Production of natural products by plant cell biotechnology: results, problems and perspectives

  • A. W. Alfermann
  • Maike Petersen
  • Elizabeth Fuss


This short review presents some examples, which demonstrate the importance and the potential of plant cell and tissue cultures for a biotechnological production of natural products. On the other hand, it still can not be denied, that despite intensive work for some 30 years all over the world a real breakthrough of this technique has been achieved only very recently (Phyton 2002). The problems we are faced with and some new possibilities to overcome these problems will be discussed (for more detailed and/or special discussion see e.g. Walton et al. 1999, Bourgaud et al. 2001, Stafford 2002.


Cell Suspension Culture Rosmarinic Acid Plant Cell Culture Tropane Alkaloid Alkaloid Biosynthesis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Airi S., Rawal R. S., Dhar U., Purohit A. N. (1997) Population studies on Podophyllum hexandrum Royle — a dwindling medicinal plant of the Himalaya. Plant Genet. Resour. Newsl. 110: 20–34.Google Scholar
  2. Akiu S., Suzuki Y., Fujinuma Y., Asahara T., Fukuda M. (1988) Inhibitory effect of arbutin on melanogenesis: Biochemical study in cultured B16 melanoma cells and effect on the UV-induced pigmentation in human skin. Proc. Japan. Soc. Invest. Dermatol. 12: 138–139.Google Scholar
  3. Alfermann A. W., Bergmann W., Figur C., Helmbold U., Schwantag D., Schuller I., Reinhard E. (1983) Biotransformation of ß-methyldigitoxin to ß-methyldigoxin by cell cultures of Digitalis lanata. In: Mantell S. H., Smith H. (eds.) Plant biotechnology. Cambridge University Press, Cambridge, pp. 67–74.Google Scholar
  4. Allison A. J., Butcher D. N., Connolly J. D., Overton K. H. (1968) Paniculides A, B, and C, bisabonolenoid lactones from tissue cultures of Andrographis paniculata. Chem. Comm. 1493.Google Scholar
  5. Anonymus (2002) Bioprocess news. Genet. Eng. News 22: 66.Google Scholar
  6. Arend J., Warzecha H., Hefner T., Stöckigt J. (2001) Utilizing genetically engineered bacteria to produce plant specific glucosides. Biotech. Bioeng. 76: 126–131.CrossRefGoogle Scholar
  7. Ball E. (1967) Production of a group of anthocyanins in a callus culture under the influence of an auxin. Plant Physiol. 42[Suppl]: S24.Google Scholar
  8. Bourgaud F., Gravot A., Milesi S., Gontier E. (2001) Production of plant secondary metabolites: a historical perspective. Plant Sci. 161: 839–851.CrossRefGoogle Scholar
  9. DeCapite L. (1955) Azione degli zuccheri e delle basse temperature sulla formatione degli antociani in radici di Daucus carota coltivato in vitro. Ric. Sci. 35: 2091–2097.Google Scholar
  10. Eilert U. F. K., Kurz W. G. W., Constabel F. (1985) Stimulation of sanguinarine accumulation in Papaver somniferum cell cultures by fungal elicitors. J. Plant Physiol. 119: 65–76.CrossRefGoogle Scholar
  11. Empt U., Alfermann A. W., Pras N., Petersen M. (2000) The use of plant cell cultures for the production of podophyllotoxin and related lignans. J. Appl. Bot. 74: 145–150.Google Scholar
  12. Farnsworth N. R. (1985) The role of medicinal plants in drug development. In: Kroogsgard-Larsen P., Brogger Christensen S., Koford H. (eds.) Natural products and drug development. Munksgaard, Copenhagen, pp. 17–30.Google Scholar
  13. Fischer R., Drossard J., Schillberg S., Artsaenko O., Emans N., Naehring J. M. (2000) Modulation of plant function and plant pathogens by antibody expression. In: Verpoorte R., Alfermann A. W. (eds.) Metabolic engineering of plant secondary metabolism. Kluwer Academic Publishers, Dordrecht, pp. 87–109.Google Scholar
