Chapter 26 : Secondary Metabolism

MyBook is a cheap paperback edition of the original book and will be sold at uniform, low price.

Ebook: Choose a downloadable PDF or ePub file. Chapter is a downloadable PDF file. File must be downloaded within 48 hours of purchase

Buy this Chapter
Digital (?) $15.00

Preview this chapter:
Zoom in

Secondary Metabolism, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555816636/9781555814731_Chap26-1.gif /docserver/preview/fulltext/10.1128/9781555816636/9781555814731_Chap26-2.gif


In this chapter, several contemporary questions are considered that have arisen as genome sequencing and genomic resources have propelled the field of secondary metabolism to the forefront of fungal biology. The approach is to use case studies to illustrate areas currently under consideration. There are four main classes of fungal compounds considered to be secondary metabolites: polyketides (PKs), nonribosomal peptides (NRPs), terpenoids, and alkaloids. The focus in subsequent sections is mainly on PKs and NRPs, as these constitute the two most prominent classes. The structure of each NRPS in each fungus is usually unique, and both monomodular and multimodular NRPSs are found. PKs are synthesized enzymatically by PK synthases (PKSs). Fungal PKSs are closely related to fatty acid synthetases (FASs). All terpenes are polymers of repeating isopentyl units built by prenyltransferases. Monoterpenes are derived from geranyl diphosphate (GPP), sesquiterpenes are derived from farnesyl diphosphate, and diterpenes are derived from geranylgeranyldiphosphate (GGPP) by the action of terpene synthases or cyclases. Ergot alkaloid toxins are assembled from prenylated tryptophan and include clavines, lysergic acid, and derivatives thereof. The study of epipolythiodioxopiperazine (ETP) clusters indicates that cluster genes share closest relationships with paralogous genes elsewhere in the genomes. The dung of herbivores is an attractive habitat for diverse species of coprophilous fungi, which appear to have adapted to this specific niche by evolving mechanisms to compete with other fungi.

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of FIGURE 1

Cartoon of maximum likelihood phylogenetic tree built with individual A domains of NRPSs extracted from fungal genomes for which genome sequences are available (Bushley and Turgeon, unpublished [available on request]). Also included were A domains from selected NRPSs deposited in GenBank. All NRPSs are included (designated NPS1-12) ( ). Thick bars indicate robust support; the arrow indicates that NRPSs from all taxa below are from filamentous ascomycetes. Note that mono-or bimodular NRPSs dominate the top of the tree, while multimodular NRPSs populate the bottom. Note that Fig. 3 through 5 are cross-referenced.

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 2

Cartoon of phylogenetic tree built with individual ketoacyl synthase domains of PKSs as reported by . Note that Fig. 6 through 8 are cross-referenced.

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 3

Comparison of neighborhoods surrounding the conserved NRPSs for intracellular (NPS2/NPS1/SidC/sid2 [A]) and extracellular (NPS6 [B]) siderophore biosynthesis. Gene annotations for are from JGI (http://genome.jgipsf.org/CocheC5_1/CocheC5_1.home.html), while the rest are from BROAD (http://www.broad.mit.edu/node/568). Note that for both NRPS lineages, which are the most conserved in filamentous fungi, some, but not all, pathway genes are present (as described in the text); otherwise, flanking genes are not conserved. The siderophore-producing NPS2/NPS1/SidC/sid2 NRPSs are found in both ascomycetes and basidiomycetes, and there is good support for this clade grouping with the multimodular NRPSs in clades found only in filamentous ascomycetes ( Fig. 1 ).

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 4

Comparison of neighborhoods surrounding the moderately conserved mono- and bimodular NRPSs ( Fig. 1 ), found in only a few filamentous ascomycetes. Monomodular NPS11 from groups with module 1 of the NRPSs for ETP and sirodesmin, while monomodular NPS12 from groups with module 2 of these NRPSs and with monomodular NRPSs from bacteria, chytrids, ascomycetes, and basidiomycetes ( Fig. 1 ). While the predicted proteins of genes adjacent to are typical of those involved in secondary metabolism, they are different from those at the ETP/sirodesmin loci (where several genes are conserved across all).

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 5

Discontinuously distributed, multimodular ChNPS1 and ChNPS3 are related, and some modules of each enzyme group in the SIMA clade (B) for cyclosporin biosynthesis, while others group in an unrelated clade (A) ( Fig. 1 ). The monomodular members related to SIMA suggest that the multimodular SIMA NRPS arose by repeated duplication. NPS1 and NPS3 evolution must have been more complicated and involved duplication and recombination. Neither gene has a complete counterpart in any other known genome sequence.

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 6

The PKSs involved in HST production are unique. (A and B) race-T genome sequence reveals 25 s. and are unrelated, but both are required for Ttoxin production. Neither occurs in race O. The closest known PKS is of . (C) Comparison of the loci for T-toxin production in and for PM-toxin production in . The locus of is two loci ( and ) on two different chromosomes, while the locus of is single. Only the genes are orthologous. For gene designations see .

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 7

is an ortholog of .

