Different polyketide folding modes converge to an identical molecular architecture

Article metrics


Metabolic diversity is being studied intensively by evolutionary biologists, but so far there has been no comparison of biosynthetic pathways leading to a particular secondary metabolite in both prokaryotes and eukaryotes. We have detected the bioactive anthraquinone chrysophanol, which serves as a chemical defense in diverse eukaryotic organisms, in a bacterial Nocardia strain, thereby permitting the first comparative biosynthetic study. Two basic modes of folding a polyketide chain to fused-ring aromatic structures have so far been described1: mode F (referring to fungi) and mode S (from Streptomyces). We have demonstrated that in eukaryotes (fungi, higher plants and insects), chrysophanol is formed via folding mode F. In actinomycetes, by contrast, the cyclization follows mode S. Thus, chrysophanol is the first polyketide synthase product that is built up by more than one polyketide folding mode.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2: The four biosynthetic folding modes that might lead from acetyl coenzyme A to chrysophanol (1) in nature, with their joint (4) and individually different (5a5d) hypothetical intermediates, with the expected characteristic 13C labeling patterns for 1.
Figure 3
Figure 4: 2D INADEQUATE NMR spectrum of 1 from Nocardia strain Acta 1057 after feeding sodium [1,2-13C2]acetate; the labeling pattern with its pairwise 13C-13C correlations of incorporated intact [13C2] units indicates the presence of mode S folding.


  1. 1

    Thomas, R. A biosynthetic classification of fungal and streptomycete fused-ring aromatic polyketides. ChemBioChem 2, 612–627 (2001).

  2. 2

    Bringmann, G., Wohlfarth, M., Rischer, H., Rückert, M. & Schlauer, J. The polyketide folding in the biogenesis of isoshinanolone and plumbagin from Ancistrocladus heyneanus (Ancistrocladaceae). Tetrahedr. Lett. 39, 8445 (1998).

  3. 3

    Bringmann, G., Wohlfarth, M., Rischer, H., Grüne, M. & Schlauer, J. A new biosynthetic pathway to alkaloids in plants: acetogenic isoquinolines. Angew. Chem. Int. Edn. Engl. 39, 1464–1466 (2000).

  4. 4

    Thomson, R.H. Naturally occurring quinones III 383 (Chapman and Hall, New York, 1987).

  5. 5

    Howard, D.F., Phillips, D.W., Jones, T.H. & Blum, M.S. Anthraquinones and anthrones: occurrence and defensive function in a chrysomelid beetle. Naturwissenschaften 69, 91–92 (1982).

  6. 6

    Hilker, M. & Schulz, S. Anthraquinones in different development stages of Galeruca tanaceti (Coleoptera: Chrysomelidae). J. Chem. Ecol. 17, 2323 (1991).

  7. 7

    Hilker, M., Eschbach, U. & Dettner, K. Occurrence of anthraquinones in eggs and larvae of several Galerucinae (Coleoptera: Chrysomelidae). Naturwissenschaften 79, 271 (1992).

  8. 8

    Kunze, A., Witte, L., Aregullin, M., Rodriguez, E. & Proksch, P. Anthraquinones in the leaf beetle Trirhabda geminata (Chrysomelidae). Z. Naturforsch. [C] 51, 249–252 (1996).

  9. 9

    Mishchenko, N.P., Stepanenko, L.S., Krivoshchekova, O.E. & Maksimov, O.B. Anthraquinones of the lichen Asahinea chrysantha. Him. Prir. Soedin. 2, 160–165 (1980).

  10. 10

    Krivoshchekova, O.E., Stepanenko, L.S., Mishchenko, N.P., Denisenko, V.A. & Maksimov, O.B. Study of lichens from the Parmeliaceae family. II. Pigments. Him. Prir. Soedin. 3, 283–289 (1983).

  11. 11

    Fotso, S. et al. Bhimamycin AE and bhimanone: isolation, structure elucidation and biological activity of novel quinone antibiotics from a terrestrial streptomycete. J. Antibiot. 56, 931–941 (2003).

  12. 12

    Funa, N. et al. A new pathway for polyketide synthesis in microorganisms. Nature 400, 897–899 (1999).