  14. Fujita Y., Tabata M., Nishi A., Yamada Y. (1982) New medium and production of secondary compounds with the two-staged culture method. In: Fujiwara A. (ed.) Plant tissue culture 1982. Maruzen, Tokyo, pp. 399–400.Google Scholar
  15. Gautheret R. J. (1939) Sur la possibilité de réaliser la culture indéfinie des tissus de tubercules de carotte. C. R. Acad. Sci. Paris 208: 118–120.Google Scholar
  16. Gautheret R. J. (1941) Action du saccharose sur la croissance des tissus de carotte. C. R. Soc. Biol. 135: 875–878.Google Scholar
  17. Gräther G., Schneider B. (2001) The metabolic diversity of plant cell and tissue cultures. Progr. Bot. 62: 276–304.Google Scholar
  18. Grotewold E., Chamberlin M., Snook M., Siame B., Butler L., Swenson J., Maddock S., St.Clair G. Bowen B. (1998) Engineering secondary metabolism in maize cells by ectopic expression of transcription factors. Plant Cell 10: 721–740.Google Scholar
  19. Gupta R., Sethi K. L. (1983) Conservation of medicinal plant resources in Himalayan region. In: Jain S. K., Mehra K. L. (eds.) Conservation of tropical plant resources. Botanical Survey of India, Howrah, pp. 101–107.Google Scholar
  20. Haberlandt G. (1902) Culturversuche mit isolierten Pflanzenzellen. Sitzungsberichte Math. Naturw. Kl. Kais. Akad. Wiss. Wien 111: 69 – 92.Google Scholar
  21. Hain R., Bieseler B., Kindl H., Schröder G., Stöcker R. (1990) Expression of a stilbene synthase gene in Nicotiana tabacum results in synthesis of the phytoalexin resveratrol. Plant Mol. Biol. 15: 325–335.Google Scholar
  22. Hain R., Reif H. J., Krause E., Langebartels R., Kindl H., Vornam B., Wiese W., Schmelzer E., Schreier P. H., Stöcker R. H., Stenzel K. (1993) Disease resistance results from foreign phytoalexin expression in a novel plant. Nature 361: 153–156.PubMedCrossRefGoogle Scholar
  23. Hampp N., Zenk M. H. (1988) Homogeneous strictosidine synthase from cell suspension cultures of Rauwolfia serpentina. Phytochemistry 27: 3811–3815.CrossRefGoogle Scholar
  24. Hartmann T. (1985) Principles of plant secondary metabolism. Plant Syst. Evol.150:13–34.Google Scholar
  25. Hashimoto T., Yamada Y. (1992) Biosynthesis of scopolamine and its application for genetic engineering of medicinal plants. In: Oono R., Hirabayashi T., Kiruchi S., Handa H., Kahwara S. (eds.) Plant tissue culture and gene manipulation for breeding and formation of phytochemicals. National Institute of Agrobiological Resources, Tsukuba/Japan, pp. 255–259.Google Scholar
  26. Heide L., Tabata M. (1987a) Enzyme activities in cell-free extracts of shikoninproducing Lithospermum erythrorhizon cell suspension cultures. Phytochemistry 26: 1645–1650.CrossRefGoogle Scholar
  27. Heide L., Tabata M. (1987b) Geranylpyrophosphate:p-hydroxybenzoate geranyltransferase activity in extracts of Lithospermum erythrorhizon cell cultures. Phytochemistry 26: 1651–1655.CrossRefGoogle Scholar
  28. Henkel T., Brunne R. M., Müller H., Reichel F. (1999) Statistical investigation into the structural complementarity of natural products and synthetic compounds. Angew. Chem. Int. Ed. 38: 643–647.CrossRefGoogle Scholar
  29. Herbers K., Wilke I., Sonnewald U. (1995) A thermostable xylanase from Clostridium thermocellum expressed at high levels in the apoplast of transgenic tobacco has no detrimental effects and is easily purified. Bio/Technology 13: 63–66.CrossRefGoogle Scholar
  30. Inoue H., Ueda S., Inoue K., Matsumura H. (1979) Biosynthesis of shikonin in callus cultures of Lithospermum erythrorhizon. Phytochemistry 18: 1301–1308.CrossRefGoogle Scholar
  31. Kesselring (1985) Pflanzenzellkulturen (PZK) zur Auffindung neuer, therapeutisch relevanter Naturstoffe und deren Gewinnung durch Fermentationsprozesse. In: Bundesminister für Forschung und Technologie (ed.) Pflanzliche Zellkulturen. Projektträger Biotechnologie, KFA Jülich, pp. 111–129.Google Scholar
