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Molecular biological and biochemical investigations of prenyltransferases from different Aspergillus species

Prenylated aromatic compounds are widely distributed in nature and many of these compounds display interesting biological and pharmaceutical activities. The transfer of prenyl moieties to aromatic substrates is catalysed by aromatic prenyltransferases, and the multitude of possibilities for attac...

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Bibliographic Details
Main Author:	Pockrandt, Daniel
Contributors:	Li, Shu-Ming (Prof. Dr.) (Thesis advisor)
Format:	Dissertation
Language:	English
Published:	Philipps-Universität Marburg 2014 Pharmazeutische Biologie
Subjects:	Aspergillus Biowissenschaften, Biologie Prenyltransferases Prenyltransferasen Life sciences
Online Access:	PDF Full Text
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1. Nicholson, M. J., Koulman, A., Monahan, B. J., Pritchard, B. L., Payne, G. A. & Scott, B. (2009). Identification of two aflatrem biosynthetic gene loci in Aspergillus flavus and metabolic engineering in Penicillium paxilli to elucidate gene function. Appl. Environ. Microbiol. 75, 7469-7481.

2. Yu, X. & Li, S.-M. (2012). Prenyltransferases of the dimethylallyltryptophan synthase superfamily. Methods Enzymol. 516, 259-278.

3. Fumitremorgin C reverses multidrug resistance in cells transfected with the breast cancer resistance protein. Cancer Res. 60, 47-50.

4. Fedorova, N. D., Khaldi, N., Joardar, V. S., Maiti, R. et al. (2008). Genomic islands in the pathogenic filamentous fungus Aspergillus fumigatus. PLoS. Genet. 4, e1000046.

5. Frisvad, J. C., Larsen, T. O., Thrane, U., Meijer, M., Varga, J., Samson, R. A. & Nielsen, K. F. (2011). Fumonisin and ochratoxin production in industrial Aspergillus niger strains. PLoS. One. 6, e23496.

6. Epifano, F., Genovese, S., Fiorito, S., Mathieu, V. & Kiss, R. (2013). Lapachol and its congeners as anticancer agents: a review. Phytochem. Rev. DOI: 10.1007/s11101-013-9289-1.

7. Liebhold, M., Xie, X. & Li, S.-M. (2013). Breaking cyclic dipeptide prenyltransferase regioselectivity by unnatural alkyl donors. Org. Lett. 15, DOI:10.1021/ol401247s.

8. Yin, W.-B., Ruan, H.-L., Westrich, L., Grundmann, A. & Li, S.-M. (2007). CdpNPT, an N- prenyltransferase from Aspergillus fumigatus: overproduction, purification and biochemical characterisation. Chembiochem 8, 1154-1161.

9. Grundmann, A., Kuznetsova, T., Afiyatullov, S. S. & Li, S.-M. (2008). FtmPT2, an N- prenyltransferase from Aspergillus fumigatus, catalyses the last step in the biosynthesis of fumitremorgin B. Chembiochem 9, 2059-2063.

10. Stec, E., Pistorius, D., Müller, R. & Li, S.-M. (2011). AuaA, a membrane-bound farnesyltransferase from Stigmatella aurantiaca, catalyzes the prenylation of 2-methyl-4- hydroxyquinoline in the biosynthesis of aurachins. Chembiochem 12, 1724-1730.

11. Pockrandt, D. & Li, S. M. (2013). Geranylation of cyclic dipeptides by the dimethylallyl transferase AnaPT resulting in a shift of prenylation position on the indole ring. Chembiochem. 14, 2023-2028.

12. Boonnak, N., Karalai, C., Chantrapromma, S., Ponglimanont, C., Kanjana-Opas, A., Chantrapromma, K. & Fun, H. K. (2007). Quinonoids from the barks of Cratoxylum formosum subsp.pruniflorum. Can. J. Chem. 85, 341-345.

13. Williams, R. M., Stocking, E. M. & Sanz-Cervera, J. F. (2000). Biosynthesis of prenylated alkaloids derived from tryptophan. Topics Curr. Chem. 209, 97-173.

14. Yoon, J., Maruyama, J. & Kitamoto, K. (2011). Disruption of ten protease genes in the filamentous fungus Aspergillus oryzae highly improves production of heterologous proteins.

15. Zou, H.-X., Xie, X., Zheng, X.-D. & Li, S.-M. (2011). The tyrosine O-prenyltransferase SirD catalyzes O-, N-, and C-prenylations. Appl. Microbiol. Biotechnol. 89, 1443-1451.

