2941–2946. [CrossRef] [PubMed]
115. Lee, W.-H.; Park, J.-B.; Park, K.; Kim, M.-D.; Seo, J.-H. Enhanced production of ε-caprolactone by overexpression of nadph-regenerating glucose 6-phosphate dehydrogenase in recombinant Escherichia coli harboring cyclohexanone monooxygenase gene. Appl. Microbiol. Biotechnol. 2007, 76, 329–338. [CrossRef] [PubMed]
116. Chin, J.W.; Cirino, P.C. Improved nadph supply for xylitol production by engineered Escherichia coli with glycolytic mutations. Biotechnol. Prog. 2011, 27, 333–341. [CrossRef] [PubMed]
117. Wang, Y.; San, K.-Y.; Bennett, G. Improvement of nadph bioavailability in Escherichia coli through the use of phosphofructokinase deficient strains. Appl. Microbiol. Biotechnol. 2013, 97, 6883–6893. [CrossRef] [PubMed]
118. Chemler, J.A.; Fowler, Z.L.; McHugh, K.P.; Koffas, M.A.G. Improving nadph availability for natural product biosynthesis in Escherichia coli by metabolic engineering. Metab. Eng. 2010, 12, 96–104. [CrossRef] [PubMed]
119. Kim, S.; Lee, C.H.; Nam, S.W.; Kim, P. Alteration of reducing powers in an isogenic phosphoglucose isomerase (pgi)-disrupted Escherichia coli expressing nad(p)-dependent malic enzymes and nadp-dependent glyceraldehyde 3-phosphate dehydrogenase. Lett. Appl. Microbiol. 2011, 52, 433–440. [CrossRef] [PubMed]
120. Sánchez, A.M.; Andrews, J.; Hussein, I.; Bennett, G.N.; San, K.-Y. Effect of overexpression of a soluble pyridine nucleotide transhydrogenase (udha) on the production of poly(3-hydroxybutyrate) in Escherichia coli. Biotechnol. Prog. 2006, 22, 420–425. [CrossRef] [PubMed]
121. Chou, H.-H.; Marx, C.J.; Sauer, U. Transhydrogenase promotes the robustness and evolvability of E. Coli deficient in nadph production. PLoS Genet. 2015, 11, e1005007. [CrossRef] [PubMed]
122. Jones, K.L.; Kim, S.W.; Keasling, J.D. Low-copy plasmids can perform as well as or better than high-copy plasmids for metabolic engineering of bacteria. Metab. Eng. 2000, 2, 328–338. [CrossRef] [PubMed]
123. King, T.; Lucchini, S.; Hinton, J.C.D.; Gobius, K. Transcriptomic analysis of Escherichia coli o157:H7 and k-12 cultures exposed to inorganic and organic acids in stationary phase reveals acidulant-and strain-specific acid tolerance responses. Appl. Environ. Microbiol. 2010, 76, 6514–6528. [CrossRef] [PubMed]
124. Rui, B.; Shen, T.; Zhou, H.; Liu, J.; Chen, J.; Pan, X.; Liu, H.; Wu, J.; Zheng, H.; Shi, Y. A systematic investigation of Escherichia coli central carbon metabolism in response to superoxide stress. BMC Syst. Biology 2010, 4, 122. [CrossRef] [PubMed]
125. Perkins, J.B.; Sloma, A.; Hermann, T.; Theriault, K.; Zachgo, E.; Erdenberger, T.; Hannett, N.; Chatterjee, N.P.; Williams, V., II; Rufo, G.A., Jr.; et al. Genetic engineering of bacillus subtilis for the commercial production of riboflavin. J. Ind. Microbiol. Biotech. 1999, 22, 8–18. [CrossRef]
126. Sauer, U.; Hatzimanikatis, V.; Bailey, J.E.; Hochuli, M.; Szyperski, T.; Wuthrich, K. Metabolic fluxes in riboflavin-producing bacillus subtilis. Nat. Biotech. 1997, 15, 448–452. [CrossRef] [PubMed]
127. Dauner, M.; Bailey, J.E.; Sauer, U. Metabolic flux analysis with a comprehensive isotopomer model in bacillus subtilis. Biotechnol. Bioeng. 2001, 76, 144–156. [CrossRef] [PubMed]
128. Fischer, E.; Sauer, U. Large-scale in vivo flux analysis shows rigidity and suboptimal performance of bacillus subtilis metabolism. Nat. Genet. 2005, 37, 636–640. [CrossRef] [PubMed]
129. Tannler, S.; Decasper, S.; Sauer, U. Maintenance metabolism and carbon fluxes in bacillus species. Microb. Cell Fact. 2008, 7, 19. [CrossRef] [PubMed]
130. Sauer, U.; Hatzimanikatis, V.; Hohmann, H.P.; Manneberg, M.; van Loon, A.P.; Bailey, J.E. Physiology and metabolic fluxes of wild-type and riboflavin-producing bacillus subtilis. Appl. Environ. Microbiol. 1996, 62, 3687–3696. [PubMed]
131. Wiechert, W.; de Graaf, A.A. In vivo stationary flux analysis by 13c labeling experiments. In Metabolic Engineering; Sahm, H., Wandrey, C., Eds.; Springer: Berlin, Germany, 1996; Volume 54, pp. 109–154.