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 8

Ten of the 15 genes at the locus are conserved in .

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of FIGURE 9

s and s tend to map to supercontig ends. Shown are the four chromosomes (C.1 through C.4) and (squares) or (ovals) gene locations, adapted from Cuomo et. al. (2007). Lines above the chromosomes represent supercontigs; “S” indicates supercontig number, and placement indicates first nucleotide of the sequence. Circles indicate high SNP or recombination regions. Scale is in megabases.

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Abraham, W. R. 2001. Bioactive sesquiterpenes produced by fungi: are they useful for humans as well? Curr. Med. Chem. 8:583606.
2. Baker, S.,, S. Kroken,, P. Inderbitzin,, T. Asvarak,, B.-Y. Li,, L. Shi,, O. C. Yoder, and, B. G. Turgeon. 2006. Two polyke-tide synthase-encoding genes are required for biosynthesis of the polyketide virulence factor, T-toxin, by Cochliobolus heterostrophus. Mol. Plant-Microbe Interact. 19:139149.
3. Balibar, C. J.,, F. H. Vaillancourt, and, C. T. Walsh. 2005. Generation of D amino acid residues in assembly of arthrofactin by dual condensation/epimerization domains. Chem. Biol. 12:11891200.
4. Bayram, O.,, S. Krappmann,, M. Ni,, J. W. Bok,, K. Helm-staedt,, O. Valerius,, S. Braus-Stromeyer,, N. J. Kwon,, N. P. Keller,, J. H. Yu, and, G. H. Braus. 2008. VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science 320:15041506.
5. Benitez, T.,, A. M. Rincon,, M. C. Limon, and, A. C. Codon. 2004. Biocontrol mechanisms of Trichoderma strains. Int. Microbiol. 7:249260.
6. Bok, J. W.,, D. Chung,, S. A. Balajee,, K. A. Marr,, D. Andes,, K. F. Nielsen,, J. C. Frisvad,, K. A. Kirby, and, N. P. Keller. 2006a. GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus virulence. Infect. Immun. 74:67616768.
7. Bok, J. W., and, N. P. Keller. 2004. LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot. Cell 3:527535.
8. Bok, J. W.,, D. Noordermeer,, S. P. Kale, and, N. P. Keller. 2006b. Secondary metabolic gene cluster silencing in Aspergillus nidulans. Mol. Microbiol. 61:16361645.
9. Borel, J. F. 2002. History of the discovery of cyclosporin and of its early pharmacological development. Wien. Klin. Wochenschr. 114:433437.
10. Brakhage, A. A.,, Q. Al-Abdallah,, A. Tuncher, and, P. Sprote. 2005. Evolution of beta-lactam biosynthesis genes and recruitment of trans-acting factors. Phytochemistry 66:12001210.
11. Brian, P.,, A. Dawkins,, J. Grove,, H. Hemming,, R. Lowe, and, G. Morris. 1961. Phytotoxic compounds from Fusarium equiseti. J. Exp. Bot. 12:112.
12. Brown, D. W.,, R. A. E. Butchko,, M. Busman, and, R. H. Proctor. 2007. The Fusarium verticillioides FUM gene cluster encodes a Zn(II)2Cys6 protein that affects FUM gene expression and fumonisin production. Eukaryot. Cell 6:12101218.
13. 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.
14. Burmeister, H. R., and, R. D. Plattner. 1987. Enniatin production by Fusarium tricinctum and its effect on germinating wheat seeds. Phytopathology 77:14831487.
15. Bushley, K. E.,, D. R. Ripoll, and, B. G. Turgeon. 2008. Module evolution and substrate specificity of fungal nonribosomal peptide synthetases involved in siderophore biosynthesis. BMC Evol. Biol. 8:328.
16. Caboche, S.,, M. Pupin,, V. Leclere,, A. Fontaine,, P. Jacques, and, G. Kucherov. 2008. NORINE: a database of nonribosomal peptides. Nucleic Acids Res. 36:326331.
17. Camazine, S. 1983. Mushroom chemical defense—food aversion learning induced by hallucinogenic toxin, Muscimol. J. Chem. Ecol. 9:14731481.
18. Cary, J. W., and, K. C. Ehrlich. 2006. Aflatoxigenicity in Aspergillus: molecular genetics, phylogenetic relationships and evolutionary implications. Mycopathologia 162:167177.
19. Castoe, T. A.,, T. Stephens,, B. P. Noonan, and, C. Calestani. 2007. A novel group of type I polyketide synthases (PKS) in animals and the complex phylogenomics of PKSs. Gene 392:4758.