16. Sakai, K., Kinoshita, H. & Nihira, T. (2012). Heterologous expression system in Aspergillus oryzae for fungal biosynthetic gene clusters of secondary metabolites. Appl. Microbiol. Biotechnol. 93, 2011-2022.

17. Yin, S., Yu, X., Wang, Q., Liu, X. Q. & Li, S.-M. (2013a). Identification of a brevianamide F reverse prenyltransferase BrePT from Aspergillus versicolor with a broad substrate specificity towards tryptophan-containing cyclic dipeptides. Appl. Microbiol. Biotechnol. 97, 1649-1660.

18. Kuck, U. & Bohm, J. (2013). Mating type genes and cryptic sexuality as tools for genetically manipulating industrial molds. Appl Microbiol Biotechnol 97, 9609-9620.

19. Greve, H., Mohamed, I., Pontius, A., Kehraus, S., Gross, H. & KÃ ¶nig, G. (2010). Fungal metabolites: structural diversity as incentive for anticancer drug development. Phytochem Rev 9, 537-545. References 118

20. Park, K. H., Park, Y. D., Han, J. M., Im, K. R., Lee, B. W., Jeong, I. Y., Jeong, T. S. & Lee, W. S. (2006). Anti-atherosclerotic and anti-inflammatory activities of catecholic xanthones and flavonoids isolated from Cudrania tricuspidata. Bioorg. Med. Chem. Lett. 16, 5580-5583.

21. Schneider, P., Weber, M. & Hoffmeister, D. (2008). The Aspergillus nidulans enzyme TdiB catalyzes prenyltransfer to the precursor of bioactive asterriquinones. Fungal. Genet. Biol. 45, 302-309.

22. Shin-Ya, K., Furihata, K., Hayakawa, Y. & Seto, H. (1990a). Biosynthetic studies of naphterpin, a terpenoid metabolite of Streptomyces. Tetrahedron Lett. 31, 6025-6026.

23. Rukachaisirikul, V., Kamkaew, M., Sukavisit, D., Phongpaichit, S., Sawangchote, P. & Taylor, W. C. (2003). Antibacterial xanthones from the leaves of Garcinia nigrolineata. J. Nat. Prod. 66, 1531-1535.

24. Kralj, A., Kehraus, S., Krick, A., Eguereva, E., Kelter, G., Maurer, M., Wortmann, A., Fiebig, H. H. & König, G. M. (2006). Arugosins G and H: prenylated polyketides from the marine-derived fungus Emericella nidulans var. acristata. J. Nat. Prod. 69, 995-1000.

25. Keller, N. P., Turner, G. & Bennett, J. W. (2005). Fungal secondary metabolism -from biochemistry to genomics. Nat. Rev. Microbiol. 3, 937-947.

26. Hoffmeister, D. & Keller, N. P. (2007). Natural products of filamentous fungi: enzymes, genes, and their regulation. Nat. Prod. Rep. 24, 393-416.

27. Gunasekera, S. P., Jayatilake, G. S., Selliah, S. S. & Sultanbawa, M. U. (1977). Chemical investigation of ceylonese plants. Part 27. Extractives of Calophyllum cuneifolium Thw. and Calophyllum soulattri Burm. f. (Guttiferae). J. Chem. Soc. ,Perkin Trans. 1 1505-1511.

28. Lenta, B. N., Kamdem, L. M., Ngouela, S., Tantangmo, F., Devkota, K. P., Boyom, F. F., Rosenthal, P. J. & Tsamo, E. (2011). Antiplasmodial constituents from the fruit pericarp of Pentadesma butyracea. Planta Med. 77, 377-379.

29. Oku, H., Ueda, Y., Iinuma, M. & Ishiguro, K. (2005). Inhibitory effects of xanthones from guttiferae plants on PAF-induced hypotension in mice. Planta Med. 71, 90-92.

30. Bennett, J. W. (2009). Aspergillus: a primer for the novice. Med. Mycol. 47 Suppl 1, S5-12.

31. Na, Z. & Xu, Y. K. (2010). A new prenylated xanthone from Garcinia xipshuanbannaensis Y.H. Li. Nat. Prod. Res. 24, 1648-1653.

32. Grundmann, A. & Li, S.-M. (2005). Overproduction, purification and characterization of FtmPT1, a brevianamide F prenyltransferase from Aspergillus fumigatus. Microbiology 151, 2199-2207.

