Current and Emerging Options for Taxol Production

  • Yi Li
  • Guojian Zhang
  • Blaine A. PfeiferEmail author
Part of the Advances in Biochemical Engineering/Biotechnology book series (ABE, volume 148)


Paclitaxel (trademark “Taxol”) is a plant-derived isoprenoid natural product that exhibits potent anticancer activity. Taxol was originally isolated from the Pacific yew tree in 1967 and triggered an intense scientific and engineering venture to provide the compound reliably to cancer patients. The choices available for production include synthetic and biosynthetic routes (and combinations thereof). This chapter focuses on the currently utilized and emerging biosynthetic options for Taxol production. A particular emphasis is placed on the biosynthetic production hosts including macroscopic and unicellular plant species and more recent attempts to elucidate, transfer, and reconstitute the Taxol pathway within technically advanced microbial hosts. In so doing, we provide the reader with relevant background related to Taxol and more general information related to producing valuable, but structurally complex, natural products through biosynthetic strategies.

Graphical Abstract


Paclitaxel Taxus Metabolic engineering E. coli Yeast Fungi 



Bristol-Myers Squibb


Design of experiments


dimethylallyl diphosphate


1-deoxy-D-xylulose 5-phosphate synthase


Food and Drug Administration


farnesyl diphosphate


farnesyl diphosphate synthase


geranylgeranyl diphosphate synthase




isopentenyl diphosphate


4-diphosphocytidyl-2-C-methyl-D-erythritol synthase


2-C-methyl-D-erythritol 2,4-cyclodiphosphate synthase


isopentenyl diphosphate isomerase


Investigational new drug






National Cancer Institute


  1. 1.
    Cragg GM (1998) Paclitaxel (Taxol®): a success story with valuable lessons for natural product drug discovery and development. Med Res Rev 18:315–331Google Scholar
  2. 2.
    Skeel RT, Khleif SN (2011) Handbook of cancer chemotherapy, vol IV. Lippincott Williams & Wilkins, Philadelphia, p 803Google Scholar
  3. 3.
    Thayer A (2010) More than a supplier. Chem Eng News 88:25–27Google Scholar
  4. 4.
    Goodman J, Walsh V (2001) The story of taxol: nature and politics in the pursuit of an anti-cancer drug, vol 323(7304). Cambridge University Press, CambridgeGoogle Scholar
  5. 5.
    Voigt W, Kegel T, Weiss M, Mueller T, Simon H, Schmoll HJ (2005) Potential activity of paclitaxel, vinorelbine and gemcitabine in anaplastic thyroid carcinoma. J cancer Res Clin Oncol 131:585–590Google Scholar
  6. 6.
    Galsky MD (2005) The role of taxanes in the management of bladder cancer. Oncologist 10:792–798Google Scholar
  7. 7.
    Chougule PB, Akhtar MS, Rathore R, Koness J, McRae R, Nigri P, Radie-Keane K, Kennedy T, Wanebo HJ, Ready N (2008) Concurrent chemoradiotherapy with weekly paclitaxel and carboplatin for locally advanced head and neck cancer: Long-term follow-up of a Brown University Oncology Group Phase II Study (HN-53). Head Neck 30:289–296Google Scholar
  8. 8.
    Crown J, O’Leary M, Ooi WS (2004) Docetaxel and paclitaxel in the treatment of breast cancer: a review of clinical experience. Oncologist 2:24–32Google Scholar
  9. 9.
    Wani MC, Taylor HL, Wall ME, Coggon P, McPhail AT (1971) Plant antitumor agents. VI. The isolation and structure of taxol, a novel antileukemic and antitumor agent from Taxus brevifolia. J Am Chem Soc 93:2325–2327Google Scholar
  10. 10.
    Holton RA, Biediger RJ, Boatman PD (1995) Semisynthesis of taxol and taxotere. Taxol Science Appl:97–121Google Scholar