  13. 13

    Yagi, A., Makino, K. & Nishioka, I. Constituents of Aloe saponaria. I. Structures of tetrahydroanthracene derivatives and the related anthraquinones. Chem. Pharm. Bull. (Tokyo) 22, 1159–1166 (1974).

  14. 14

    Bartel, P.L. et al. Biosynthesis of anthraquinones by interspecies cloning of actinorhodin genes in streptomycetes: clarification of actinorhodin gene functions. J. Bacteriol. 172, 4816–4826 (1990).

  15. 15

    Leistner, E. & Zenk, M. Chrysophanol (1,8-dihydroxy-3-methylanthraquinone) biosynthesis in higher plants. J. Chem. Soc. Chem. Commun. 210–211 (1969).

  16. 16

    Fairbairn, J.W. & Muhtadi, F.J. Biosynthesis and metabolism of anthraquinones in Rumex obtusifolius. Phytochemistry 11, 215–219 (1972).

  17. 17

    Leistner, E. Second pathway leading to anthraquinones in higher plants. Phytochemistry 10, 3015–3020 (1971).

  18. 18

    Ahmed, S.A., Bardshiri, E. & Simpson, T.J. A convenient synthesis of isotopically labeled anthraquinones, chrysophanol, islandicin, and emodin. Incorporation of [methyl-2H3]chrysophanol into tajixanthone in Aspergillus variecolor. J. Chem. Soc. Chem. Commun. 883–884 (1987).

  19. 19

    Van Eijk, G.W. Chrysophanol and emodin from Drechslera catenaria. Phytochemistry 13, 650 (1974).

  20. 20

    Bax, A., Freeman, R. & Frenkiel, T.A. An NMR technique for tracing out the carbon skeleton of an organic molecule. J. Am. Chem. Soc. 103, 2102–2104 (1981).

  21. 21

    Berger, S. Selective INADEQUATE. A farewell to 2D-NMR? Angew. Chem. Int. Edn. Engl. 27, 1196–1197 (1988).

  22. 22

    Bringmann, G., Noll, T. & Rischer, H. In vitro germination and establishment of tissue cultures of Bulbine caulescens and of two Kniphofia species (Asphodelaceae). Plant Cell Rep. 21, 125–129 (2002).

  23. 23

    Styles, P. & Stoffe, N.F. A high-resolution NMR probe in which the coil and preamplifier are cooled with liquid helium. J. Magn. Reson. 60, 397–404 (1984).

  24. 24

    Fiedler, H-P. Biosynthetic capacities of actinomycetes. 1. Screening for new secondary metabolites using UV-visible absorbance spectral libraries. Nat. Prod. Lett. 2, 119–128 (1993).

  25. 25

    Agarwaj, S.K., Singh, S.S., Verma, S. & Kumar, S. Antifungal activity of anthraquinone derivatives from Rheum emodi. J. Ethnopharmacol. 72, 43–46 (2000).

  26. 26

    Semple, S.J., Pyke, S.M., Reynolds, G.D. & Flower, R.L.P. In vitro antiviral activity of the anthraquinone chrysophanic acid against poliovirus. Antiviral Res. 49, 169–178 (2001).

  27. 27

    Hilker, M. & Köpf, A. Evaluation of the palatability of chrysomelid larvae containing anthraquinones to birds. Oecologia 100, 421–429 (1995).

  28. 28

    Goodfellow, M., Isik, K. & Yates, E. Actinomycete systematics: an unfinished synthesis. Nova Acta Leopold. 312, 47–82 (1999).

Download references


This work is dedicated to Burchard Franck on the occasion of his 80th birthday. Financial support from the Fonds der Chemischen Industrie, the European Commission (grant QLK3-CT-2001-01783; project ACTAPHARM), and the German Research Foundation (DFG Hi 416/16-2) are gratefully acknowledged. We thank D. Moskau (Bruker Biospin AG, Fällanden, Switzerland) for the acquisition of a 2D INADEQUATE spectrum with a cryoprobe and F. Meyer for technical support.

Author information

Correspondence to Gerhard Bringmann.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Further reading