33. Beuchat, L. R. (1986). Extraordinary Heat Resistance of Talaromyces flavus and Neosartorya fischeri Ascospores in Fruit Products. Journal of Food Science 51, 1506-1510.

34. Stanzani, M., Orciuolo, E., Lewis, R., Kontoyiannis, D. P., Martins, S. L., St John, L. S. & Komanduri, K. V. (2005). Aspergillus fumigatus suppresses the human cellular immune response via gliotoxin-mediated apoptosis of monocytes. Blood 105, 2258-2265.

35. Vieira, L. M. & Kijjoa, A. (2005). Naturally-occurring xanthones: recent developments. Curr. Med. Chem. 12, 2413-2446.

36. El-Seedi, H. R., El-Ghorab, D. M. H., El-Barbary, M. A., Zayed, M. F., Göransson, U., Larsson, S. & Verpoorte, R. (2009). Naturally occurring xanthones; latest investigations: isolation, structure elucidation and chemosystematic significance. Curr. Med. Chem. 16, 2581- 2626.

37. El-Seedi, H. R., El-Barbary, M. A., El-Ghorab, D. M. H., Bohlin, L., Borg-Karlson, A. K., Göransson, U. & Verpoorte, R. (2010). Recent insights into the biosynthesis and biological activities of natural xanthones. Curr. Med. Chem. 17, 854-901.

38. Pinto, M. M. M. & Castanheiro, R. A. P. (2009). Synthesis of prenylated xanthones: an overview. Curr. Org. Chem. 13, 1215-1240.

39. Role of some fermentation parameters on cyclosporin A production by a new isolate of Aspergillus terreus. J Gen. Appl. Microbiol. 49, 321-328.

40. M. (2009). Antitumor activity of some prenylated xanthones. Pharmaceuticals 2, 33-43.

41. el, K. A. & Atoui, A. (2010). Ochratoxin a: general overview and actual molecular status. Toxins. (Basel) 2, 461-493.

42. & Gupta, M. P. (2003). Bioactive constituents from three Vismia species. J. Nat. Prod. 66, 858-860.

43. Hussein, A. A., Barberena, I., Capson, T. L., Kursar, T. A., Coley, P. D., Solis, P. N. & Gupta, M. P. (2004). New cytotoxic naphthopyrane derivatives from Adenaria floribunda. J. Nat. Prod. 67, 451-453.

44. Botta B, Vitali A, Menendez P, Misiti D, Delle MG (2005) Prenylated flavonoids: pharmacology and biotechnology. Curr Med Chem 12: 717–739

45. Structure and catalytic mechanism of a cyclic dipeptide prenyltransferase with broad substrate promiscuity. J. Mol. Biol. 422, 87-99. References 124

46. Chooi, Y. H., Fang, J., Liu, H., Filler, S. G., Wang, P. & Tang, Y. (2013). Genome mining of a prenylated and immunosuppressive polyketide from pathogenic fungi. Org. Lett. 15, 780- 783.

47. Chooi YH, Tang Y (2012) Navigating the fungal polyketide chemical space: from genes to molecules. J Org Chem 77:9933–9953

48. Hussain, H., Krohn, K., Ahmad, V. U., Miana, G. A. & Green, I. R. (2007). Lapachol: An overview. ARKIVOC (Gainesville,FL,U. S. ) 145-171. References 119

49. Yazaki, K., Sasaki, K. & Tsurumaru, Y. (2009). Prenylation of aromatic compounds, a key diversification of plant secondary metabolites. Phytochemistry 70, 1739-1745.

50. Chen, L. G., Yang, L. L. & Wang, C. C. (2008). Anti-inflammatory activity of mangostins from Garcinia mangostana. Food Chem. Toxicol. 46, 688-693.

51. Yu, X., Xie, X. & Li, S.-M. (2011). Substrate promiscuity of secondary metabolite enzymes: prenylation of hydroxynaphthalenes by fungal indole prenyltransferases. Appl. Microbiol. Biotechnol. 92, 737-748.

52. Feofilova, E. P. (2001). The Kingdom Fungi: Heterogeneity of Physiological and Biochemical Properties and Relationships with Plants, Animals, and Prokaryotes (Review). Applied Biochemistry and Microbiology 37, 124-137.

53. Wang, Y., Xia, Z., Xu, J. R., Wang, Y. X., Hou, L. N., Qiu, Y. & Chen, H. Z. (2012). Alpha- mangostin, a polyphenolic xanthone derivative from mangosteen, attenuates beta-amyloid oligomers-induced neurotoxicity by inhibiting amyloid aggregation. Neuropharmacology 62, 871-881.

