Chapter 17 : : a Model for Elucidation of Secondary Metabolism

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This chapter reviews the contributions made by to the understanding of fungal secondary metabolism and the ways in which advances in our understanding of this species have spurred parallel studies of . The most thorough insight into fungal secondary metabolite regulation has arisen from studies of the mycotoxin sterigmatocystin (ST) and the antibiotic penicillin in . With possibly the exception of the penicillin metabolic cluster, the most thoroughly examined fungal secondary-metabolite gene clusters are those involved in mycotoxin biosynthesis, particularly the aflatoxin (AF) and ST biosynthetic clusters found in several spp. Coordinate regulation is largely explained by transcriptional control by pathway-specific regulatory factors (e.g., aflR) and global regulatory proteins including transcription factors mediating environmental signals (pH, carbon, and nitrogen) and the cluster-specific methylase, LaeA. Specific oxylipins, e.g., various prostaglandins, are ligands to G-protein-coupled receptors (GPCR), which are important in inflammatory and immune responses in mammals. Interestingly, recent studies have identified three GPCR that impact asexual and sexual spore production, and efforts are under way to determine if Ppo products may be potential ligands for these receptors. PGs, along with leukotrienes, comprise a class of oxylipins called eicosanoids formed from C fatty acids (dihomo-γ-linolenic acid, arachidonic acid, and eicosanopentaenoic acid). Initial studies of and function in indicate a potent role for these secondarymetabolite genes in pathogenesis. A thorough understanding of the function of these and other secondary metabolism genes may assist in the development of future therapeutics.

Citation: Keller N. 2006. : a Model for Elucidation of Secondary Metabolism, p 235-243. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch17
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Image of Figure 1.
Figure 1.

ST (A) and gliotoxin (B) gene clusters. The function of each protein is listed. AF, aflatoxin.

Citation: Keller N. 2006. : a Model for Elucidation of Secondary Metabolism, p 235-243. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch17
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Image of Figure 2.
Figure 2.

(A) Thin-layer chromatography of organic extracts of the and mutants compared to the wild type (WT). ST, sterigmatocystin standard: G, gliotoxin standard. Note that both mutants are deficient in the production of many metabolites, not just ST () or G (). (B) Northern analysis of sterigmatocystin genes, and , in wild-type and Δ strains at the 12-, 24-, 48-, and 72-h time points. Expression of both genes is repressed in the Δ mutant. Reprinted from reference with permission.

Citation: Keller N. 2006. : a Model for Elucidation of Secondary Metabolism, p 235-243. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch17
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Image of Figure 3.
Figure 3.

Proposed model of G-protein signaling in regulating sporulation and mycotoxin biosynthesis in spp. Oxylipin acts as a ligand to initiate the G-protein signaling cascade, which can lead to either suppression of toxin formation and sporulation (shown here) or activation of both processes (via different GPCR and different α subunits of the heterotrimeric G proteins). FadA, alpha subunit of a heterotrimeric G protein; FlbA, RGS protein; PkaA, protein kinase A; LaeA, global regulator of secondary metabolites.

Citation: Keller N. 2006. : a Model for Elucidation of Secondary Metabolism, p 235-243. In Heitman J, Filler S, Edwards, Jr. J, Mitchell A (ed), Molecular Principles of Fungal Pathogenesis. ASM Press, Washington, DC. doi: 10.1128/9781555815776.ch17
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1. Bennett, J. W., and, M. Klich. 2003. Mycotoxins. Clin. Microbiol. Rev. 16: 497516.
2. Bok, J. W,, S. A. Balajee,, K. A. Marr,, D. Andes,, K. Fog., J. C. Frisvad, and, N. P. Keller. 2005. LaeA, a regulator of virulence determinants in Aspergillus fumigatus. Eukaryot. Cell 4: 15741582.