  32. Kingston D. G. I., Newman D. J. (2002) Mother nature’s combinatorial libraries; their influence on the synthesis of drugs. Curr. Opinion Drug Discovery & Development 5: 304–316.Google Scholar
  33. Konuklugil B., Schmidt T. J., Alfermann A. W. (1999) Accumulation of aryltetralin lactone lignans in cell suspension cultures of Linum nodiflorum. Planta Med. 65: 587–588.PubMedCrossRefGoogle Scholar
  34. Konuklugil B., Schmidt T. J., Alfermann A. W. (2001) Accumulation of lignans in suspension cultures of Linum mucronatum ssp. armenum (Bordz.) Davis. Z. Naturforsch. 56c: 1164–1165.Google Scholar
  35. Kurz W. G. W., Tyler R. T., Roewer I. A. (1990) Elicitation — a method to induce metabolite production by plant cells. In: Durand G., Bobichon L., Florent J. (eds.) Proc. 8th Int. Biotechnol. Symp., vol. 1. Soc. Franc. Microbiol., Paris, pp. 193–204.Google Scholar
  36. Kutchan T. M. (1989) Expression of enzymatically active cloned strictosidine synthase from the higher plant Rauwolfia serpentina in Escherichia coll. FEBS Lett. 257: 127–130.PubMedCrossRefGoogle Scholar
  37. Kutchan T., Dittrich H., Bracher D., Zenk M. H. (1991) Enzymology and molecular biology of alkaloid biosynthesis. Tetrahedron 47: 5945–5954.CrossRefGoogle Scholar
  38. Lutterbach R., Stöckigt J. (1992) High-yield formation of arbutin from hydroquinone by cell-suspension cultures of Rauwolfia serpentina. Hely. Chim. Acta 75: 2009–2011.Google Scholar
  39. Lutterbach R., Ruyter C. M., Stöckigt J. (1994) Isolation and characterization of an UDPG-dependent glucosyltransferase activity from Rauwolfia serpentina Benth. cell suspension cultures. Can. J. Chem. 72: 51–55.Google Scholar
  40. Memelink J, Verpoorte R., Kijne J. W. (2001) ORCAnisation of jasmonate-responsive gene expression in alkaloid metabolism. Trends Plant Sci. 6: 212–219.PubMedCrossRefGoogle Scholar
  41. Menke F. L. H., Champion A., Kijne J. W., Memelink J. (1999) A novel jasmonateresponsive element in the periwinkle secondary metabolite biosynthetic gene Str interacts with a jasmonate-and elicitor-inducible AP2-domain transcription factor, ORCA2. EMBO J. 18: 4455–4463.CrossRefGoogle Scholar
  42. Mizukami H., Terato T., Miura H., Ohashi H. (1983) Glucosylation of salicyl alcohol in cultured plant cells. Phytochemistry 22: 679–680.CrossRefGoogle Scholar
  43. Mizukami H., Terato T., Ohashi H. (1985) Partial purification and characterization of UDP-glucose:salicyl alcohol glucosyltransferase from Gardenia jasminoides cell cultures. Planta Med. 46: 104–107.CrossRefGoogle Scholar
  44. Mizukami H., Terato T., Amano A., Ohashi H. (1986) Glucosylation of salicyl alcohol by Gardenia jasminoides cell cultures. Plant Cell Physiol. 27: 645–650.Google Scholar
  45. Mizukami H., Terato T., Ohashi H. (1987) Effect of substituent groups on the glucosyl formation of xenobiotic phenols by cultured cells of Gardenia jasminoides. Plant Sci. 48: 11–15.CrossRefGoogle Scholar
  46. Mohagheghzadeh A., Schmidt T. J., Alfermann A. W. (2002) Arylnaphthalene lignans from in vitro cultures of Linum austriacum. J. Nat. Prod. 65: 69–71.PubMedCrossRefGoogle Scholar
  47. Molog G. A., Empt U., Kuhlmann S., van Uden W., Pras N., Alfermann A. W., Petersen M. (2001) Deoxypodophyllotoxin 6-hydroxylase, a cytochrome P450 monooxygenase from cell cultures of Linum flavum involved in the biosynthesis of cytotoxic lignans. Planta 214: 288–294.PubMedCrossRefGoogle Scholar
  48. Nobécourt P. (1937) Culture en série de tissus végétaux sur milieu artificiel. C.R. Séances Soc. Biol. 205: 521–523.Google Scholar
  49. Pabsch K., Petersen M., Rao N. N., Alfermann A. W., Wandrey C. (1991) Chemo-enzymatic synthesis of rosmarinic acid. Rec. Tray. Chim. Pays-Bas 110: 199–205.CrossRefGoogle Scholar