132. Wittmann, C.; Heinzle, E. Application of maldi-tof ms to lysine-producing corynebacterium glutamicum. Eur. J. Biochem. 2001, 268, 2441–2455. [CrossRef] [PubMed]
133. Klapa, M.I.; Aon, J.-C.; Stephanopoulos, G. Systematic quantification of complex metabolic flux networks using stable isotopes and mass spectrometry. Eur. J. Biochem. 2003, 270, 3525–3542. [CrossRef] [PubMed]
134. Quek, L.-E.; Wittmann, C.; Nielsen, L.; Kromer, J. Openflux: Efficient modelling software for 13c-based metabolic flux analysis. Microb. Cell Fact. 2009, 8, 25. [CrossRef] [PubMed]
135. Krömer, J.O.; Sorgenfrei, O.; Klopprogge, K.; Heinzle, E.; Wittmann, C. In-depth profiling of lysine-producing corynebacterium glutamicum by combined analysis of the transcriptome, metabolome, and fluxome. J. Bacteriol. 2004, 186, 1769–1784. [CrossRef] [PubMed]
136. Becker, J.; Klopprogge, C.; Herold, A.; Zelder, O.; Bolten, C.J.; Wittmann, C. Metabolic flux engineering of l-lysine production in corynebacterium glutamicum—Over expression and modification of g6p dehydrogenase. J. Biotechnol. 2007, 132, 99–109. [CrossRef] [PubMed]
137. Becker, J.; Zelder, O.; Häfner, S.; Schröder, H.; Wittmann, C. From zero to hero—Design-based systems metabolic engineering of corynebacterium glutamicum for l-lysine production. Metab. Eng. 2011, 13, 159–168. [CrossRef] [PubMed]
138. Becker, J.; Klopprogge, C.; Zelder, O.; Heinzle, E.; Wittmann, C. Amplified expression of fructose 1,6-bisphosphatase in corynebacterium glutamicum increases in vivo flux through the pentose phosphate pathway and lysine production on different carbon sources. Appl. Environ. Microbiol. 2005, 71, 8587–8596. [CrossRef] [PubMed]
139. Bommareddy, R.R.; Chen, Z.; Rappert, S.; Zeng, A.-P. A de novo nadph generation pathway for improving lysine production of corynebacterium glutamicum by rational design of the coenzyme specificity of glyceraldehyde 3-phosphate dehydrogenase. Metab. Eng. 2014, 25, 30–37. [CrossRef] [PubMed]
140. Sreekrishna, K.; Brankamp, R.G.; Kropp, K.E.; Blankenship, D.T.; Tsay, J.-T.; Smith, P.L.; Wierschke, J.D.; Subramaniam, A.; Birkenberger, L.A. Strategies for optimal synthesis and secretion of heterologous proteins in the methylotrophic yeast pichia pastoris. Gene 1997, 190, 55–62. [CrossRef]
141. Cregg, J.; Cereghino, J.; Shi, J.; Higgins, D. Recombinant protein expression in pichia pastoris. Mol. Biotechnol. 2000, 16, 23–52. [CrossRef]
142. Cereghino, J.L.; Cregg, J.M. Heterologous protein expression in the methylotrophic yeast pichia pastoris. FEMS Microbiol. Rev. 2000, 24, 45–66. [CrossRef] [PubMed]