3. Bok, J.-W.,, D. Hoffmeister,, L. Maggio-Hall,, R. Murillo,, J. D. Glasner, and, N. P. Keller. 2006. Genomic mining for Aspergillus natural products. Chem. Biol. 13: 3137.
4. Bok, J. W., and, N. P. Keller. 2004. LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot. Cell 3: 527535.
5. Brakhage, A. A. 1998. Molecular regulation of β-lactam biosynthesis in filamentous fungi. Microbiol. Mol. Biol. Rev. 62: 547585.
6. Brodowsky, I. D., and, E. H. Oliw. 1993. Biosynthesis of 8R-hydroperoxylinoleic acid by the fungus Laetisaria arvalis. Biochim. Biophys. Acta 20: 6872.
7. Brown, D. W.,, J. H. Yu,, H. S. Kelkar,, M. Fernandes,, T. C. Nesbitt,, N. P. Keller,, T. H. Adams, and, T. J. Leonard. 1996. Twenty-five coregulated transcripts define a sterigmatocystin gene cluster in Aspergillus nidulans. Proc. Natl. Acad. Sci. USA 93: 14181422.
8. Burow, G. B.,, T. C. Nesbitt,, J. D. Dunlap, and, N. P. Keller. 1997. Seed lipoxygenase products modulate Aspergillus mycotoxin biosynthesis. Mol. Plant-Microbe Interact. 10: 380387.
9. Calvo, A.,, H. W. Gardner, and, N. P. Keller. 2001. Genetic connection between fatty acid metabolism and sporulation in Aspergillus nidulans. J. Biol. Chem. 276: 2576625774.
10. Calvo, A. M.,, R. A. Wilson,, J. W. Bok, and, N. P. Keller. 2002. Relationship between secondary metabolism and fungal development. Microbiol. Mol. Biol. Rev. 66: 447459.
11. Champe, S. P., and, A. A. E. El-Zayat. 1989. Isolation of a sexual sporulation hormone from Aspergillus nidulans. J. Bacteriol. 171: 39823988.
12. Champe, S. P.,, P. Rao, and, A. Chang. 1987. An endogenous inducer of sexual development in Aspergillus nidulans. J. Gen. Microbiol. 133: 13831388.
13. Chang, P. K.,, J. W. Cary,, D. Bhatnagar,, T. E. Cleveland,, J. W. Bennett,, J. E. Linz,, C. P. Woloshuk, and, G. A. Payne. 1993. Cloning of the Aspergillus parasiticus apa-2 gene associated with the regulation of aflatoxin biosynthesis. Appl. Environ. Microbiol. 59: 32733279.
14. Chang, P. K.,, J. Yu,, D. Bhatnagar, and, T. E. Cleveland. 1999. Repressor-AFLR interaction modulates aflatoxin biosynthesis in Aspergillus parasiticus. Mycopathologia 147: 105112.
15. Denning, D. W., and, D. A. Stevens. 1990. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev. Infect. Dis. 12: 11471201.
16. Ehrlich, K. C.,, B. G. Montalbano,, D. Bhatnagar, and, T. E. Cleveland, 1998. Alteration of different domains in aflR affects aflatoxin pathway metabolism in Aspergillus parasiticus transformants. Fungal Genet. Biol. 23: 279287.
17. Ehrlich, K. C.,, B. G. Montalbano, and, J. W. Cary. 1999. Binding of the C 6-zinc cluster protein, AflR, to the promoters of aflatoxin pathway biosynthesis genes in Aspergillus parasiticus. Gene 230: 249257.
18. Fernandes, M.,, N. P. Keller, and, T. H. Adams. 1998. Sequence-specific binding by Aspergillus nidulans AflR, a C6 zinc cluster protein regulating mycotoxin biosynthesis. Mol. Microbiol. 28: 13551365.