  11. 11.
    Danishefsky SJ, Masters JJ, Young WB, Link JT, Snyder LB, Magee TV, Jung DK, Isaacs RCA, Bornmann WG, Alaimo CA et al (1996) Total synthesis of baccatin III and Taxol. J Am Chem Soc 118:2843–2859Google Scholar
  12. 12.
    Zhang H, Boghigian BA, Armando J, Pfeifer BA (2011) Methods and options for the heterologous production of complex natural products. Nat Prod Rep 28:125–151Google Scholar
  13. 13.
    Ongley SE, Bian X, Neilan BA, Muller R (2013) Recent advances in the heterologous expression of microbial natural product biosynthetic pathways. Nat Prod Rep 30:1121–1138Google Scholar
  14. 14.
    De Brabander M, Geuens G, Nuydens R, Willebrords R, De Mey J (1981) Taxol induces the assembly of free microtubules in living cells and blocks the organizing capacity of the centrosomes and kinetochores. Proc Natl Acad Sci USA 78:5608–5612Google Scholar
  15. 15.
    Manfredi JJ, Parness J, Horwitz SB (1982) Taxol binds to cellular microtubules. J Cell Biol 94:688–696Google Scholar
  16. 16.
    Dostál V, Libusová L (2014) Microtubule drugs: action, selectivity, and resistance across the kingdoms of life. Protoplasma 1:1–15Google Scholar
  17. 17.
    Young DH, Michelotti EL, Swindell CS, Krauss NE (1992) Antifungal properties of taxol and various analogues. Experientia 48:882–885Google Scholar
  18. 18.
    Schiff PB, Fant J, Horwitz SB (1979) Promotion of microtubule assembly in vitro by taxol. Nature 277:665–667Google Scholar
  19. 19.
    Cragg GM, Schepartz SA, Suffness M, Grever MR (1993) The taxol supply crisis. New NCI policies for handling the large-scale production of novel natural product anticancer and anti-HIV agents. J Nat Prod 56:1657–1668Google Scholar
  20. 20.
    McGuire WP, Rowinsky EK, Rosenshein NB, Grumbine FC, Ettinger DS, Armstrong DK, Donehower RC (1989) Taxol: a unique antineoplastic agent with significant activity in advanced ovarian epithelial neoplasms. Ann Intern Med 111:273–279Google Scholar
  21. 21.
    Trimble E, Adams J, Vena D, Hawkins M, Friedman M, Fisherman J, Christian M, Canetta R, Onetto N, Hayn R (1993) Paclitaxel for platinum-refractory ovarian cancer: results from the first 1,000 patients registered to National Cancer Institute Treatment Referral Center 9103. J Clin Oncol 11:2405–2410Google Scholar
  22. 22.
    Suffness M, Wall M, Suffness M (2002) Taxol: Science and Applications, 1995. Mekhail TM Markman M Expert Opin Pharmacother 3:755Google Scholar
  23. 23.
    Wilson WH, Wittes R (1996) Taxol treatment of breast cancer. US5496846 AGoogle Scholar
  24. 24.
    Horwitz SB (1994) How to make taxol from scratch. Nature 367:593–594Google Scholar
  25. 25.
    Chun M-K, Shin H-W, Lee H (1996) Supercritical fluid extraction of paclitaxel and baccatin III from needles of Taxus cuspidata. J Supercrit Fluids 9:192–198Google Scholar
  26. 26.
    van Rozendaal EL, Lelyveld GP, van Beek TA (2000) Screening of the needles of different yew species and cultivars for paclitaxel and related taxoids. Phytochemistry 53:383–389Google Scholar
  27. 27.
    Kingston DG, Chaudhary AG, Gunatilaka A, Middleton ML (1994) Synthesis of taxol from baccatin III via an oxazoline intermediate. Tetrahedron Lett 35:4483–4484Google Scholar
  28. 28.
    Holton RA (1993) Semi-synthesis of taxane derivatives using metal alkoxides and oxazinones. EP0568203 A1:C07D265/06Google Scholar
  29. 29.
    Jaziri M, Zhiri A, Guo Y-W, Dupont J-P, Shimomura K, Hamada H, Vanhaelen M, Homès J (1996) Taxus sp. cell, tissue and organ cultures as alternative sources for taxoids production: a literature survey. Plant Cell Tissue Organ Cult 46:59–75Google Scholar