20. Champe, S. P.,, P. Rao, and, A. Chang. 1987. An endogenous inducer of sexual development in Aspergillus nidulans. J. Gen. Microbiol. 133:13831387.
21. Chang, P. K.,, D. Bhatnagar,, T. E. Cleveland, and, J. W. Bennett. 1995. Sequence variability in homologs of the aflatoxin pathway gene aflR distinguishes species in Aspergillus section flavi. Appl. Environ. Microbiol. 61:4043.
22. Chen, H.,, M. H. Lee,, M. E. Daub, and, K. R. Chung. 2007. Molecular analysis of the cercosporin biosynthetic gene cluster in Cercospora nicotianae. Mol. Microbiol. 64:755770.
23. Chiang, Y. M.,, E. Szewczyk,, T. Nayak,, A. D. Davidson,, J. F. Sanchez,, H. C. Lo,, W. Y. Ho,, H. Simityan,, E. Kuo,, A. Praseuth,, K. Watanabe,, B. R. Oakley, and, C. C. Wang. 2008. Molecular genetic mining of the Aspergillus secondary metabolome: discovery of the Emericellamide biosynthetic pathway. Chem. Biol. 15:527532.
24. Chitarra, G. S.,, T. Abee,, F. M. Rombouts,, M. A. Posthumus, and, J. Dijksterhuis. 2004. Germination of Penicillium paneum conidia is regulated by 1-octen-3-ol, a volatile self-inhibitor. Appl. Environ. Microbiol. 70:28232829.
25. Choi, D. W.,, R. C. Kunz,, E. S. Boyd,, J. D. Semrau,, W. E. Antholine,, J. I. Han,, J. A. Zahn,, J. M. Boyd,, A. M. de la Mora, and, A. A. DiSpirito. 2003. The membrane-associated methane monooxygenase (pMMO) and pMMONADH:quinone oxidoreductase complex from Methylococcus capsulatus Bath. J. Bacteriol. 185:57555764.
26. Chooi, Y. H.,, D. M. Stalker,, M. A. Davis,, I. Fujii,, J. A. Elix,, S. H. Louwhoff, and, A. C. Lawrie. 2008. Cloning and sequence characterization of a non-reducing polyketide synthase gene from the lichen Xanthoparmelia semiviridis. Mycol. Res. 112:147161.
27. Clay, K., and, C. Schardl. 2002. Evolutionary origins and ecological consequences of endophyte symbiosis with grasses. Am. Nat. 160 (Suppl. 4):S99S127.
28. Collemare, J.,, M. Pianfetti,, A. E. Houlle,, D. Morin,, L. Camborde,, M. J. Gagey,, C. Barbisan,, I. Fudal,, M. H. Lebrun, and, H. U. Boehnert. 2008. Magnaporthe grisea avirulence gene ACE1 belongs to an infection-specific gene cluster involved in secondary metabolism. New Phytol. 179:196208.
29. Colmenares, A. J.,, J. Aleu,, R. Duran-Patron,, I. G. Collado, and, R. Hernandez-Galan. 2002. The putative role of botry-dial and related metabolites in the infection mechanism of Botrytis cinerea. J. Chem. Ecol. 28:9971005.
30. Cosmina, P.,, F. Rodriguez,, F. de Ferra,, G. Grandi,, M. Perego,, G. Venema, and, D. van Sinderen. 1993. Sequence and analysis of the genetic locus responsible for surfactin synthesis in Bacillus subtilis. Mol. Microbiol. 8:821831.
31. Cox, R. J. 2007. Polyketides, proteins and genes in fungi: programmed nano-machines begin to reveal their secrets. Org. Biomol. Chem. 5:20102026.
32. Cramer, R. A., Jr.,, M. P. Gamcsik,, R. M. Brooking,, L. K. Najvar,, W. R. Kirkpatrick,, T. F. Patterson,, C. J. Balibar,, J. R. Graybill,, J. R. Perfect,, S. N. Abraham, and, W. J. Steinbach. 2006. Disruption of a nonribosomal peptide synthetase in Aspergillus fumigatus eliminates gliotoxin production. Eukaryot. Cell 5:972980.
33. Cuomo, C. A.,, U. Guldener,, J. R. Xu,, F. Trail,, B. G. Turgeon,, A. Di Pietro,, J. D. Walton,, L. J. Ma,, S. E. Baker,, M. Rep,, G. Adam,, J. Antoniw,, T. Baldwin,, S. Calvo,, Y. L. Chang,, D. Decaprio,, L. R. Gale,, S. Gnerre,, R. S. Goswami,, K. Hammond-Kosack,, L. J. Harris,, K. Hilburn,, J. C. Kennell,, S. Kroken,, J. K. Magnuson,, G. Mannhaupt,, E. Mauceli,, H. W. Mewes,, R. Mitterbauer,, G. Muehlbauer,, M. Munsterkotter,, D. Nelson,, K. O’Donnell,, T. Ouellet,, W. Qi,, H. Quesneville,, M. I. Roncero,, K. Y. Seong,, I. V. Tetko,, M. Urban,, C. Waalwijk,, T. J. Ward,, J. Yao,, B. W. Birren, and, H. C. Kistler. 2007. The Fusarium graminearum genome reveals a link between localized polymorphism and pathogen specialization. Science 317:14001402.