54. Akao, T., Sano, M., Yamada, O., Akeno, T. et al. (2007). Analysis of expressed sequence tags from the fungus Aspergillus oryzae cultured under different conditions. DNA Res. 14, 47- 57.

55. Yu, X., Liu, Y., Xie, X., Zheng, X.-D. & Li, S.-M. (2012). Biochemical characterization of indole prenyltransferases: Filling the last gap of prenylation positions by a 5- dimethylallyltryptophan synthase from Aspergillus clavatus. J. Biol. Chem. 287, 1371-1380.

56. Bok, J. W., Chiang, Y. M., Szewczyk, E., Reyes-Dominguez, Y. et al. (2009). Chromatin- level regulation of biosynthetic gene clusters. Nat Chem Biol 5, 462-464.

57. Chooi, Y. H., Wang, P., Fang, J., Li, Y., Wu, K., Wang, P. & Tang, Y. (2012). Discovery and characterization of a group of fungal polycyclic polyketide prenyltransferases. J. Am. Chem. Soc. 134, 9428-9437.

58. Kondoh, M., Usui, T., Mayumi, T. & Osada, H. (1998). Effects of tryprostatin derivatives on microtubule assembly in vitro and in situ. J. Antibiot. 51, 801-804.

59. Dhillon, G. S., Brar, S. K., Verma, M. & Tyagi, R. D. (2011). Enhanced solid-state citric acid bio-production using apple pomace waste through surface response methodology. J. Appl. Microbiol.

60. Schardl, C. L., Panaccione, D. G. & Tudzynski, P. (2006). Ergot alkaloids--biology and molecular biology. The Alkaloids, Chem. Biol. 63, 45-86.

61. Wallwey, C. & Li, S.-M. (2011). Ergot alkaloids: structure diversity, biosynthetic gene clusters and functional proof of biosynthetic genes. Nat. Prod. Rep. 28, 496-510.

62. Haarmann, T., Rolke, Y., Giesbert, S. & Tudzynski, P. (2009). Ergot: from witchcraft to biotechnology. Mol. Plant Pathol. 10, 563-577.

63. Li, S.-M. (2009). Evolution of aromatic prenyltransferases in the biosynthesis of indole derivatives. Phytochemistry 70, 1746-1757.

64. Liebhold, M., Xie, X. & Li, S.-M. (2012). Expansion of enzymatic Friedel-Crafts alkylation on indoles: Acceptance of unnatural beta-unsaturated allyl diphospates by dimethylallyl- tryptophan synthases. Org. Lett. 14, 4884-4885.

65. Kumano, T., Tomita, T., Nishiyama, M. & Kuzuyama, T. (2010). Functional characterization of the promiscuous prenyltransferase responsible for furaquinocin biosynthesis: identification of a physiological polyketide substrate and its prenylated reaction products. J. Biol. Chem. 285, 39663-39671.

66. Vining, L. C. (1990). Functions of secondary metabolites. Annu. Rev Microbiol 44, 395-427.

67. Prigozhina, N. L., Oakley, C. E., Lewis, A. M., Nayak, T., Osmani, S. A. & Oakley, B. R. (2004). gamma-tubulin plays an essential role in the coordination of mitotic events. Mol. Biol Cell 15, 1374-1386. References 123

68. Kato, N., Tokuoka, M., Shinohara, Y., Kawatani, M. et al. (2011). Genetic safeguard against mycotoxin cyclopiazonic acid production in Aspergillus oryzae. Chembiochem. 12, 1376-1382.

69. Yazaki, K., Kunihisa, M., Fujisaki, T. & Sato, F. (2002). Geranyl diphosphate:4- hydroxybenzoate geranyltransferase from Lithospermum erythrorhizon. Cloning and characterization of a key enzyme in shikonin biosynthesis. J. Biol. Chem. 277, 6240-6246.

70. Szewczyk, E., Chiang, Y. M., Oakley, C. E., Davidson, A. D., Wang, C. C. & Oakley, B. R. (2008). Identification and characterization of the asperthecin gene cluster of Aspergillus nidulans. Appl. Environ. Microbiol. 74, 7607-7612.

71. & Seto, H. (1990b). Isolation and structural elucidation of an antioxidative agent, naphterpin.