143. Sreekrishna, K.; Potenz, R.H.; Cruze, J.A.; McCombie, W.R.; Parker, K.A.; Nelles, L.; Mazzaferro, P.K.; Holden, K.A.; Harrison, R.G.; Wood, P.J. High level expression of heterologous proteins in methylotrophic yeast pichia pastoris. J. Basic Microbiol. 1988, 28, 265–278. [CrossRef] [PubMed]
144. Ahmad, M.; Hirz, M.; Pichler, H.; Schwab, H. Protein expression in pichia pastoris: Recent achievements and perspectives for heterologous protein production. Appl. Microbiol. Biotechnol. 2014, 98, 5301–5317. [CrossRef] [PubMed]
145. Daly, R.; Hearn, M.T.W. Expression of heterologous proteins in pichia pastoris: A useful experimental tool in protein engineering and production. J. Mol. Recognit. 2005, 18, 119–138. [CrossRef] [PubMed]
146. Hofmann, G.; Diano, A.; Nielsen, J. Recombinant bacterial hemoglobin alters metabolism of aspergillus niger. Metab. Eng. 2009, 11, 8–12. [CrossRef] [PubMed]
147. Morikawa, Y.; Karube, I.; Suzuki, S. Penicillin g production by immobilized whole cells of penicillium chrysogenum. Biotechnol. Bioeng. 1979, 21, 261–270. [CrossRef] [PubMed]
148. Pandey, S.; Ahmad, T.; Aryal, S.; Rana, B.; Sapkota, B. Penicillin production and history: An overview. Int. J. Microbiol. Allied Sci. 2014, 1, 5.
149. Hu, X.-Q.; Chu, J.; Zhang, S.-L.; Zhuang, Y.-P.; Wang, Y.-H.; Zhu, S.; Zhu, Z.-G.; Yuan, Z.-Y. A novel feeding strategy during the production phase for enhancing the enzymatic synthesis of s-adenosyl-l-methionine by methylotrophic pichia pastoris. Enzym. Microb. Technol. 2007, 40, 669–674. [CrossRef]
150. Hu, X.-Q.; Chu, J.; Zhang, Z.; Zhang, S.-L.; Zhuang, Y.-P.; Wang, Y.-H.; Guo, M.-J.; Chen, H.-X.; Yuan, Z.-Y. Effects of different glycerol feeding strategies on s-adenosyl-l-methionine biosynthesis by pgap-driven pichia pastoris overexpressing methionine adenosyltransferase. J. Biotechnol. 2008, 137, 44–49. [CrossRef] [PubMed]
151. Driouch, H.; Melzer, G.; Wittmann, C. Integration of in vivo and in silico metabolic fluxes for improvement of recombinant protein production. Metab. Eng. 2012, 14, 47–58. [CrossRef] [PubMed]
152. Pedersen, H.; Christensen, B.; Hjort, C.; Nielsen, J. Construction and characterization of an oxalic acid nonproducing strain of aspergillus niger. Metab. Eng. 2000, 2, 34–41. [CrossRef] [PubMed]
153. van Gulik, W.M.; de Laat, W.T.A.M.; Vinke, J.L.; Heijnen, J.J. Application of metabolic flux analysis for the identification of metabolic bottlenecks in the biosynthesis of penicillin-g. Biotechnol. Bioeng. 2000, 68, 602–618. [CrossRef]
154. McKinlay, J.B.; Oda, Y.; Rühl, M.; Posto, A.L.; Sauer, U.; Harwood, C.S. Non-growing rhodopseudomonas palustris increases the hydrogen gas yield from acetate by shifting from the glyoxylate shunt to the tricarboxylic acid cycle. J. Biol. Chem. 2014, 289, 1960–1970. [CrossRef] [PubMed]
