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Aspects of cytotoxic lignan biosynthesis in suspension cultures of Linum nodiflorum

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Abstract

Plant cell suspension cultures of Linum flavum, Linum nodiflorum and Linum album have been used to characterize the growth and production of cytotoxic lignans as well as to study the biosynthesis of these lignans. A cell culture of Linum nodiflorum accumulated up to 1.7% of the cell dry weight as 6-methoxypodophyllotoxin in only nine days of cultivation. The biosynthesis of podophyllotoxin and 6-methoxypodophyllotoxin follows the formation of the first aryltetralin lignan deoxypodophyllotoxin. Hydroxylation in position 7 by deoxypodophyllotoxin 7-hydroxylase leads to podophyllotoxin. Hydroxylation in position 6 by the cytochrome P450 monooxygenase deoxypodophyllotoxin 6-hydroxylase yields β-peltatin which is further methylated by S-adenosylmethionine:β-peltatin 6-O-methyltransferase to β-peltatin-A methylether and then hydroxylated to 6-methoxypodophyllotoxin. Both, podophyllotoxin as well as 6-methoxypodophyllotoxin are stored as glucosides in the vacuole. Certain enzymes of these transformations have been isolated and characterized from Linum cell cultures.

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References

  • Airi S, Rawal RS, Dhar U & Purohit AN (1997) Population studies on Podophyllum hexandrum Royle-a dwindling medicinal plant of the Himalaya. Plant Genet. Resour. Newsl. 110: 20–34.

    Google Scholar 

  • Bohlin L & Rosen B (1996) Podophyllotoxin derivatives: drug discovery and development. Drug Discovery Today 1: 343–351.

    Google Scholar 

  • Canel C, Moraes RM, Dayan FE & Ferreira D (2000) Podophyllotoxin. Phytochemistry 54: 115–120.

    Google Scholar 

  • Chu A, Dinkova A, Davin LB, Bedgar DL & Lewis NG (1992) Stereospecificity of (+)-pinoresinol and (+)-lariciresinol reductases from Forsythia intermedia. J. Biol. Chem. 268: 27026–27033.

    Google Scholar 

  • Damayanthi Y & Lown JW (1998) Podophyllotoxins: Current status and recent developments. Curr. Med. Chem. 5: 205–252.

    Google Scholar 

  • Davin LB & Lewis NG (2000) Dirigent proteins and dirigent sites explain the mystery of specificity of radical precursor coupling in lignan and lignin biosynthesis. Plant Physiol. 123: 453–461.

    Google Scholar 

  • Davin LB, Wang HB, Crowell AL, Bedgar DL, Martin DM, Sarkanen S & Lewis NG (1997) Stereoselective bimolecular phenoxy radical coupling by an auxiliary (dirigent) protein without an active center. Science 275: 362–366.

    Google Scholar 

  • Dinkova-Kostova AT, Gang DR, Davin LB, Bedgar DL, Chu A & Lewis NG (1996) (+)-Pinoresinol/(+)-lariciresinol reductase from Forsythia intermedia: protein purification, cDNA cloning, heterologous expression and comparison to isoflavone reductase. J. Biol. Chem. 271: 29473–29482.

    Google Scholar 

  • Empt U, Alfermann AW, 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 

  • Gang DR, Costa MA, Fujita M, Dinkova-Kostova AT, Wang HB, Burlat V, Martin W, Sarkanen S, Davin LB & Lewis NG (1999) Regiochemical control of monolignol radical coupling: a new paradigm for lignin and lignan biosynthesis. Chem. Biol. 6: 143–151.

    Google Scholar 

  • Gupta R & Sethi KL (1983) Conservation of medicinal plant resources in Himalayan region. In: Jain SK & Mehra KL (eds) Conservation of tropical plant resources (pp. 101–107). Botanical Survey of India, Howrah.

    Google Scholar 

  • Henges A (1999) Biosynthese und Kompartimentierung von Lignanen in Zellkulturen von Linum album. PhD Thesis, University of Düsseldorf, Germany.

    Google Scholar 

  • Imbert TF (1998) Discovery of podophyllotoxins. Biochimie 80: 207–222.

    Google Scholar 

  • Konuklugil B, Schmidt TJ & Alfermann AW (1999) Accumulation of aryltetralin lactone lignans in cell suspension cultures of Linum nodiflorum. Planta Med. 65: 587–588.

    Google Scholar 

  • Konuklugil B, Schmidt TJ & Alfermann AW (2001) Accumulation of lignans in suspension cultures of Linum mucronatum ssp. armenum (Bordz.) Davis. Z. Naturforsch. 56c: 1164–1165.

    Google Scholar 

  • Kranz K & Petersen M (2001) ?-Peltatin 6-O-methyltransferase from cell cultures of Linum nodiflorum. In: Kreis W (ed) Traits, tracks and traces. International congress and 49th annual meeting of the Society for medicinal plant research (p. 225). Erlangen, Germany.

  • Kuhlmann S, Molog G, Empt U, Van Uden W, Pras N, Alfermann AW & Petersen M (2001) Characterisation of deoxypodophyllotoxin 6-hydroxylase (DOP6H), a cytochrome P450-dependent enzyme in lignan biosynthesis of Linum species. In: Kreis W (ed) Traits, tracks and traces. International congress and 49th annual meeting of the Society for medicinal plant research (p. 224). Erlangen, Germany.