72. Demain, A. L. & Sanchez, S. (2009). Microbial drug discovery: 80 years of progress. J Antibiot (Tokyo) 62, 5-16.

73. Brandt, W., Brauer, L., Gunnewich, N., Kufka, J. et al. (2009). Molecular and structural basis of metabolic diversity mediated by prenyldiphosphate converting enzymes. Phytochemistry 70, 1758-1775.

74. Kato, H., Yoshida, T., Tokue, T., Nojiri, Y., Hirota, H., Ohta, T., Williams, R. M. & Tsukamoto, S. (2007). Notoamides A-D: prenylated indole alkaloids isolated from a marine- derived fungus, Aspergillus sp. Angew. Chem Int. Ed Engl. 46, 2254-2256.

75. Botta, B., Monache, G. D., Menendez, P. & Boffi, A. (2005a). Novel prenyltransferase enzymes as a tool for flavonoid prenylation. Trends Pharmacol. Sci. 26, 606-608.

76. Li, S.-M. (2010). Prenylated indole derivatives from fungi: structure diversity, biological activities, biosynthesis and chemoenzymatic synthesis. Nat. Prod. Rep. 27, 57-78.

77. Heide, L. (2009). Prenyl transfer to aromatic substrates: genetics and enzymology. Curr. Opin. Chem. Biol. 13, 171-179.

78. Horn, B. W., Olarte, R. A., Peterson, S. W. & Carbone, I. (2013). Sexual reproduction in Aspergillus tubingensis from section Nigri. Mycologia. 105, 1153-1163.

79. Seto, H., Watanabe, H. & Furihata, K. (1996). Simultaneous operation of the mevalonate and non-mevalonate pathways in the biosynthesis of isopentenyl diphosphate in Streptomyces aeriouvifer. Tetrahedron Lett. 37, 7979-7982.

80. Khaldi, N., Seifuddin, F. T., Turner, G., Haft, D., Nierman, W. C., Wolfe, K. H. & Fedorova, N. D. (2010). SMURF: Genomic mapping of fungal secondary metabolite clusters. Fungal. Genet. Biol. 47, 736-741.

81. Kabak, B., Dobson, A. D. & Var, I. (2006). Strategies to prevent mycotoxin contamination of food and animal feed: a review. Crit Rev. Food Sci. Nutr. 46, 593-619.

82. Structure-function analysis of an enzymatic prenyl transfer reaction identifies a reaction chamber with modifiable specificity. J. Am. Chem. Soc. 132, 17849-17858.

83. Huang, Y. L., Chen, C. C., Chen, Y. J., Huang, R. L. & Shieh, B. J. (2001). Three xanthones and a benzophenone from Garcinia mangostana. J. Nat. Prod. 64, 903-906.

84. Allergens/Antigens, toxins and polyketides of important Aspergillus species. Indian J Clin. Biochem. 26, 104-119.

85. Cui, C. B., Kakeya, H., Okada, G., Onose, R., Ubukata, M., Takahashi, I., Isono, K. & Osada, H. (1995). Tryprostatins A and B, novel mammalian cell cycle inhibitors produced by Aspergillus fumigatus. J. Antibiot. 48, 1382-1384. References 117

86. Neosartorya fischeri var fischeri (Wehmer) Malloch and Cain 1972 (Anamorph: Aspergillus fischerianus Samson and Gams 1985) as a cause of mycotic keratitis. Eur J Epidemiol 6, 382- 385.

87. Pinto, M. M., Sousa, M. E. & Nascimento, M. S. (2005). Xanthone derivatives: new insights in biological activities. Curr. Med. Chem. 12, 2517-2538.

88. Kremer, A., Westrich, L. & Li, S.-M. (2007). A 7-dimethylallyltryptophan synthase from Aspergillus fumigatus: overproduction, purification and biochemical characterization. Microbiology 153, 3409-3416.

89. Kremer, A. & Li, S.-M. (2010). A tyrosine O-prenyltransferase catalyses the first pathway- specific step in the biosynthesis of sirodesmin PL. Microbiology 156, 278-286. References 120

90. Yu, X. & Li, S.-M. (2011). Prenylation of flavonoids by using a dimethylallyltryptophan synthase 7-DMATS from Aspergillus fumigatus. Chembiochem 12, 2280-2283.

91. Simpson, T. J. (2012). Genetic and biosynthetic studies of the fungal prenylated xanthone shamixanthone and related metabolites in Aspergillus spp. revisited. Chembiochem 13, 1680- 1688.