  30. 30.
    Gibson D, Ketchum R, Vance N, Christen A (1993) Initiation and growth of cell lines of Taxus brevifolia (Pacific yew). Plant Cell Rep 12:479–482Google Scholar
  31. 31.
    Rohr R (1973) Production of callus by the male gametophytes of Taxus baccata L. cultured on artificial medium. Study with light and electron microscopes. Caryologia 25:177–189Google Scholar
  32. 32.
    Roberts SC (2007) Production and engineering of terpenoids in plant cell culture. Nat Chem Biol 3:387–395Google Scholar
  33. 33.
    Kim BJ, Gibson DM, Shuler ML (2004) Effect of subculture and elicitation on instability of taxol production in Taxus sp. suspension cultures. Biotechnol Prog 20:1666–1673Google Scholar
  34. 34.
    Ketchum REB, Gibson DM (1996) Paclitaxel production in suspension cell cultures of Taxus. Plant Cell Tissue Organ Cult 46:9–16Google Scholar
  35. 35.
    Fett-Neto AG, Melanson SJ, Nicholson SA, Pennington JJ, DiCosmo F (1994) Improved taxol yield by aromatic carboxylic acid and amino acid feeding to cell cultures of Taxus cuspidata. Biotechnol Bioeng 44:967–971Google Scholar
  36. 36.
    Kwon IC, Yoo YJ, Lee JH, Hyun JO (1998) Enhancement of taxol production by in situ recovery of product. Process Biochem 33:701–707Google Scholar
  37. 37.
    Xu JF, Yin PQ, Wei XG, Su ZG (1998) Self-immobilized aggregate culture of Taxus cuspidata for improved taxol production. Biotechnol Tech 12:241–244Google Scholar
  38. 38.
    Bentebibel S, Moyano E, Palazon J, Cusido RM, Bonfill M, Eibl R, Pinol MT (2005) Effects of immobilization by entrapment in alginate and scale-up on paclitaxel and baccatin III production in cell suspension cultures of Taxus baccata. Biotechnol Bioeng 89:647–655Google Scholar
  39. 39.
    Tabata H (2004) Paclitaxel production by plant-cell-culture technology. Biomanufacturing 87:1–23Google Scholar
  40. 40.
    Yukimune Y, Tabata H, Higashi Y, Hara Y (1996) Methyl jasmonate-induced overproduction of paclitaxel and baccatin III in Taxus cell suspension cultures. Nat Biotechnol 14:1129–1132Google Scholar
  41. 41.
    Li YC, Tao WY, Cheng L (2009) Paclitaxel production using co-culture of Taxus suspension cells and paclitaxel-producing endophytic fungi in a co-bioreactor. Appl Microbiol Biotechnol 83:233–239Google Scholar
  42. 42.
    Bringi V, Kadkade PG, Prince CL, Roach BL (2007) Enhanced production of taxol and taxanes by cell cultures of Taxus species. C12N5/02Google Scholar
  43. 43.
    Zhang CH, Mei XG, Liu L, Yu LJ (2000) Enhanced paclitaxel production induced by the combination of elicitors in cell suspension cultures of Taxus chinensis. Biotechnol Lett 22:1561–1564Google Scholar
  44. 44.
    Wu J, Lin L (2003) Enhancement of taxol production and release in Taxus chinensis cell cultures by ultrasound, methyl jasmonate and in situ solvent extraction. Appl Microbiol Biotechnol 62:151–155Google Scholar
  45. 45.
    Fett-Neto AG, Melanson SJ, Sakata K, DiCosmo F (1993) Improved growth and taxol yield in developing calli of Taxus cuspidata by medium composition modification. Nat Biotechnol 11:731–734Google Scholar
  46. 46.
    Huang T-K, McDonald KA (2009) Bioreactor engineering for recombinant protein production in plant cell suspension cultures. Biochem Eng J 45:168–184Google Scholar
  47. 47.
    Kolewe ME, Gaurav V, Roberts SC (2008) Pharmaceutically active natural product synthesis and supply via plant cell culture technology. Mol Pharm 5:243–256Google Scholar
  48. 48.