34. Cusack, R. M.,, L. Grondahl,, D. P. Fairlie,, G. R. Hanson, and, L. R. Gahan. 2003. Studies of the interaction of potassium(I), calcium(II), magnesium(II), and copper(II) with cyclosporin A. J. Inorg. Biochem. 97:191198.
35. Dancer, R. J.,, A. Jones, and, D. P. Fairlie. 1995. Binding of the immunosuppressant peptide Cyclosporine A to calcium, zinc and copper—is Cyclosporine A an ionophore. Aust. J. Chem. 48:18351841.
36. da Silva, M. F.,, M. S. Soares,, J. B. Fernandes, and, P. C. Vieria. 2007. Alkyl, aryl, alkylarylquinoline, and related alkaloids. Alkaloids Chem. Biol. 64:139214.
37. Dean, R. A.,, N. J. Talbot,, D. J. Ebbole,, M. L. Farman,, T. K. Mitchell,, M. J. Orbach,, M. Thon,, R. Kulkarni,, J. R. Xu,, H. Q. Pan,, N. D. Read,, Y. H. Lee,, I. Carbone,, D. Brown,, Y. Y. Oh,, N. Donofrio,, J. S. Jeong,, D. M. Soanes,, S. Djonovic,, E. Kolomiets,, C. Rehmeyer,, W. X. Li,, M. Harding,, S. Kim,, M. H. Lebrun,, H. Bohnert,, S. Coughlan,, J. Butler,, S. Calvo,, L. J. Ma,, R. Nicol,, S. Purcell,, C. Nusbaum,, J. E. Galagan, and, B. W. Birren. 2005. The genome sequence of the rice blast fungus Magnaporthe grisea. Nature 434:980986.
38. Degenkolb, T.,, H. von Dohren,, K. F. Nielsen,, G. J. Samuels, and, H. Bruckner. 2008. Recent advances and future prospects in peptaibiotics, hydrophobin, and mycotoxin research, and their importance for chemotaxonomy of Trichoderma and Hypocrea. Chem. Biodivers. 5:671680.
39. Deighton, N.,, I. Muckenschnabel,, A. J. Colmenares,, I. G. Collado, and, B. Williamson. 2001. Botrydial is produced in plant tissues infected by Botrytis cinerea. Phytochemistry 57:689692.
40. Demain, A., and, A. Fang. 2000. The natural functions of secondary metabolites. Adv. Biochem. Eng. Biotechnol. 69:139.
41. Desjardins, A. 2006. Fusarium Mycotoxins, Chemistry, Genetics, and Biology. The American Phytopathological Society, St. Paul, MN.
42. Donnelly, D.,, D. Coveney,, N. Fukuda, and, J. Polonsky. 1986. New sesquiterpene aryl esters from Armillaria mellea. J. Nat. Prod. 49:111116.
43. Donnelly, D.,, S. Sanada,, J. Oreilly,, J. Polonsky,, T. Prange, and, C. Pascard. 1982. Isolation and structure (X-ray-analysis) of the orsellinate of Armillol, a new antibacterial metabolite from Armillaria mellea. J. Chem. Soc. Chem. Commun. 1982:135137.
44. Eichhorn, H.,, F. Lessing,, B. Winterberg,, J. Schirawski,, J. Kamper,, P. Muller, and, R. Kahmann. 2006. A ferroxidation/permeation iron uptake system is required for virulence in Ustilago maydis. Plant Cell 18:33323345.
45. Eisendle, M.,, M. Schrettl,, C. Kragl,, D. Muller,, P. Illmer, and, H. Haas. 2006. The intracellular siderophore ferricrocin is involved in iron storage, oxidative-stress resistance, germination, and sexual development in Aspergillus nidulans. Eukaryot. Cell 5:15961603.
46. Fedorova, N. D.,, N. Khaldi,, V. S. Joardar,, R. Maiti,, P. Amedeo,, M. J. Anderson,, J. Crabtree,, J. C. Silva,, J. H. Badger,, A. Albarraq,, S. Angiuoli,, H. Bussey,, P. Bowyer,, P. J. Cotty,, P. S. Dyer,, A. Egan,, K. Galens,, C. M. Fraser-Liggett,, B. J. Haas,, J. M. Inman,, R. Kent,, S. Lemieux,, I. Malavazi,, J. Orvis,, T. Roemer,, C. M. Ronning,, J. P. Sundaram,, G. Sutton,, G. Turner,, J. C. Venter,, O. R. White,, B. R. Whitty,, P. Youngman,, K. H. Wolfe,, G. H. Goldman,, J. R. Wortman,, B. Jiang,, D. W. Denning, and, W. C. Nierman. 2008. Genomic islands in the pathogenic filamentous fungus Aspergillus fumigatus. PLoS Genet. 4:e1000046.
47. 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.
48. Finking, R., and, M. A. Marahiel. 2004. Biosynthesis of nonribosomal peptides. Annu. Rev. Microbiol. 58:453488.
49. Fleetwood, D. J.,, B. Scott,, G. A. Lane,, A. Tanaka, and, R. D. Johnson. 2007. A complex ergovaline gene cluster in epichloe endophytes of grasses. Appl. Environ. Microbiol. 73:25712579.