92. Mundt, K., Wollinsky, B., Ruan, H. L., Zhu, T. & Li, S.-M. (2012). Identification of the verruculogen prenyltransferase FtmPT3 by a combination of chemical, bioinformatic and biochemical approaches. Chembiochem 13, 2583-2592.

93. Haagen, Y., Unsöld, I., Westrich, L., Gust, B., Richard, S. B., Noel, J. P. & Heide, L. (2007). A soluble, magnesium-independent prenyltransferase catalyzes reverse and regular C- prenylations and O-prenylations of aromatic substrates. FEBS Lett. 581, 2889-2893.

94. Nielsen, M. L., Nielsen, J. B., Rank, C., Klejnstrup, M. L. et al. (2011). A genome-wide polyketide synthase deletion library uncovers novel genetic links to polyketides and meroterpenoids in Aspergillus nidulans. FEMS Microbiol. Lett. 321, 157-166.

95. Frisvad, J., Thrane, U., Samson, R. & Pitt, J. (2006). Important mycotoxins and the fungi which produce them. In Advances in Food Mycology, pp. 3-31. Edited by. A. D. Hocking, J. I. Pitt, R. Samson & U. Thrane Springer US.

96. Lin, H. C., Chooi, Y. H., Dhingra, S., Xu, W., Calvo, A. M. & Tang, Y. (2013). The Fumagillin Biosynthetic Gene Cluster in Aspergillus fumigatus Encodes a Cryptic Terpene Cyclase Involved in the Formation of Î²-trans-Bergamotene. Journal of the American Chemical Society 135, 4616-4619. References 122

97. L. & Cook, J. M. (2002). Biological activity of the tryprostatins and their diastereomers on human carcinoma cell lines. J. Med. Chem. 45, 1559-1562.

98. Guttiferone F, the first prenylated benzophenone from Allanblackia stuhlmannii. J. Nat. Prod. 62, 130-132.

99. Yin, W.-B., Yu, X., Xie, X.-L. & Li, S.-M. (2010). Preparation of pyrrolo[2,3-b]indoles carrying a ß-configured reverse C3-dimethylallyl moiety by using a recombinant prenyltransferase CdpC3PT. Org. Biomol. Chem. 8, 2430-2438.

100. Galagan, J. E., Calvo, S. E., Cuomo, C., Ma, L. J. et al. (2005). Sequencing of Aspergillus nidulans and comparative analysis with A. fumigatus and A. oryzae. Nature 438, 1105-1115.

101. Inglis, D. O., Binkley, J., Skrzypek, M. S., Arnaud, M. B., Cerqueira, G. C., Shah, P., Wymore, F., Wortman, J. R. & Sherlock, G. (2013). Comprehensive annotation of secondary metabolite biosynthetic genes and gene clusters of Aspergillus nidulans, A. fumigatus, A. niger and A. oryzae. BMC. Microbiol. 13, 91.

102. Sousa, M. E. & Pinto, M. M. (2005). Synthesis of xanthones: an overview. Curr. Med Chem 12, 2447-2479.

103. Steffan, N., Grundmann, A., Yin, W.-B., Kremer, A. & Li, S.-M. (2009). Indole prenyltransferases from fungi: a new enzyme group with high potential for the production of prenylated indole derivatives. Curr. Med. Chem. 16, 218-231.

104. Yin, W.-B., Grundmann, A., Cheng, J. & Li, S.-M. (2009). Acetylaszonalenin biosynthesis in Neosartorya fischeri: Identification of the biosynthetic gene cluster by genomic mining and functional proof of the genes by biochemical investigation. J. Biol. Chem. 284, 100-109.

105. Haug-Schifferdecker, E., Arican, D., Brueckner, R. & Heide, L. (2010). A new group of aromatic prenyltransferases in fungi, catalyzing a 2,7-dihydroxynaphthalene dimethylallyltransferase reaction. J. Biol. Chem. 285, 16487-16494.

106. Hertweck, C. (2009). Hidden biosynthetic treasures brought to light. Nat Chem Biol 5, 450- 452.

107. Bergmann, S., Schumann, J., Scherlach, K., Lange, C., Brakhage, A. A. & Hertweck, C. (2007). Genomics-driven discovery of PKS-NRPS hybrid metabolites from Aspergillus nidulans. Nat. Chem Biol 3, 213-217.

108. Balibar, C. J., Howard-Jones, A. R. & Walsh, C. T. (2007). Terrequinone A biosynthesis through L-tryptophan oxidation, dimerization and bisprenylation. Nat. Chem. Biol. 3, 584-592.