155. Becker, J.; Reinefeld, J.; Stellmacher, R.; Schäfer, R.; Lange, A.; Meyer, H.; Lalk, M.; Zelder, O.; von Abendroth, G.; Schröder, H.; et al. Systems-wide analysis and engineering of metabolic pathway fluxes in bio-succinate producing basfia succiniciproducens. Biotechnol. Bioeng. 2013, 110, 3013–3023. [CrossRef] [PubMed]
156. Ravikirthi, P.; Suthers, P.F.; Maranas, C.D. Construction of an E. Coli genome-scale atom mapping model for mfa calculations. Biotechnol. Bioeng. 2011, 108, 1372–1382. [CrossRef] [PubMed]
157. Zamboni, N.; Sauer, U. Novel biological insights through metabolomics and 13c-flux analysis. Curr. Opin. Microbiol. 2009, 12, 553–558. [CrossRef] [PubMed]
158. Büscher, J.M.; Czernik, D.; Ewald, J.C.; Sauer, U.; Zamboni, N. Cross-platform comparison of methods for quantitative metabolomics of primary metabolism. Anal. Chem. 2009, 81, 2135–2143. [CrossRef] [PubMed]
159. Christen, S.; Sauer, U. Intracellular characterization of aerobic glucose metabolism in seven yeast species by 13c flux analysis and metabolomics. FEMS Yeast Res. 2011, 11, 263–272. [CrossRef] [PubMed]
160. Kumar, A.; Maranas, C.D. Clca: Maximum common molecular substructure queries within the metrxn database. J. Chem. Inf. Model. 2014, 54, 3417–3438. [CrossRef] [PubMed]
161. Kumar, A.; Suthers, P.; Maranas, C. Metrxn: A knowledgebase of metabolites and reactions spanning metabolic models and databases. BMC Bioinf. 2012, 13, 6. [CrossRef] [PubMed]
162. Gopalakrishnan, S.; Maranas, C.D. 13c metabolic flux analysis at a genome-scale. Metab. Eng. 2015, 32, 12–22. [CrossRef] [PubMed]
163. Jazmin, L.; O’Grady, J.; Ma, F.; Allen, D.; Morgan, J.; Young, J. Isotopically nonstationary mfa (inst-mfa) of autotrophic metabolism. In Plant Metabolic Flux Analysis; Dieuaide-Noubhani, M., Alonso, A.P., Eds.; Humana Press: New York, NY, USA, 2014; Volume 1090, pp. 181–210.
164. Murphy, T.A.; Dang, C.V.; Young, J.D. Isotopically nonstationary 13c flux analysis of myc-induced metabolic reprogramming in b-cells. Metab. Eng. 2013, 15, 206–217. [CrossRef] [PubMed]
165. Jazmin, L.; Young, J. Isotopically nonstationary 13c metabolic flux analysis. In Systems Metabolic Engineering; Alper, H.S., Ed.; Humana Press: New York, NY, USA, 2013; Volume 985, pp. 367–390.
166. Wiechert, W.; Nöh, K. Isotopically non-stationary metabolic flux analysis: Complex yet highly informative. Curr. Opin. Biotechnol. 2013, 24, 979–986. [CrossRef] [PubMed]
167. Wiechert, W.; Nöh, K. From stationary to instationary metabolic flux analysis. In Technology Transfer in Biotechnology; Kragl, U., Ed.; Springer: Berlin, Germany, 2005; Volume 92, pp. 145–172.