50. Fox, E. M.,, D. M. Gardiner,, N. P. Keller, and, B. J. Howlett. 2008. A Zn(II)2Cys6 DNA binding protein regulates the sirodesmin PL biosynthetic gene cluster in Leptosphaeria maculans. Fungal Genet. Biol. 45:671682.
51. Friesen, T. L.,, J. D. Faris,, P. S. Solomon, and, R. P. Oliver. 2008. Host-specific toxins: effectors of necrotrophic pathogenicity. Cell. Microbiol. 10:14211428.
52. Friesen, T. L.,, E. H. Stukenbrock,, Z. H. Liu,, S. Meinhardt,, H. Ling,, J. D. Faris,, J. B. Rasmussen,, P. S. Solomon,, B. A. McDonald, and, R. P. Oliver. 2006. Emergence of a new disease as a result of interspecific virulence gene transfer. Nat. Genet. 38:953956.
53. Fudal, I.,, J. Collemare,, H. U. Bohnert,, D. Melayah, and, M. H. Lebrun. 2007. Expression of Magnaporthe grisea avirulence gene ACE1 is connected to the initiation of appressorium-mediated penetration. Eukaryot. Cell 6:546554.
54. Gaffoor, I.,, D. W. Brown,, R. Plattner,, R. H. Proctor,, W. H. Qi, and, F. Trail. 2005. Functional analysis of the polyketide synthase genes in the filamentous fungus Gibberella zeae (Anamorph Fusarium graminearum). Eukaryot. Cell 4:19261933.
55. Gaspar, M.,, R. Grazina,, A. Bodor,, E. Farkas, and, M. A. Santos. 1999. Siderophore analogues: a new macrocyclic tetraamine tris (hydroxamate) ligand; synthesis and solution chemistry of the iron(III), aluminium(III) and copper(II) complexes. J. Chem. Soc. Dalton Trans. 5:799806.
56. Glinski, M.,, C. Urbanke,, T. Hornbogen, and, R. Zocher. 2002. Enniatin synthetase is a monomer with extended structure: evidence for an intramolecular reaction mechanism. Arch. Microbiol. 178:267273.
57. Gloer, J.,, M. TePaske,, J. Sima,, D. Wicklow, and, P. Dowd. 1988. Antiinsectan aflavanine derivatives from the sclerotia of Aspergillus flavus. J. Org. Chem. 53:54575460.
58. Gloer, J. B. 1995. The chemistry of fungal antagonism and defense. Can. J. Bot. 73:S1265S1274.
59. Gottlieb, D. 1973. Endogenous inhibitors of spore germination. Phytopathology 63:13261327.
60. Grovel, O.,, Y. F. Pouchus,, T. R. du Pont,, M. Montagu,, Z. Amzil, and, J. F. Verbist. 2002. Ion trap MSn for identification of gliotoxin as the cytotoxic factor of a marine strain of Aspergillus fumigatus Fresenius. J. Microbiol. Methods 48:171179.
61. Grunewald, J., and, M. A. Marahiel. 2006. Chemoenzymatic and template-directed synthesis of bioactive macrocyclic peptides. Microbiol. Mol. Biol. Rev. 70:121126.
62. Haarmann, T.,, N. Lorenz, and, P. Tudzynski. 2008. Use of a nonhomologous end joining deficient strain (Deltaku70) of the ergot fungus Claviceps purpurea for identification of a nonribosomal peptide synthetase gene involved in ergota-mine biosynthesis. Fungal Genet. Biol. 45:3544.
63. Haas, H.,, M. Eisendle, and, B. G. Turgeon. 2008. Siderophores in fungal physiology and virulence. Annu. Rev. Phytopathol. 46:149188.
64. Hall, C., and, F. S. Dietrich. 2007. The reacquisition of biotin prototrophy in Saccharomyces cerevisiae involved horizontal gene transfer, gene duplication and gene clustering. Genetics 177:22932307.
65. Hawkesworth, D. 1991. The fungal dimension of biodiversity: magnitude, significance, and conservation. Mycol. Res. 95:641655.
66. Heckman, D. S.,, D. M. Geiser,, B. R. Eidell,, R. L. Stauffer,, N. L. Kardos, and, S. B. Hedges. 2001. Molecular evidence for the early colonization of land by fungi and plants. Science 293:11291133.
67. Herrmann, M.,, R. Zocher, and, A. Haese. 1996a. Effect of disruption of the enniatin synthetase gene on the virulence of Fusarium avenaceum. Mol. Plant-Microbe Interact. 9:226232.
68. Herrmann, M.,, R. Zocher, and, A. Haese. 1996b. Enniatin production by Fusarium strains and its effect on potato tuber tissue. Appl. Environ. Microbiol. 62:393398.
69. Hof, C.,, K. Eisfeld,, K. Welzel,, L. Antelo,, A. J. Foster, and, H. Anke. 2007. Ferricrocin synthesis in Magnaporthe grisea and its role in pathogenicity in rice. Mol. Plant Pathol. 8:163172.