19. Funk, C. D. 2001. Prostaglandins and leukotrienes: advances in eicosanoid biology. Science 294: 18711875.
20. Gao, S., and, D. L. Nuss. 1996. Distinct roles for two G protein α subunits in fungal virulence, morphology, and reproduction revealed by targeted gene disruption. Proc. Natl. Acad. Sci. USA 93: 1412214127.
21. Gardiner, D. M, and, B. J. Howlett. 2005. Bioinformatic and expression analysis of the putative gliotoxin biosynthetic gene cluster of Aspergillus fumigatus. FEMS Microbiol. Lett. 248: 241248.
22. Gardiner, D. M.,, A. J. Cozijnsen,, L. M. Wilson,, M. S. C. Pedras, and, B. J. Howlett. 2004. The sirodesmin biosynthetic gene cluster of the plant pathogenic fungus Leptosphaeria maculans. Mol. Microbiol. 53: 13071318.
23. Grovel, O.,, Y. F. Pouchus,, T. Robiou du Pont,, M. Montagu,, Z. Amzil, and, J. Verbist. 2002. Ion trap MS(n) for identification of gliotoxin as the cytotoxic factor of a marine strain of Aspergillus fumigatus Fresenius. J. Microbiol. Methods 48: 171179.
24. Hamberg, M.,, C. Su, and, E. Oliw. 1998. Manganese lipoxygenase. Discovery of a bisallylic hydroperoxide as product and intermediate in a lipoxygenase reaction. J. Biol. Chem. 273: 1308013088.
25. Hammond, T. M., and, N. P. Keller. 2005. RNA silencing in Aspergillus nidulans is independent of RNA-dependent RNA polymerases. Genetics 169: 607617.
26. Han, K.-H.,, J.-A. Seo, and, J.-H. Yu, 2004. A putative G protein-coupled receptor negatively controls sexual development in Aspergillus nidulans. Mol. Microbiol. 51: 13331345.
27. Han, K.-H.,, J.-A. Seo, and, J.-H. Yu. 2004. Regulators of G-protein signaling in Aspergillus nidulans: RgsA down regulates stress response and stimulates asexual sporulation through attenuation of GanB (Gα) signaling. Mol. Microbiol. 53: 529540.
28. Hata, A. N., and, R. M. Breyer. 2004. Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation. Pharmacol. Ther. 103: 147166.
29. Herbert, R. B. 1989. The Biosynthesis of Secondary-metabolites. Chapman & Hall, Ltd., London, United Kingdom.
30. Herman, R. P. 1998. Oxylipin production and action in fungi and related organisms, p. 115–130. In A. F. Rowley, H. Kuhn, and T. Schewe (ed.), Eicosanoids and Related Compounds in Plants and Animals. Princeton University Press, Princeton, N.J.
31. Herman, R. P., and, C. A. Herman. 1985. Prostaglandins or prostaglandin like substances are implicated in normal growth and development in oomycetes. Prostaglandins 29: 819830.
32. Hicks, J. K.,, K. Shimizu, and, N. P. Keller. 2002. Genetics and biosynthesis of aflatoxins and sterigmatocystin, p. 55–69. In F. Kempken and J. Bennett (ed.), The Mycota XI. Springer-Verlag, KG, Berlin, Germany.
33. Hicks, J. K.,, J.-H. Yu,, N. P. Keller, and, T. H. Adams. 1997. Aspergillus sporulation and mycotoxin production both require inactivation of the FadA Gα protein-dependent signaling pathway. EMBO J. 16: 49164923.
34. Hogan, L. H.,, B. S. Klein, and, S. M. Levitz. 1996. Virulence factors of medically important fungi. Clin. Microbiol. Rev. 9: 469488.
35. Jahn, B.,, F. Boukhallouk,, J. Lotz,, K. Langfelder,, G. Wanner, and, A. A. Brakhage. 2000. Interaction of human phagocytes with pigmentless Aspergillus conidia. Infect. Immun. 68: 37363739.