109. Calvo, A. M., Wilson, R. A., Bok, J. W. & Keller, N. P. (2002). Relationship between secondary metabolism and fungal development. Microbiol. Mol. Biol Rev. 66, 447-59, table.

110. CloQ, a prenyltransferase involved in clorobiocin biosynthesis. Proc. Natl. Acad. Sci.

111. Schiff, P. L. (2006). Ergot and its alkaloids. Am. J. Pharma. Edu. 70, 1-10.

112. Geiser, D. M., Pitt, J. I. & Taylor, J. W. (1998). Cryptic speciation and recombination in the aflatoxin-producing fungus Aspergillus flavus. Proc. Natl. Acad. Sci. U. S. A 95, 388-393.

113. Nielsen, P. V., Beuchat, L. R. & Frisvad, J. C. (1988). Growth of and fumitremorgin production by Neosartorya fischeri as affected by temperature, light, and water activity. Appl. Environ. Microbiol. 54, 1504-1510.

114. Rohlfs, M., Albert, M., Keller, N. P. & Kempken, F. (2007). Secondary chemicals protect mould from fungivory. Biol Lett. 3, 523-525.

115. Jain, H. D., Zhang, C., Zhou, S., Zhou, H. et al. (2008). Synthesis and structure-activity relationship studies on tryprostatin A, a potent inhibitor of breast cancer resistance protein. Bioorg. Med. Chem. 16, 4626-4651.

116. Ukil, L., De Souza, C. P., Liu, H. L. & Osmani, S. A. (2009). Nucleolar separation from chromosomes during Aspergillus nidulans mitosis can occur without spindle forces. Mol. Biol Cell 20, 2132-2145.

117. Chemoenzymatic syntheses of prenylated aromatic small molecules using Streptomyces prenyltransferases with relaxed substrate specificities. Bioorg. Med. Chem. 16, 8117-8126.

118. Tello, M., Kuzuyama, T., Heide, L., Noel, J. P. & Richard, S. B. (2008). The ABBA family of aromatic prenyltransferases: broadening natural product diversity. Cell Mol. Life Sci. 65, 1459-1463.

119. Kuzuyama, T., Noel, J. P. & Richard, S. B. (2005). Structural basis for the promiscuous biosynthetic prenylation of aromatic natural products. Nature 435, 983-987.

120. Takahashi, S., Takagi, H., Toyoda, A., Uramoto, M., Nogawa, T., Ueki, M., Sakaki, Y. & Osada, H. (2010). Biochemical characterization of a novel indole prenyltransferase from Streptomyces sp. SN-593. J. Bacteriol. 192, 2839-2851.

121. Chooi, Y. H., Cacho, R. & Tang, Y. (2010). Identification of the viridicatumtoxin and griseofulvin gene clusters from Penicillium aethiopicum. Chem. Biol. 17, 483-494.

122. Palmer, J. M. & Keller, N. P. (2010). Secondary metabolism in fungi: does chromosomal location matter? Curr. Opin. Microbiol. 13, 431-436.

123. Sanchez, J. F., Entwistle, R., Hung, J. H., Yaegashi, J., Jain, S., Chiang, Y. M., Wang, C. C. & Oakley, B. R. (2011). Genome-based deletion analysis reveals the prenyl xanthone biosynthesis pathway in Aspergillus nidulans. J. Am. Chem Soc. 133, 4010-4017.

124. Sasaki, K., Tsurumaru, Y., Yamamoto, H. & Yazaki, K. (2011). Molecular characterization of a membrane-bound prenyltransferase specific for isoflavone from Sophora flavescens. J. Biol. Chem. 286, 24125-24134.

125. Bonitz, T., Alva, V., Saleh, O., Lupas, A. N. & Heide, L. (2011). Evolutionary relationships of microbial aromatic prenyltransferases. PLoS One 6, e27336.

126. Andersen, M. R., Nielsen, J. B., Klitgaard, A., Petersen, L. M. et al. (2013). Accurate prediction of secondary metabolite gene clusters in filamentous fungi. Proceedings of the National Academy of Sciences 110, E99-E107.

127. A nonribosomal peptide synthetase-derived iron(III) complex from the pathogenic fungus Aspergillus fumigatus. J. Am. Chem. Soc. 135, 2064-2067.

128. Yoon, J., Kikuma, T., Maruyama, J. & Kitamoto, K. (2013). Enhanced production of bovine chymosin by autophagy deficiency in the filamentous fungus Aspergillus oryzae. PLoS. One. 8, e62512. References 126

129. Yin, W. & Keller, N. P. (2011). Transcriptional regulatory elements in fungal secondary metabolism. J Microbiol. 49, 329-339.