    Hefner J, Rubenstein SM, Ketchum RE, Gibson DM, Williams RM, Croteau R (1996) Cytochrome P450-catalyzed hydroxylation of taxa-4(5),11(12)-diene to taxa-4(20),11(12)-dien-5alpha-ol: the first oxygenation step in taxol biosynthesis. Chem Biol 3:479–489Google Scholar
  49. 49.
    Hefner J, Ketchum RE, Croteau R (1998) Cloning and functional expression of a cDNA encoding geranylgeranyl diphosphate synthase from Taxus canadensis and assessment of the role of this prenyltransferase in cells induced for taxol production. Arch Biochem Biophys 360:62–74Google Scholar
  50. 50.
    Koepp AE, Hezari M, Zajicek J, Vogel BS, LaFever RE, Lewis NG, Croteau R (1995) Cyclization of geranylgeranyl diphosphate to taxa-4(5),11(12)-diene is the committed step of taxol biosynthesis in Pacific yew. J Biol Chem 270:8686–8690Google Scholar
  51. 51.
    Hezari M, Lewis NG, Croteau R (1995) Purification and characterization of taxa-4(5),11(12)-diene synthase from Pacific yew (Taxus brevifolia) that catalyzes the first committed step of taxol biosynthesis. Arch Biochem Biophys 322:437–444Google Scholar
  52. 52.
    Guerra-Bubb J, Croteau R, Williams RM (2012) The early stages of taxol biosynthesis: an interim report on the synthesis and identification of early pathway metabolites. Nat Prod Rep 29:683–696Google Scholar
  53. 53.
    Koksal M, Jin Y, Coates RM, Croteau R, Christianson DW (2011) Taxadiene synthase structure and evolution of modular architecture in terpene biosynthesis. Nature 469:116–120Google Scholar
  54. 54.
    Kuzuyama T (2002) Mevalonate and nonmevalonate pathways for the biosynthesis of isoprene units. Biosci Biotechnol Biochem 66:1619–1627Google Scholar
  55. 55.
    Kuzuyama T, Seto H (2003) Diversity of the biosynthesis of the isoprene units. Nat Prod Rep 20:171–183Google Scholar
  56. 56.
    Miziorko HM (2011) Enzymes of the mevalonate pathway of isoprenoid biosynthesis. Arch Biochem Biophys 505:131–143Google Scholar
  57. 57.
    Martin VJ, Pitera DJ, Withers ST, Newman JD, Keasling JD (2003) Engineering a mevalonate pathway in Escherichia coli for production of terpenoids. Nat Biotechnol 21:796–802Google Scholar
  58. 58.
    Dahl RH, Zhang F, Alonso-Gutierrez J, Baidoo E, Batth TS, Redding-Johanson AM, Petzold CJ, Mukhopadhyay A, Lee TS, Adams PD et al (2013) Engineering dynamic pathway regulation using stress-response promoters. Nat Biotechnol 31:1039–1046Google Scholar
  59. 59.
    Jennewein S, Wildung MR, Chau M, Walker K, Croteau R (2004) Random sequencing of an induced Taxus cell cDNA library for identification of clones involved in Taxol biosynthesis. Proc Nat Acad Sci USA 101:9149–9154Google Scholar
  60. 60.
    Jung ST, Lauchli R, Arnold FH (2011) Cytochrome P450: taming a wild type enzyme. Curr Opin Biotechnol 22:809–817Google Scholar
  61. 61.
    Ajikumar PK, Xiao WH, Tyo KEJ, 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 330:70–74Google Scholar
  62. 62.
    Huang Q, Roessner CA, Croteau R, Scott AI (2001) Engineering Escherichia coli for the synthesis of taxadiene, a key intermediate in the biosynthesis of taxol. Bioorg Med Chem 9:2237–2242Google Scholar
  63. 63.
    Ma SM, Garcia DE, Redding-Johanson AM, Friedland GD, Chan R, Batth TS, Haliburton JR, Chivian D, Keasling JD, Petzold CJ et al (2011) Optimization of a heterologous mevalonate pathway through the use of variant HMG-CoA reductases. Metab Eng 13:588–597Google Scholar
  64. 64.
    Zhang C, Chen X, Zou R, Zhou K, Stephanopoulos G, Too HP (2013) Combining genotype improvement and statistical media optimization for isoprenoid production in E. coli. Plos One 8:10Google Scholar