70. Hohn, T., and, F. VanMiddlesworth. 1986. Purification and characterization of the sesquiterpene cyclase trichodiene synthetase from Fusarium sporotrichioides. Arch. Biochem. Biophys. 251:756761.
71. Hopwood, D. A. 1997. Genetic contributions to understanding polyketide synthases. Chem. Rev. 97:24652498.
72. Hopwood, D. A., and, C. Khosla. 1992. Genes for polyketide secondary metabolic pathways in microorganisms and plants, p. 88–112. In D. J. Chadwick and J. Whelan (ed.), Secondary Metabolites: Their Function and Evolution, vol. 171. John Wiley & Sons, Chichester, United Kingdom.
73. Howard, R. J., and, B. Valent. 1996. Breaking and entering: host penetration by the fungal rice blast pathogen Magna-porthe grisea. Annu. Rev. Microbiol. 50:491512.
74. Hutchinson, C. R. 1999. Microbial polyketide synthases: more and more prolific. Proc. Natl. Acad. Sci. USA 96:33363338.
75. Hutchinson, C. R. 2003. Polyketide and non-ribosomal peptide synthases: falling together by coming apart. Proc. Natl. Acad. Sci. USA 100:30103012.
76. Hutchinson, C. R.,, J. Kennedy,, C. Park,, S. Kendrew,, K. Auclair, and, J. Vederas. 2000. Aspects of the biosynthesis of non-aromatic fungal polyketides by iterative polyketide synthases. Antonie van Leeuwenhoek Int. J. Gen. Mol. Micro-biol. 78:287295.
77. Jacobson, E. S.,, E. Hove, and, H. S. Emery. 1995. Antioxidant function of melanin in black fungi. Infect. Immun. 63:49444945.
78. Jegorov, A.,, M. Hajduch,, M. Sulc, and, V. Havlicek. 2006. Nonribosomal cyclic peptides: specific markers of fungal infections. J. Mass Spectrom. 41:563576.
79. Johnson, L. 2008. Iron and siderophores in fungal-host interactions. Mycol. Res. 112:170183.
80. Johnson, R. D.,, L. Johnson,, Y. Itoh,, M. Kodama,, H. Otani, and, K. Kahmoto. 2000. Cloning and characterization of a cyclic peptide synthetase gene from Alternaria alternata apple pathotype whose product is involved in AM-toxin synthesis and pathogenicity. Mol. Plant-Microbe Interact. 13:742753.
81. Joshi, B. K.,, J. B. Gloer,, D. T. Wicklow, and, P. F. Dowd. 1999. Sclerotigenin: a new antiinsectan benzodiazepine from the sclerotia of Penicillium sclerotigenum. J. Nat. Prod. 62:650652.
82. Jumpponen, A., and, J. M. Trappe. 1998. Dark septate endophytes: a review of facultative biotrophic root-colonizing fungi. New Phytol. 140:295310.
83. Kawamura, C.,, T. Tsujimoto, and, T. Tsuge. 1999. Targeted disruption of a melanin biosynthesis gene affects conidial development and UV tolerance in the Japanese pear pathotype of Alternaria alternata. Mol. Plant-Microbe Interact. 12:5963.
84. Keller, N. P., and, T. M. Hohn. 1997. Metabolic pathway gene clusters in filamentous fungi. Fungal Genet. Biol. 21:1729.
85. Kers, J. A.,, K. D. Cameron,, M. V. Joshi,, R. A. Bukhalid,, J. E. Morello,, M. J. Wach,, D. M. Gibson, and, R. Loria. 2005. A large, mobile pathogenicity island confers plant pathogenicity on Streptomyces species. Mol. Microbiol. 55:10251033.
86. Khaldi, N.,, J. Collemare,, M. H. Lebrun, and, K. H. Wolfe. 2008. Evidence for horizontal transfer of a secondary metabolite gene cluster between fungi. Genome Biol. 9:R18.
87. Kim, H. J.,, D. W. Graham,, A. A. DiSpirito,, M. A. Alterman,, N. Galeva,, C. K. Larive,, D. Asunskis, and, P. M. A. Sherwood. 2004. Methanobactin, a copper-acquisition compound from methane-oxidizing bacteria. Science 305:16121615.
88. Kim, J. E.,, J. Jin,, H. Kim,, J. C. Kim,, S. H. Yun, and, Y. W. Lee. 2006. GIP2, a putative transcription factor that regulates the aurofusarin biosynthetic gene cluster in Gibberella zeae. Appl. Environ. Microbiol. 72:16451652.
89. Kim, K. H.,, Y. Cho,, M. La Rota,, R. A. Cramer, and, C. B. Lawrence. 2007. Functional analysis of the Alternaria brassicicola non-ribosomal peptide synthetase gene AbNPS2 reveals a role in conidial cell wall construction. Mol. Plant Pathol. 8:2339.
90. Kleinkauf, H., and, H. Von Doehren. 1996. A nonribosomal system of peptide biosynthesis. Eur. J. Biochem. 236:335351.