36. Jahn, B.,, A. Koch,, A. Schmidt,, G. Wanner,, H. Gehringer,, S. Bhakdi, and, A. A. Brakhage. 1997. Isolation and characterization of a pigmentless-conidium mutant of Aspergillus fumigatus with altered conidial surface and reduced virulence. Infect. Immun. 65: 51105117.
37. Kasahara, S., and, D. L. Nuss. 1997. Targeted disruption of a fungal G-protein beta subunit gene results in increased vegetative growth but reduced virulence. Mol. Plant-Microbe Interact. 10: 984993.
38. Keller, N. P., and, T. M. Hohn. 1997. Metabolic pathway gene clusters in filamentous fungi. Fungal Genet. Biol. 21: 1729.
39. Klich, M. A.,, L. A.,, L. H. Tiffany, and, G. Knaphus. 1992. Ecology of the aspergilli in soils and litter, p. 329–353. In J. W. Bennett and M. A. Klich (ed.), Aspergillus: Biology and Industrial Applications. Butterworth-Heinemann, Boston, Mass.
40. Kweon, Y. O.,, Y. H. Paik,, B. Schnabl,, T. Qian,, J. J. Lemasters, and, D. A. Brenner. 2003. Gliotoxin-mediated apoptosis of activated human hepatic stellate cells. J. Hepatol. 39: 3846.
41. Latge, J. P. 1999. Aspergillus fumigatus and aspergillosis. Clin. Microbiol. Rev. 12: 310350.
42. Liebmann, B.,, M. Mäller,, A. Braun, and, A. A. Brakhage. 2004. The cyclic AMP-dependent protein kinase a network regulates development and virulence in Aspergillus fumigatus. Infect. Immun. 72: 51935203.
43. Lin, S. J.,, J. Schranz, and, S. M. Teutsch. 2001. Aspergillosis case-fatality rate: systematic review of the literature. Clin. Infect. Dis. 32: 358366.
44. Mazur, P.,, K. Nakanishi,, A. A. E. El-Zayat, and, S. P. Champe. 1991. Structure and synthesis of sporogenic psi factors from Aspergillus nidulans. J. Chem. Soc. Chem. Commun. 20: 14861487.
45. McDonald, T.,, T. Devi,, K. Shimizu,, S.-C. Sim, and, N. P. Keller. 2004. Signaling events connecting mycotoxin biosynthesis and sporulation in Aspergillus and Fusarium spp., p. 139–147. In T. Yoshizawa (ed.), New Horizon of Mycotoxicology for Assuring Food Safety. Proceedings of the International Symposium of Mycotoxicolog y. Takamatsu, Kagawa, Japan.
46. Minto, R. E., and, C. A. Townsend. 1997. Enzymology and molecular biology of aflatoxin biosynthesis. Chem. Rev. 97: 25372556.
47. Nielsen, K. F., and, J. Smedsgaard. 2003. Fungal metabolite screening: database of 474 mycotoxins and fungal metabolites for dereplication by standardised liquid chromatography-UV-mass spectrometry methodology. J. Chromatogr. Ser. A. 1002: 111136.
48. Nieminen, S. M.,, J. Maki-Paakkanen,, M. R. Hirvonen,, M. Roponen, and, A. von Wright. 2002. Genotoxicity of gliotoxin, a secondary-metabolite of Aspergillus fumigatus, in a battery of short-term test systems. Mutat. Res. 520: 161170.
49. Noverr, M. C.,, J. R. Erb-Downward, and, G. B. Huffnagle. 2003. Production of eicosanoids and other oxylipins by pathogenic eukaryotic microbes. Clin. Microbiol. Rev. 16: 517533.
50. Patterson, T. F.,, W. R. Kirkpatrick,, M. White,, J. W. Hiemenz,, J. R. Wingard,, B. Dupont,, M. G. Rinaldi,, D. A. Stevens,, J. R. Graybill, and the I3 Aspergillus Study Group. 2000. Invasive aspergillosi, s. Disease. treatment practices, and outcomes. Medicine 79: 250260.