  65. 65.
    Yuan LZ, Rouviere PE, Larossa RA, Suh W (2006) Chromosomal promoter replacement of the isoprenoid pathway for enhancing carotenoid production in E. coli. Metab Eng 8:79–90Google Scholar
  66. 66.
    Misawa N, Nakagawa M, Kobayashi K, Yamano S, Izawa Y, Nakamura K, Harashima K (1990) Elucidation of the Erwinia uredovora carotenoid biosynthetic pathway by functional analysis of gene products expressed in Escherichia coli. J Bacteriol 172:6704–6712Google Scholar
  67. 67.
    Harker M, Bramley PM (1999) Expression of prokaryotic 1-deoxy-D-xylulose-5-phosphatases in Escherichia coli increases carotenoid and ubiquinone biosynthesis. Febs Lett 448:115–119Google Scholar
  68. 68.
    Wang C-W, Oh M-K, Liao JC (1999) Engineered isoprenoid pathway enhances astaxanthin production. Biotechnol Bioeng 62:235–241Google Scholar
  69. 69.
    Huang KX, Huang QL, Wildung MR, Croteau R, Scott AI (1998) Overproduction, in Escherichia coli, of soluble taxadiene synthase, a key enzyme in the Taxol biosynthetic pathway. Protein Expr Purif 13:90–96Google Scholar
  70. 70.
    Jiang M, Stephanopoulos G, Pfeifer BA (2012) Toward biosynthetic design and implementation of Escherichia coli-derived paclitaxel and other heterologous polyisoprene compounds. Appl Environ Microbiol 78:2497–2504Google Scholar
  71. 71.
    Alper H, Miyaoku K, Stephanopoulos G (2005) Construction of lycopene-overproducing E. coli strains by combining systematic and combinatorial gene knockout targets. Nat Biotech 23:612–616Google Scholar
  72. 72.
    Newman JD, Marshall J, Chang M, Nowroozi F, Paradise E, Pitera D, Newman KL, Keasling JD (2006) High-level production of amorpha-4,11-diene in a two-phase partitioning bioreactor of metabolically engineered Escherichia coli. Biotechnol Bioeng 95:684–691Google Scholar
  73. 73.
    Boghigian BA, Salas D, Ajikumar PK, Stephanopoulos G, Pfeifer BA (2012) Analysis of heterologous taxadiene production in K- and B-derived Escherichia coli. Appl Microbiol Biotechnol 93:1651–1661Google Scholar
  74. 74.
    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 93:2063–2073Google Scholar
  75. 75.
    Jennewein S, Long RM, Williams RM, Croteau R (2004) Cytochrome P450 taxadiene 5 alpha-hydroxylase, a mechanistically unusual monooxygenase catalyzing the first oxygenation step of taxol biosynthesis. Chem Biol 11:379–387Google Scholar
  76. 76.
    Jardine O, Gough J, Chothia C, Teichmann SA (2002) Comparison of the small molecule metabolic enzymes of Escherichia coli and Saccharomyces cerevisiae. Genome Res 12:916–929Google Scholar
  77. 77.
    Gruchattka E, Hadicke O, Klamt S, Schutz V, Kayser O (2013) In silico profiling of Escherichia coli and Saccharomyces cerevisiae as terpenoid factories. Microb Cell Fact 12:1475–2859Google Scholar
  78. 78.
    Engels B, Dahm P, Jennewein S (2008) Metabolic engineering of taxadiene biosynthesis in yeast as a first step towards Taxol (Paclitaxel) production. Metab Eng 10:201–206Google Scholar
  79. 79.
    Preuss D, Mulholland J, Kaiser CA, Orlean P, Albright C, Rose MD, Robbins PW, Botstein D (1991) Structure of the yeast endoplasmic reticulum: localization of ER proteins using immunofluorescence and immunoelectron microscopy. Yeast 7:891–911Google Scholar
  80. 80.
    Paddon CJ, Keasling JD (2014) Semi-synthetic artemisinin: a model for the use of synthetic biology in pharmaceutical development. Nat Rev Microbiol 12:355–367Google Scholar
  81. 81.