91. Kroken, S.,, N. L. Glass,, J. W. Taylor,, O. C. Yoder, and, B. G. Turgeon. 2003. Phylogenomic analysis of type I polyke-tide synthase genes in pathogenic and saprobic ascomycetes. Proc. Natl. Acad. Sci. USA 100:1567015675.
92. Kutil, B. L.,, C. Greenwald,, G. Liu,, M. J. Spiering,, C. L. Schardl, and, H. H. Wilkinson. 2007. Comparison of loline alkaloid gene clusters across fungal endophytes: predicting the co-regulatory sequence motifs and the evolutionary history. Fungal Genet. Biol. 44:10021010.
93. 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.
94. Lautru, S., and, G. L. Challis. 2004. Substrate recognition by nonribosomal peptide synthetase multi-enzymes. Microbiology 150:16291636.
95. Lawrence, J. G. 1999. Gene transfer, speciation, and the evolution of bacterial genomes. Curr. Opin. Microbiol. 2:519523.
96. Lawrence, J. G., and, H. Ochman. 2002. Reconciling the many faces of lateral gene transfer. Trends Microbiol. 10:14.
97. Lee, B. N.,, S. Kroken,, D. Y. T. Chou,, B. Robbertse,, O. C. Yoder, and, B. G. Turgeon. 2005. Functional analysis of all nonribosomal peptide synthetases in Cochliobolus heterostrophus reveals a factor, NPS6, involved in virulence and resistance to oxidative stress. Eukaryot. Cell 4:545555.
98. Lehr, N. A.,, A. Meffert,, L. Antelo,, O. Sterner,, H. Anke, and, R. W. Weber. 2006. Antiamoebins, myrocin B and the basis of antifungal antibiosis in the coprophilous fungus Stil-bella erythrocephala (syn. S. fimetaria). FEMS Microbiol. Ecol. 55:105112.
99. Leite, B., and, R. L. Nicholson. 1992. Mycosporine alanine— a self-inhibitor of germination from the conidial mucilage of Colletotrichum-graminicola. Exp. Mycol. 16:7686.
100. Leonard, K. J. 1977. Virulence, temperature optima and competitive abilities of isolines of races T and O of Bipolaris maydis. Phytopathology 67:12731279.
101. Leppik, R. A.,, W. Bottomle, and, D. W. Hollomon. 1972. Quiesone: an inhibitor of germination of Peronospora tabacina conidia. Phytochemistry 11:20552063.
102. Li, W.,, C. J. Rehmeyer,, C. Staben, and, M. L. Farman. 2005. TERMINUS—Telomeric End-Read Mining IN Unassembled Sequences. Bioinformatics 21:16951698.
103. Lorenz, N.,, E. V. Wilson,, C. Machado,, C. L. Schardl, and, P. Tudzynski. 2007. Comparison of ergot alkaloid biosynthesis gene clusters in Claviceps species indicates loss of late pathway steps in evolution of C. fusiformis. Appl. Environ. Micro-biol. 73:71857191.
104. Macko, V.,, R. C. Staples,, H. Gershon, and, J. A. A. Ren-wick. 1970. Self-inhibitor of bean rust uredospores—methyl 3, 4-dimethoxycinnamate. Science 170:539540.
105. Marahiel, M. A. 1992. Multidomain enzymes involved in peptide synthesis. FEBS Lett. 307:4043.
106. Marahiel, M. A. 1997. Protein templates for the biosynthesis of peptide antibiotics. Chem. Biol. 4:561567.
107. Marahiel, M. A.,, T. Stachelhaus, and, H. D. Mootz. 1997. Modular peptide synthetases involved in nonribosomal peptide synthesis. Chem. Rev. 97:26512674.
108. Markert, A.,, N. Steffan,, K. Ploss,, S. Hellwig,, U. Steiner,, C. Drewke,, S. M. Li,, W. Boland, and, E. Leistner. 2008. Biosynthesis and accumulation of ergoline alkaloids in a mutualistic association between Ipomoea asarifolia (Convolvulaceae) and a clavicipitalean fungus. Plant Physiol. 147:296305.
109. Marquez-Fernandez, O.,, A. Trigos,, J. L. Ramos-Balderas,, G. Viniegra-Gonzalez,, H. B. Deising, and, J. Aguirre. 2007. Phosphopantetheinyl transferase CfwA/NpgA is required for Aspergillus nidulans secondary metabolism and asexual development. Eukaryot. Cell 6:710720.
110. Meehan, F., and, H. C. Murphy. 1947. Differential phytotoxicity of metabolic by-products of Helminthosporium victoriae. Science 106:270271.
111. Michael, J. P. 2008. Quinoline, quinazoline and acridone alkaloids. Nat. Prod. Rep. 25:166187.