  50. Petersen M. (1995) Plant cell cultures as a source of enzymes involved in natural product biosynthesis. Proc. 7th Europ. Congr. Biotechnol., Nice, France.Google Scholar
  51. Petersen M., Alfermann A. W. (2001) The production of cytotoxic lignans byplant cell cultures. Appl. Microbiol. Biotechnol. 55: 135–142.PubMedCrossRefGoogle Scholar
  52. Petersen M., Seitz H. U. (1985) Cytochrome P-450 dependent digitoxin 12ßhydroxylase from cell cultures of Digitalis lanata. FEBS Lett. 188: 11–14.CrossRefGoogle Scholar
  53. Petersen M., Seitz H. U. (1988) Reconstitution of cytochrome P-450 dependent digitoxin 12ß-hydroxylase from cell cultures of Digitalis lanata Ehrh. Biochem. J. 252: 537–543.Google Scholar
  54. Petersen M., Seitz H. U., Reinhard E. (1988) Characterization and localization of digitoxin 12ß-hydroxylase from cell cultures of Digitalis lanata Ehrh. Z. Naturforsch. 43c: 199–206.Google Scholar
  55. Petersen M., Alfermann A. W., Reinhard E., Seitz H. U. (1987) Immobilization of digitoxin 12ß-hydroxylase, a cytochrome P-450-dependent enzyme from cell cultures of Digitalis lanata EHRH. Plant Cell Rep. 6: 200–203.CrossRefGoogle Scholar
  56. Petersen M., Dombrowski K., Gertlowski C., Häusler E., Karwatzki B., Meinhard J., Alfermann A. W. (1992) The use of plant cell cultures to study natural product biosynthesis. In: Oono R., Hirabayashi T., Kiruchi S., Handa H., Kahwara S. (eds.) Plant tissue culture and gene manipulation for breeding and formation of phytochemicals. National Institute of Agrobiological Resources, Tsukuba/Japan, pp. 297–310.Google Scholar
  57. Pfitzner U., Zenk M. H. (1982) Immobilization of strictosidine synthase from Catharanthus cell cultures and preparative synthesis of strictosidine. Planta Med. 46: 10–14.PubMedCrossRefGoogle Scholar
  58. Phyton Inc. (2002) Phyton expands commercial partnership with Bristol-Myers Sqibb for paclitaxel supply. Press release July 10, 2002.Google Scholar
  59. Pilgrim H. (1970) Untersuchungen zur Glycosidbildung in pflanzlichen Gewebekulturen. Pharmazie 25: 568.PubMedGoogle Scholar
  60. Reinert J., Clauss H., von Ardenne R. (1964) Anthocyanbildung in Gewebekulturen von Haplopappus gracilis in Licht verschiedener Qualität. Naturwissenschaften 51: 87.CrossRefGoogle Scholar
  61. Romeike A. (1960) Die Rolle von Sproß und Wurzel bei der Umwandlung des Hyoscyamins in verschiedenen Datura Arten. Planta Med. 8: 491–496.CrossRefGoogle Scholar
  62. Routien J. B., Nickel L. G. (1952) Cultivation of Plant Tissue. US Patent 2,747,334. Ruyter C. M., Stöckigt J. (1989) Novel natural products from plant cell and tissuecultures — an update. GIT Fachz. Lab. 4: 283–293.Google Scholar
  63. Scott A. I. (1994) Genetically engineered synthesis of natural products. J. Nat. Prod. 57: 557–573.PubMedCrossRefGoogle Scholar
  64. Seidel V., Windhövel J., Eaton G., Alfermann W., Arroo R. R., Medarde M., Petersen M., Woolley J. G. (2002) Biosynthesis of podophyllotoxin in Linum album cell cultures. Planta: published online July 25.Google Scholar
  65. Smollny T., Wichers H., Kalenberg S., Shahsavary A., Petersen M., Alfermann A W. (1998) Accumulation of podophyllotoxin and related lignans in cell suspension cultures of Linum album. Phytochemistry 48: 975–979.CrossRefGoogle Scholar
  66. Stafford A. M. (2002) Plant cell cultures as a source of bioactive small molecules. Curr. Opinion Drug Discovery & Development 5: 296–303.Google Scholar
  67. Stöckigt J. (1993) Biotransformations with plant cells. Agro-Food-Industry Hi-Tech, 25–28.Google Scholar
  68. Suzuki T., Yoshioka T., Tabata M., Fujita Y. (1987) Potential of Datura innoxia cell suspension cultures for glycosylating hydroquinone. Plant Cell Rep. 6: 275–278.CrossRefGoogle Scholar