130. Hesseltine, C. W., Shotwell, O. L., Ellis, J. J. & Stubblefield, R. D. (1966). Aflatoxin formation by Aspergillus flavus. Bacteriol. Rev 30, 795-805.

131. Sanchez, J. F., Somoza, A. D., Keller, N. P. & Wang, C. C. (2012). Advances in Aspergillus secondary metabolite research in the post-genomic era. Nat. Prod. Rep. 29, 351-371.

132. Latge, J. P. (1999). Aspergillus fumigatus and aspergillosis. Clin. Microbiol. Rev 12, 310-350.

133. Sasaki, K., Mito, K., Ohara, K., Yamamoto, H. & Yazaki, K. (2008). Cloning and characterization of naringenin 8-prenyltransferase, a flavonoid-specific prenyltransferase of Sophora flavescens. Plant Physiol. 146, 1075-1084.

134. Lee, M. R. (2009a). The history of ergot of rye (Claviceps purpurea) I: from antiquity to 1900.

135. Botta, B., Delle Monache, F., Delle Monache, G., MariniBettolo, G. B. & Oguakwa, J. U. (1983). 3-Geranyloxy-6-methyl-1,8-dihydroxyanthraquinone and vismiones C, D and E from Psorospermum febrifugum. Phytochemistry 22, 539-542. References 116

136. Tsai, H. F., Wang, H., Gebler, J. C., Poulter, C. D. & Schardl, C. L. (1995). The Claviceps purpurea gene encoding dimethylallyltryptophan synthase, the committed step for ergot alkaloid biosynthesis. Biochem. Biophys. Res. Commun. 216, 119-125.

137. Ryu, H. W., Cho, J. K., Curtis-Long, M. J., Yuk, H. J., Kim, Y. S., Jung, S., Kim, Y. S., Lee, B. W. & Park, K. H. (2011). Alpha-glucosidase inhibition and antihyperglycemic activity of prenylated xanthones from Garcinia mangostana. Phytochemistry 72, 2148-2154.

138. Gustafson, K. R., Blunt, J. W., Munro, M. H. G., Fuller, R. W., McKee, T. C., Cardellina II, J. H., McMahon, J. B., Cragg, G. M. & Boyd, M. R. (1992). The guttiferones, HIV- inhibitory benzophenones from Symphonia globulifera, Garcinia livingstonei, Garcinia ovalifolia and Clusia rosea. Tetrahedron 48, 10093-10102.

139. Boonnak, N., Karalai, C., Chantrapromma, S., Ponglimanont, C., Fun, H. K., Kanjana- Opas, A. & Laphookhieo, S. (2006). Bioactive prenylated xanthones and anthraquinones from Cratoxylum formosum ssp. pruniflorum. Tetrahedron 62, 8850-8859.

140. Bok, J. W., Hoffmeister, D., Maggio-Hall, L. A., Murillo, R., Glasner, J. D. & Keller, N. P. (2006). Genomic mining for Aspergillus natural products. Chem. Biol. 13, 31-37.

141. Osmani, S. A. & Mirabito, P. M. (2004). The early impact of genetics on our understanding of cell cycle regulation in Aspergillus nidulans. Fungal. Genet. Biol 41, 401-410.

142. Goldman, G. H. & Kafer, E. (2004). Aspergillus nidulans as a model system to characterize the DNA damage response in eukaryotes. Fungal. Genet. Biol 41, 428-442.

143. Accurate prediction of the Aspergillus nidulans terrequinone gene cluster boundaries using the transcriptional regulator LaeA. Fungal. Genet. Biol 44, 1134-1145.

144. von Döhren, H. (2009). A survey of nonribosomal peptide synthetase (NRPS) genes in Aspergillus nidulans. Fungal. Genet. Biol. 46 Suppl 1, S45-S52.

145. Adrio, J. L. & Demain, A. L. (2003). Fungal biotechnology. Int. Microbiol. 6, 191-199.

146. Saadat, N. & Gupta, S. V. (2012). Potential role of garcinol as an anticancer agent. J. Oncol. 2012, 647206.

147. Laphookhieo, S., Maneerat, W. & Koysomboon, S. (2009). Antimalarial and cytotoxic phenolic compounds from Cratoxylum maingayi and Cratoxylum cochinchinense. Molecules 14, 1389-1395.