  • Lewis NG & Davin LB (1999) Lignans: Biosynthesis and function. In: Barton DHR, Nakanishi K & Meth-Coon O (eds) Comprehensive natural products chemistry, Vol. 1, Sankawa U (ed) Polyketides and other secondary metabolites including fatty acids and their derivatives (pp. 639–712). Elsevier Science, Oxford.

    Google Scholar 

  • Lücking B (2001) Charakterisierung von Suspensionskulturen von Linum nodiflorum L. Diploma Thesis, Universities of Marburg and Halle-Wittenberg.

  • Mohagheghzadeh A, Schmidt TJ & Alfermann AW (2002) Arylnaphthalene lignans from in vitro cultures of Linum austriacum. J. Nat. Prod. 65: 69–71.

    Google Scholar 

  • Molog GA, Empt U, Kuhlmann S, Van Uden W, Pras N, Alfermann AW & Petersen M (2001) Deoxypodophyllotoxin 6-hydroxylase, a cytochrome P450 monooxygenase from cell cultures of Linum flavum involved in lignan biosynthesis. Planta 214: 288–294.

    Google Scholar 

  • Petersen M & Alfermann AW (2001) The production of cytotoxic lignans by plant cell cultures. Appl. Microbiol. Biotechnol. 55: 135–142.

    Google Scholar 

  • Smollny T, Wichers H, de Rijk T, van Zwam A, Shahsavari A & Alfermann AW (1992) Formation of lignans in suspension cultures of Linum album. Planta Med. 58 (Suppl. 1): A622–A623.

    Google Scholar 

  • Smollny T, Wichers H, Kalenberg S, Shahsavari A, Petersen M & Alfermann AW (1998) Accumulation of podophyllotoxin and related lignans in cell suspension cultures of Linum album. Phytochemistry 48: 975–979.

    Google Scholar 

  • Umezawa T, Davin LB & Lewis NG (1991) Formation of lignans (?)-secoisolariciresinol and (?)-matairesinol with Forsythia intermedia cell-free extracts. J. Biol. Chem. 266: 10210–10217.

    Google Scholar 

  • Van Uden W, Bos JA, Boeke GM, Woerdenbag HJ & Pras N (1997a) The large-scale isolation of deoxypodophyllotoxin from rhizomes of Anthriscus sylvestris followed by its bioconversion into 5-methoxypodophyllotoxin ?-D-glucoside by cell cultures of Linum flavum. J. Nat. Prod. 60: 401–403.

    Google Scholar 

  • Van Uden W, Bouma AS, Bracht Walker JF, Middel O, Wichers HJ, De Waard P, Woerdenbag HJ, Kellog RM & Pras N (1995) The production of podophyllotoxin and its 5-methoxy derivative through bioconversion of cyclodextrin-complexed desoxypodophyllotoxin by plant cell cultures. Plant Cell Tiss. Org. Cult. 42: 73–79.

    Google Scholar 

  • Van Uden W, Holidi Oeij K, Woerdenbag HJ & Pras N (1993) Glucosylation of cyclodextrin-complexed podophyllotoxin by cell cultures of Linum flavum L.. Plant Cell Tiss. Org. Cult. 34: 169–175.

    Google Scholar 

  • Van Uden W, Lalbahadoersing R, Molog GA, Petersen M, Woerdenbag HJ, Alfermann AW & Pras N (1997b) The isolation of ?-peltatin from podophyllin and its bioconversion into 5-methoxypodophyllotoxin-?-D-glucoside by cell cultures of Linum flavum. In: Franz G, Viweger U (eds) 45th Annual congress of the Society for medicinal plant research (p. L14). JF Lehmanns Fachbuchhandlung GmbH, Köln.

    Google Scholar 

  • Van Uden W, Pras N, Vossebeld EM, Mol JNM & Malingré TM (1990) Production of 5-methoxypodophyllotoxin in cell suspension cultures of Linum flavum L. Plant Cell Tiss. Org. Cult. 20: 81–87.

    Google Scholar 

  • Wichers H, Harkes MP & Arroo RRJ (1990) Occurrence of 5-methoxypodophyllotoxin in plants, cell cultures and regenerated plants of Linum flavum. Plant Cell Tiss. Org. Cult. 23: 93–100.

    Google Scholar 

  • Xia ZQ, Costa MA, Pélissier HC, Davin LB & Lewis NG (2001) Secoisolariciresinol dehydrogenase purification, cloning and functional expression: Implications for human health protection. J. Biol. Chem. 276: 12614–12623.

    Google Scholar 

  • Xia ZQ, Costa MA, Proctor J, Davin LB & Lewis NG (2000) Dirigent-mediated podophyllotoxin biosynthesis in Linum flavum and Podophyllum peltatum. Phytochemistry 55: 537–549.

    Google Scholar 

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Authors and Affiliations

  1. Institut für Pharmazeutische Biologie, Philipps-Universität Marburg, Deutschhausstr. 17 A, D-35037, Marburg, Germany

    S. Kuhlmann, K. Kranz, B. Lücking & M. Petersen

  2. Institut für Entwicklungs- und Molekularbiologie der Pflanzen, Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, D-40225, Düsseldorf, Germany

    A.W. Alfermann

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  1. S. Kuhlmann
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  2. K. Kranz
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  3. B. Lücking
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  4. A.W. Alfermann
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  5. M. Petersen
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Kuhlmann, S., Kranz, K., Lücking, B. et al. Aspects of cytotoxic lignan biosynthesis in suspension cultures of Linum nodiflorum . Phytochemistry Reviews 1, 37–43 (2002). https://doi.org/10.1023/A:1015876001812

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