51. Payne, G. A., and, M. P. Brown. 1998. Genetics and physiology of aflatoxin biosynthesis. Annu. Rev. Phytopathol. 36: 329362.
52. Pedley, K. F., and, J. D. Walton. 2001. Regulation of cyclic peptide biosynthesis in a plant pathogenic fungus by a novel transcription factor. Proc. Natl. Acad. Sci. USA 98: 1417414179.
53. Proctor, R. H.,, T. M. Hohn,, S. P. McCormick, and, A. E. Desjardins. 1995. Tri6 encodes an unusual zinc finger protein involved in regulation of trichothecene biosynthesis in Fusarium sporotrichioides. Appl. Environ. Microbiol. 61: 19231930.
54. Rosén, S.,, J.-H. Yu, and, T. H. Adams. 1999. The Aspergillus nidulans sfaD gene encodes a G protein beta subunit that is required for normal growth and repression of sporulation. EMBO J. 18: 55925600.
55. Roze, L. V.,, R. M. Beaudry,, N. P. Keller, and, J. E. Linz. 2004. Regulation of aflatoxin synthesis by FadA/cAMP/ protein kinase A signaling in Aspergillus parasiticus. Mycopathologia 158: 219232.
56. Samson, R. A. 1992. Current taxonomic schemes of the genus Aspergillus and its teleomorphs. Bio/Technology 23: 355390.
57. Seo, J.-A.,, K.-H. Han, and, J.-H. Yu. 2004. The gprA and gprB genes encode putative G protein-coupled receptors required for self-fertilization in Aspergillus nidulans. Mol. Microbiol. 53: 16111623.
58. Shimizu, K.,, J. K. Hicks,, T. P. Huang, and, N. P. Keller. 2003. Pka, Ras and RGS protein interactions regulate activity of AflR, a Zn(II) 2Cys 6 transcription factor in Aspergillus nidulans. Genetics 165: 10951104.
59. Shimizu, K., and, N. P. Keller. 2001. Genetic involvement of a cAMP-dependent protein kinase in a G protein signaling pathway regulating morphological and chemical transitions in Aspergillus nidulans. Genetics 157: 591600.
60. Smith, W. L.,, D. L. DeWitt, and, R. M. Garavito. 2000. Cyclooxygenases: structural, cellular, and molecular biology. Annu. Rev. Biochem. 69: 145182.
61. Stevens, D. A.,, V. L. Kan,, M. A. Judson,, V. A. Morrison,, S. Dummer,, D. W. Denning,, J. E. Bennett,, T. J. Walsh,, T. F. Patterson, and, G. A. Pankey. 2000. Practice guidelines for diseases caused by Aspergillus. Clin. Infect. Dis. 30: 696709.
62. Su, C.,, M. Sahlin, and, E. H. Oliw. 1998. Kinetics of manganese lipoxygenase with a catalytic mononuclear redox center. J. Biol. Chem. 273: 2074420751.
63. Suen, Y. K.,, K. P. Fung,, C. Y. Lee, and, S. K. Kong. 2001. Gliotoxin induces apoptosis in cultured macrophages via production of reactive oxygen species and cytochrome c release without mitochondrial depolarization. Free Radic. Res. 35: 110.
64. Tag, A.,, J. Hicks,, G. Garifullina,, C. Ake, Jr.,, T. D. Phillips,, M. Beremand, and, N. Keller. 2000. G-protein signalling mediates differential production of toxic secondary-metabolites. Mol. Microbiol. 38: 658665.
65. Todd, R. B., and, A. Andrianopoulos. 1997. Evolution of a fungal regulatory gene family: the Zn(II) 2Cys 6 binuclear cluster DNA binding motif. Fungal Genet. Biol. 21: 388405.