    Carlsen S, Ajikumar PK, Formenti LR, Zhou K, Phon TH, Nielsen ML, Lantz AE, Kielland-Brandt MC, Stephanopoulos G (2013) Heterologous expression and characterization of bacterial 2-C-methyl-D-erythritol-4-phosphate pathway in Saccharomyces cerevisiae. Appl Microbiol Biotechnol 97:5753–5769Google Scholar
  82. 82.
    Jennewein S, Park H, DeJong JM, Long RM, Bollon AP, Croteau RB (2005) Coexpression in yeast of Taxus cytochrome P450 reductase with cytochrome P450 oxygenases involved in Taxol biosynthesis. Biotechnol Bioeng 89:588–598Google Scholar
  83. 83.
    Stierle A, Strobel G, Stierle D (1993) Taxol and taxane production by Taxomyces andreanae, an endophytic fungus of Pacific yew. Science 260:214–216Google Scholar
  84. 84.
    Liu K, Ding X, Deng B, Chen W (2009) Isolation and characterization of endophytic taxol-producing fungi from Taxus chinensis. J Ind Microbiol Biotechnol 36:1171–1177Google Scholar
  85. 85.
    Heinig U, Scholz S, Jennewein S (2013) Getting to the bottom of Taxol biosynthesis by fungi. Fungal Diversity 60:161–170Google Scholar
  86. 86.
    Wang C, Wu J, Mei X (2001) Enhancement of taxol production and excretion in Taxus chinensis cell culture by fungal elicitation and medium renewal. Appl Microbiol Biotechnol 55:404–410Google Scholar
  87. 87.
    Zhao K, Ping W, Li Q, Hao S, Zhao L, Gao T, Zhou D (2009) Aspergillus niger var. taxi, a new species variant of taxol-producing fungus isolated from Taxus cuspidata in China. J Appl Microbiol 107:1202–1207Google Scholar
  88. 88.
    Ketchum RE, Wherland L, Croteau RB (2007) Stable transformation and long-term maintenance of transgenic Taxus cell suspension cultures. Plant Cell Rep 26:1025–1033Google Scholar
  89. 89.
    Vongpaseuth K, Nims E, St Amand M, Walker EL, Roberts SC (2007) Development of a particle bombardment-mediated transient transformation system for Taxus spp. cells in culture. Biotechnol Prog 23:1180–1185Google Scholar
  90. 90.
    Zhang P, Li S-T, Liu T-T, Fu C-H, Zhou P-P, Zhao C-F, Yu L-J (2011) Overexpression of a 10-deacetylbaccatin III-10 β-O-acetyltransferase gene leads to increased taxol yield in cells of Taxus chinensis. Plant Cell. Tissue Organ Cult (PCTOC) 106:63–70Google Scholar
  91. 91.
    Li Y, Pfeifer BA (2014) Heterologous production of plant-derived isoprenoid products in microbes and the application of metabolic engineering and synthetic biology. Curr Opin Plant Biol 19C:8–13Google Scholar
  92. 92.
    Vogel C, Marcotte EM (2012) Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet 13:227–232Google Scholar
  93. 93.
    Golomb M, Chamberlin M (1974) Characterization of T7-specific ribonucleic acid polymerase. IV. Resolution of the major in vitro transcripts by gel electrophoresis. J Biol Chem 249:2858–2863Google Scholar
  94. 94.
    McAllister WT, Morris C, Rosenberg AH, Studier FW (1981) Utilization of bacteriophage T7 late promoters in recombinant plasmids during infection. J Mol Biol 153:527–544Google Scholar
  95. 95.
    Khalil AS, Collins JJ (2010) Synthetic biology: applications come of age. Nat Rev Genet 11:367–379Google Scholar
  96. 96.
    Terpe K (2006) Overview of bacterial expression systems for heterologous protein production: from molecular and biochemical fundamentals to commercial systems. Appl Microbiol Biotechnol 72:211–222Google Scholar
  97. 97.
    Schlegel S, Rujas E, Ytterberg AJ, Zubarev R, Luirink J, de Gier J-W (2013) Optimizing heterologous protein production in the periplasm of E. coli by regulating gene expression levels. Microbial Cell Fact 12:24Google Scholar
  98. 98.