168. Young, J.D.; Shastri, A.A.; Stephanopoulos, G.; Morgan, J.A. Mapping photoautotrophic metabolism with isotopically nonstationary 13c flux analysis. Metab. Eng. 2011, 13, 656–665. [CrossRef] [PubMed]
169. Ma, F.; Jazmin, L.J.; Young, J.D.; Allen, D.K. Isotopically nonstationary 13c flux analysis of changes in arabidopsis thaliana leaf metabolism due to high light acclimation. Proc. Natl. Acad. Sci. USA 2014, 111, 16967–16972. [CrossRef] [PubMed]
170. Brennan, L.; Owende, P. Biofuels from microalgae—A review of technologies for production, processing, and extractions of biofuels and co-products. Renew. Sustain. Energy Rev. 2010, 14, 557–577. [CrossRef]
171. Varman, A.; Yu, Y.; You, L.; Tang, Y. Photoautotrophic production of d-lactic acid in an engineered cyanobacterium. Microb. Cell Fact. 2013, 12, 117. [CrossRef] [PubMed]
172. Zhou, J.; Li, Y. Engineering cyanobacteria for fuels and chemicals production. Protein Cell 2010, 1, 207–210. [CrossRef] [PubMed]
173. Leighty, R.W.; Antoniewicz, M.R. Complete-mfa: Complementary parallel labeling experiments technique for metabolic flux analysis. Metab. Eng. 2013, 20, 49–55. [CrossRef] [PubMed]
174. Crown, S.B.; Long, C.P.; Antoniewicz, M.R. Integrated 13c-metabolic flux analysis of 14 parallel labeling experiments in Escherichia coli. Metab. Eng. 2015, 28, 151–158. [CrossRef] [PubMed]
175. Leighty, R.W.; Antoniewicz, M.R. Parallel labeling experiments with [u-13c]glucose validate E. Coli metabolic network model for 13c metabolic flux analysis. Metab. Eng. 2012, 14, 533–541. [CrossRef] [PubMed]
176. Crown, S.B.; Antoniewicz, M.R. Parallel labeling experiments and metabolic flux analysis: Past, present and future methodologies. Metab. Eng. 2013, 16, 21–32. [CrossRef] [PubMed]
177. Srour, O.; Young, J.D.; Eldar, Y.C. Fluxomers: A new approach for (13)c metabolic flux analysis. BMC Syst. Biol. 2011, 5, 129. [CrossRef] [PubMed]
178. Gill, P.E.; Murray, W.; Saunders, M.A. Snopt: An sqp algorithm for large-scale constrained optimization. SIAM Rev. 2005, 47, 99–131. [CrossRef]
179. Sokol, S.; Millard, P.; Portais, J.-C. Influx_s: Increasing numerical stability and precision for metabolic flux analysis in isotope labelling experiments. Bioinformatics 2012, 28, 687–693. [CrossRef] [PubMed]
180. Cvijovic, M.; Olivares-Hernández, R.; Agren, R.; Dahr, N.; Vongsangnak, W.; Nookaew, I.; Patil, K.R.; Nielsen, J. Biomet toolbox: Genome-wide analysis of metabolism. Nucleic Acids Res. 2010, 38, W144–W149. [CrossRef] [PubMed]
181. Gombert, A.K.; Moreira dos Santos, M.; Christensen, B.; Nielsen, J. Network identification and flux quantification in the central metabolism of saccharomyces cerevisiae under different conditions of glucose repression. J. Bacteriol. 2001, 183, 1441–1451. [CrossRef] [PubMed]
182. Kajihata, S.; Furusawa, C.; Matsuda, F.; Shimizu, H. Openmebius: An open source software for isotopically nonstationary 13c-based metabolic flux analysis. BioMed Res. Int. 2014, 2014, 10. [CrossRef] [PubMed]
183. Press, W.H.; Flannery, B.P.; Teukolsky, S.A.; Vetterling, W.T. Numerical Recipes in C: The Art of Scientific Computing; Cambridge University Press: Cambridge, UK, 1988; p. 735.
184. Shiba, Y.; Paradise, E.M.; Kirby, J.; Ro, D.-K.; Keasling, J.D. Engineering of the pyruvate dehydrogenase bypass in saccharomyces cerevisiae for high-level production of isoprenoids. Metab. Eng. 2007, 9, 160–168. [CrossRef] [PubMed]
185. Jordà, J.; Jouhten, P.; Cámara, E.; Maaheimo, H.; Albiol, J.; Ferrer, P. Metabolic flux profiling of recombinant protein secreting pichia pastoris growing on glucose:Methanol mixtures. Microb. Cell Fact. 2012, 11, 57. [CrossRef] [PubMed]
186. Fuhrer, T.; Sauer, U. Different biochemical mechanisms ensure network-wide balancing of reducing equivalents in microbial metabolism. J. Bacteriol. 2009, 191, 2112–2121. [CrossRef] [PubMed]