66. Tsai, H. F.,, Y. C. Chang,, R. G. Washburn,, M. H. Wheeler, and, K. J. Kwon-Chung. 1998. The developmentally regulated alb1 gene of Aspergillus fumigatus: its role in modulation of conidial morphology and virulence. J. Bacteriol. 180: 30313038.
67. Tsai, H. F.,, R. G. Washburn,, Y. C. Chang, and, K. J. Kwon-Chung. 1997. Aspergillus fumigatus arp1 modulates conidial pigmentation and complement deposition. Mol. Microbiol. 26: 175183.
68. Tsai, H. F.,, M. H. Wheeler,, Y. C. Chang, and, K. J. Kwon-Chung. 1999. A developmentally regulated gene cluster involved in conidial pigment biosynthesis in Aspergillus fumigatus. J. Bacteriol. 181: 64696477.
69. Tsitsigiannis, D. I.,, J. W. Bok,, D. Andes,, K. F. Nielsen,, J. C. Frisvad, and, N. P. Keller. 2005. Aspergillus cyclooxygenase-like enzymes are associated with prostaglandin production and virulence. Infect. Immun. 73: 45484559.
70. Tsitsigiannis, D. I.,, T. Kowieski,, R. Zarnowski, and, N. P. Keller. 2004. Endogenous lipogenic regulators of spore balance in Aspergillus nidulans. Eukaryot. Cell 3: 13981411.
71. Tsitsigiannis, D. I.,, T. Kowieski,, R. Zarnowski, and, N. P. Keller. 2005. Three putative oxylipin biosynthetic genes integrate sexual and asexual development in Aspergillus nidulans. Microbiology 151: 18091821.
72. Tsitsigiannis, D. I.,, R. Zarnowski, and, N. P. Keller. 2004. The lipid body protein, PpoA, coordinates sexual and asexual sporulation in Aspergillus nidulans. J. Biol. Chem. 279: 1134411353.
73. Woloshuk, C. P.,, K. R. Fount,, J. F. Brewer,, D. Bhatnagar,, T. E. Cleveland, and, G. A. Payne. 1994. Molecular characterization of aflR, a regulatory locus for aflatoxin biosynthesis. Appl. Environ. Microbiol. 60: 24082414.
74. Yu, J.,, P. K. Chang,, K. C. Ehrlich,, J. W. Cary,, D. Bhatnagar,, T. E. Cleveland,, G. A. Payne,, J. E. Linz,, C. P. Woloshuk, and, J. W. Bennett. 2004. Clustered pathway genes in aflatoxin biosynthesis. Appl. Environ. Microbiol. 70: 12531262.
75. Yu, J.-H.,, R. A. E. Butchko,, M. Fernandes,, N. P. Keller,, T. J. Leonard, and, T. H. Adams. 1996. Conservation of structure and function of the aflatoxin regulatory gene aflR from Aspergillus nidulans and A. flavus. Curr. Genet. 29: 549555.
76. Yu, J.-H.,, J. Wieser, and, T. H. Adams. 1996b. The Aspergillus FlbA RGS domain protein antagonizes G-protein signaling to block proliferation and allow development. EMBO J. 15: 51845190.
77. Yu, J.-H.,, S. Rosèn, and, T. H. Adams. 1999. Extragenic suppressors of loss-of-function mutations in the Aspergillus FlbA regulator of G-protein signaling domain protein. Genetics 151: 97105.
78. Zhang, Y.-Q.,, H. Wilkinson,, N. P. Keller, and, D. Tsitsigiannis. 2004. Secondary-metabolite gene clusters, p. 355–386. In Z. An (ed.), Handbook of Industrial Microbiology. Marcel Dekker, Inc., New York, N.Y.
79. Zuber, S.,, M. J. Hynes, and, A. Andrianopoulos. 2003. The G-protein α-subunit GasC plays a major role in germination in the dimorphic fungus Penicillium marneffei. Genetics 164: 487499.

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