    Filipowicz W, Bhattacharyya SN, Sonenberg N (2008) Mechanisms of post-transcriptional regulation by microRNAs: are the answers in sight? Nat Rev Genet 9:102–114Google Scholar
  99. 99.
    Smolke CD, Martin VJ, Keasling JD (2001) Controlling the metabolic flux through the carotenoid pathway using directed mRNA processing and stabilization. Metab Eng 3:313–321Google Scholar
  100. 100.
    Nishizaki T, Tsuge K, Itaya M, Doi N, Yanagawa H (2007) Metabolic engineering of carotenoid biosynthesis in Escherichia coli by ordered gene assembly in Bacillus subtilis. Appl Environ Microbiol 73:1355–1361Google Scholar
  101. 101.
    Xu P, Vansiri A, Bhan N, Koffas MA (2012) ePathBrick: a synthetic biology platform for engineering metabolic pathways in E. coli. ACS Synth Biol 1:256–266Google Scholar
  102. 102.
    Yu D, Ellis HM, Lee E-C, Jenkins NA, Copeland NG (2000) An efficient recombination system for chromosome engineering in Escherichia coli. Proc Nat Acad Sci 97:5978–5983Google Scholar
  103. 103.
    Tyson GW, Chapman J, Hugenholtz P, Allen EE, Ram RJ, Richardson PM, Solovyev VV, Rubin EM, Rokhsar DS, Banfield JF (2004) Community structure and metabolism through reconstruction of microbial genomes from the environment. Nature 428:37–43Google Scholar
  104. 104.
    Wingler LM, Cornish VW (2011) Reiterative Recombination for the in vivo assembly of libraries of multigene pathways. Proce Nat Acad Sci 108:15135–15140Google Scholar
  105. 105.
    Gibson DG, Young L, Chuang RY, Venter JC, Hutchison CA 3rd, Smith HO (2009) Enzymatic assembly of DNA molecules up to several hundred kilobases. Nat Methods 6:343–345Google Scholar
  106. 106.
    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 8:536–546Google Scholar
  107. 107.
    Schofield MM, Sherman DH (2013) Meta-omic characterization of prokaryotic gene clusters for natural product biosynthesis. Curr Opin Biotechnol 24:1151–1158Google Scholar
  108. 108.
    Alper H, Jin Y-S, Moxley J, Stephanopoulos G (2005) Identifying gene targets for the metabolic engineering of lycopene biosynthesis in Escherichia coli. Metab Eng 7:155–164Google Scholar
  109. 109.
    Feist AM, Palsson BØ (2008) The growing scope of applications of genome-scale metabolic reconstructions using Escherichia coli. Nat Biotechnol 26:659–667Google Scholar
  110. 110.
    Becker SA, Feist AM, Mo ML, Hannum G, Palsson BØ, Herrgard MJ (2007) Quantitative prediction of cellular metabolism with constraint-based models: the COBRA Toolbox. Nat Protoc 2:727–738Google Scholar
  111. 111.
    Boghigian BA, Shi H, Lee K, Pfeifer BA (2010) Utilizing elementary mode analysis, pathway thermodynamics, and a genetic algorithm for metabolic flux determination and optimal metabolic network design. BMC Syst Biol 4:0509–1752Google Scholar
  112. 112.
    Bordbar A, Monk JM, King ZA, Palsson BO (2014) Constraint-based models predict metabolic and associated cellular functions. Nat Rev Genet 15:107–120Google Scholar
  113. 113.
    Zhou X, Wang Z, Jiang K, Wei Y, Lin J, Sun X, Tang K (2007) Screening of taxol-producing endophytic fungi from Taxus chinensis var. mairei. Appl Biochem Microbiol 43:439–443Google Scholar
  114. 114.
    Santos CNS, Stephanopoulos G (2008) Combinatorial engineering of microbes for optimizing cellular phenotype. Curr Opin Chem Biol 12:168–176Google Scholar
  115. 115.
    Adrio JL, Demain AL (2006) Genetic improvement of processes yielding microbial products. FEMS Microbiol Rev 30:187–214Google Scholar
  116. 116.
    Kardos N, Demain AL (2011) Penicillin: the medicine with the greatest impact on therapeutic outcomes. Appl Microbiol Biotechnol 92:677–687Google Scholar