  69. Tabata M., Ikeda F., Hiraoka N., Konoshima M. (1976) Glucosylation of phenolic compounds by Datura innoxia suspension cultures. Phytochemistry 15: 1225–1229.CrossRefGoogle Scholar
  70. Tabata M., Umetani Y., Ooya M., Tanaka S. (1988) Glucosylation of phenolic compounds by plant cell cultures. Phytochemistry 27: 809–813.CrossRefGoogle Scholar
  71. Tanaka S., Hayakawa K., Umetani Y., Tabata M. (1990) Glucosylation of isomeric hydroxybenzoic acids by cell suspension cultures of Mallotus japonicus. Phytochemistry 29: 1555–1558.CrossRefGoogle Scholar
  72. Treimer J. F., Zenk M. H. (1979) Purification and properties of strictosidine synthase,the key enzyme in indole alkaloid formation. Eur. J. Biochem. 101: 225–233.PubMedCrossRefGoogle Scholar
  73. Ushiyama K. (1991) Large scale cultivation of ginseng. In: Komamine A., MisawaA.,DiCosmo F. (eds.) Plant cell culture in Japan. CMC, Tokyo, pp. 92–98.Google Scholar
  74. Van der Fits L., Memelink J. (2000) ORCA3, a jasmonate-responsive transcriptionalregulator of plant primary and secondary metabolism. Science 289: 295–297.PubMedCrossRefGoogle Scholar
  75. Venkat K. (1998) Paclitaxel production through plant cell culture: An exciting approach to harnessing biodiversity. Pure Appl. Chem. 70: 2127.Google Scholar
  76. Verpoorte R., Alfermann A. W. (2000) Metabolic engineering of plant secondary metabolism. Kluwer Academic Publishers, Dordrecht.Google Scholar
  77. Verpoorte R., Memelink J (2002) Engineering secondary metabolite production in plants. Curr. Opinion Biotechnol. 13: 181–187.CrossRefGoogle Scholar
  78. Wahl J. (1985) Adaption konventioneller Fermenter zur Züchtung von Pflanzenzellen zum Zwecke der Gewinnung von Naturstoffen. In: Bundesminister für Forschung und Technologie (ed.) Pflanzliche Zellkulturen. Projektträger Biotechnologie, KFA Jülich, pp. 35–43.Google Scholar
  79. Walton N. J., Alfermann A. W., Rhodes M. J. C. (1999) Production of secondary metabolites in cell and differentiated organ cultures. In: Wink E. (ed.) Annual Plant Reviews 3: Functions of plant secondary metabolites and their exploitation in biotechnology. Sheffield Academic Press, Sheffield, pp. 311–345.Google Scholar
  80. Westphal K. (1990) Large scale production of new biologically active compounds in plant cell cultures. In: Nijkamp H. J. J., van der Plas L. H. W., van Aartrijk J. (eds.) Progress in plant cellular and molecular biology. Kluwer, Dordrecht, pp. 601–608.CrossRefGoogle Scholar
  81. White P. R. (1939) Potentially unlimited growth of excised plant callus in an artificial medium. Am. J. Bot. 26: 59–64.CrossRefGoogle Scholar
  82. Yokoyama M., Yanagi M. (1991) High level production of arbutin by biotransforma-tion. In: Komamine A., Misawa M. (eds.) Plant cell culture in Japan. CMC, Tokyo, pp. 79–91.Google Scholar
  83. Zenk M. H., El-Shagi H., Arens H., Stöckigt J., Weiler E. W., Deus B. (1977) Formation of indole alkaloids serpentine and ajmalicine in cell suspension cultures of Catharanthus roseus. In: Barz W., Reinhard E., Zenk M. H. (eds.) Plant tissue culture and its bio-technological application. Springer, Berlin, pp. 27–43.Google Scholar
  84. Zenk M. H. (1991) Chasing the enzymes of secondary metabolism: Plant cell cultures as a pot of gold. Phytochemistry 30: 3861–3863.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag Wien 2003

Authors and Affiliations

  • A. W. Alfermann
    • 1
    • 3
  • Maike Petersen
    • 2
  • Elizabeth Fuss
    • 1
    • 3
  1. 1.Institut für EntwicklungsHeinrich-Heine-Universität DüsseldorfDüsseldorfGermany
  2. 2.Institute für Pharmazeutische BiologiePhilipps-Universität MarburgMarburgGermany
  3. 3.Molekularbiologie der PflanzenHeinrich-Heine-Universität DüsseldorfDüsseldorfGermany

Personalised recommendations