  117. 117.
    Demain AL, Sanchez S (2009) Microbial drug discovery: 80 years of progress. J Antibiot 62:5–16Google Scholar
  118. 118.
    Demain AL, Elander RP (1999) The beta-lactam antibiotics: past, present, and future. Antonie Van Leeuwenhoek 75:5–19Google Scholar
  119. 119.
    Demain AL (2006) From natural products discovery to commercialization: a success story. J Ind Microbiol Biotechnol 33:486–495Google Scholar
  120. 120.
    Srinivasan V, Pestchanker L, Moser S, Hirasuna TJ, Taticek RA, Shuler ML (1995) Taxol production in bioreactors: kinetics of biomass accumulation, nutrient uptake, and taxol production by cell suspensions of Taxus baccata. Biotechnol Bioeng 47:666–676Google Scholar
  121. 121.
    Navia-Osorio A, Garden H, Cusidó RM, Palazón J, Alfermann AW, Piñol MT (2002) Taxol® and baccatin III production in suspension cultures of Taxus baccata and Taxus wallichiana in an airlift bioreactor. J Plant Physiol 159:97–102Google Scholar
  122. 122.
    Alper H, Miyaoku K, Stephanopoulos G (2006) Characterization of lycopene-overproducing E. coli strains in high cell density fermentations. Appl Microbiol Biotechnol 72:968–974Google Scholar
  123. 123.
    Chattopadhyay S, Farkya S, Srivastava AK, Bisaria VS (2002) Bioprocess considerations for production of secondary metabolites by plant cell suspension cultures. Biotechnol Bioprocess Eng 7:138–149Google Scholar
  124. 124.
    Sandén AM, Prytz I, Tubulekas I, Förberg C, Le H, Hektor A, Neubauer P, Pragai Z, Harwood C, Ward A (2003) Limiting factors in Escherichia coli fed-batch production of recombinant proteins. Biotechnol Bioeng 81:158–166Google Scholar
  125. 125.
    Shiloach J, Fass R (2005) Growing E. coli to high cell density–a historical perspective on method development. Biotechnol Adv 23:345–357Google Scholar
  126. 126.
    Birol G, Ündey C, Çinar A (2002) A modular simulation package for fed-batch fermentation: penicillin production. Comput Chem Eng 26:1553–1565Google Scholar
  127. 127.
    Yamane Y, Higashida K, Nakashimada Y, Kakizono T, Nishio N (1997) Influence of Oxygen and Glucose on Primary Metabolism and Astaxanthin Production by Phaffia rhodozyma in Batch and Fed-Batch Cultures: Kinetic and Stoichiometric Analysis. Appl Environ Microbiol 63:4471–4478Google Scholar
  128. 128.
    Plackett RL, Burman JP (1946) The design of optimum multifactorial experiments. Biometrika:305–325Google Scholar
  129. 129.
    Betts JI, Baganz F (2006) Miniature bioreactors: current practices and future opportunities. Microb Cell Fact 5:21Google Scholar
  130. 130.
    Lye GJ, Ayazi-Shamlou P, Baganz F, Dalby PA, Woodley JM (2003) Accelerated design of bioconversion processes using automated microscale processing techniques. Trends Biotechnol 21:29–37Google Scholar
  131. 131.
    Sajc L, Grubisic D, Vunjak-Novakovic G (2000) Bioreactors for plant engineering: an outlook for further research. Biochem Eng J 4:89–99Google Scholar
  132. 132.
    Chaudhary AG, Rimoldi JM, Kingston DG (1993) Modified taxols. 10. Preparation of 7-deoxytaxol, a highly bioactive taxol derivative, and interconversion of taxol and 7-epi-taxol. J Organ Chem 58:3798–3799Google Scholar
  133. 133.
    Verweij J, Clavel M, Chevalier B (1994) Paclitaxel (TaxolTM) and docetaxel (TaxotereTM): not simply two of a kind. Ann Oncol 5:495–505Google Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Department of Chemical and Biological EngineeringThe State University of New York at BuffaloBuffaloUSA

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