112. Moon, Y. S.,, B. G. Donzelli,, S. B. Krasnoff,, H. McLane,, M. H. Griggs,, P. Cooke,, J. D. Vandenberg,, D. M. Gibson, and, A. C. Churchill. 2008. Agrobacterium-mediated disruption of a nonribosomal peptide synthetase gene in the invertebrate pathogen Metarhizium anisopliae reveals a peptide spore factor. Appl. Environ. Microbiol. 74:43664380.
113. Mootz, H. D.,, D. Schwarzer, and, M. A. Marahiel. 2002. Ways of assembling complex natural products on modular nonribosomal peptide synthetases. Chembiochem 3:490504.
114. Nicholson, R. L., and, L. Epstein. 1991. Adhesion of fungi to the plant surface: prerequisite for pathogenesis, p. 3–23. In G. T. Cole and H. C. Hoch (ed.), Fungal Spore and Disease Initiation in Plants and Animals. Plenum, New York, NY.
115. 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.
116. Nierman, W. C.,, A. Pain,, M. J. Anderson,, J. R. Wortman,, H. S. Kim,, J. Arroyo,, M. Berriman,, K. Abe,, D. B. Archer,, C. Bermejo,, J. Bennett,, P. Bowyer,, D. Chen,, M. Collins,, R. Coulsen,, R. Davies,, P. S. Dyer,, M. Farman,, N. Fedorova,, N. Fedorova,, T. V. Feldblyum,, R. Fischer,, N. Fosker,, A. Fraser,, J. L. Garcia,, M. J. Garcia,, A. Goble,, G. H. Goldman,, K. Gomi,, S. Griffith-Jones,, R. Gwilliam,, B. Haas,, H. Haas,, D. Harris,, H. Horiuchi,, J. Huang,, S. Humphray,, J. Jimenez,, N. Keller,, H. Khouri,, K. Kitamoto,, T. Kobayashi,, S. Konzack,, R. Kulkarni,, T. Kumagai,, A. Lafton,, J.-P. Latge,, W. Li,, A. Lord,, C. Lu,, W. H. Majoros,, G. S. May,, B. L. Miller,, Y. Mohamoud,, M. Molina,, M. Monod,, I. Mouyna,, S. Mulligan,, L. Murphy,, S. O’Neil,, I. Paulsen,, M. A. Penalva,, M. Pertea,, C. Price,, B. L. Pritchard,, M. A. Quail,, E. Rabbinowitsch,, N. Rawlins,, M.-A. Rajandream,, U. Reichard,, H. Renauld,, G. D. Robson,, S. R. de Cordoba,, J. M. Rodriguez-Pena,, C. M. Ronning,, S. Rutter,, S. L. Salzberg,, M. Sanchez,, J. C. Sanchez-Ferrero,, D. Saunders,, K. Seeger,, R. Squares,, S. Squares,, M. Takeuchi,, F. Tekaia,, G. Turner,, C. R. V. de Aldana,, J. Weidman,, O. White,, J. Woodward,, J.-H. Yu,, C. Fraser,, J. E. Galagan,, K. Asai,, M. Machida,, N. Hall,, B. Barrell, and, D. W. Denning. 2005. Genomic sequence of the pathogenic and allergenic filamentous fungus Aspergillus fumigatus. Nature 438:11511156.
117. Oide, S. 2007. Functional characterization of nonribosomal peptide synthetases in the ascomycete phytopathogen Cochliobolus heterostrophus. Ph. D. thesis. Cornell University, Ithaca, NY.
118. Oide, S.,, S. B. Krasnoff,, D. M. Gibson, and, B. G. Turgeon. 2007. Intracellular siderophores are essential for ascomycete sexual development in heterothallic Cochliobolus heterostrophus and homothallic Gibberella zeae. Eukaryot. Cell 6:13371353.
119. Oide, S.,, W. Moeder,, S. Krasnoff,, D. Gibson,, H. Haas,, K. Yoshioka, and, B. G. Turgeon. 2006. NPS6, encoding a nonribosomal peptide synthetase involved in siderophore-mediated iron metabolism, is a conserved virulence determinant of plant pathogenic ascomycetes. Plant Cell 18:28362853.
120. Omura, S. 1992. Trends in the search for bioactive microbial metabolites. J. Ind. Microbiol. 10:135156.
121. Pankewitz, F., and, M. Hilker. 2008. Polyketides in insects: ecological role of these widespread chemicals and evolutionary aspects of their biogenesis. Biol. Rev. Camb. Philos. Soc. 83:209226.
122. Park, S. Y.,, R. Kim,, C. M. Ryu,, S. K. Choi,, C. H. Lee,, J. G. Kim, and, S. H. Park. 2008. Citrinin, a mycotoxin from Penicillium citrinum, plays a role in inducing motility of Paeni-bacillus polymyxa. FEMS Microbiol. Ecol. 65:229237.
123. Parker, E., and, B. Scott. 2004. Indole-diterpene biosynthesis in ascomycetous fungi. In Z. An (ed.), Handbook of Industrial Mycology, vol. 22. Marcel Dekker, New York, NY.
124. Patron, N. J.,, R. F. Waller,, A. J. Cozijnsen,, D. C. Straney,, D. M. Gardiner,, W. C. Nierman, and, B. J. Howlett. 2007. Origin and distribution of epipolythiodioxopiperazine (ETP) gene clusters in filamentous ascomycetes. BMC Evol. Biol. 7:174.
125. Perrin, R. M.,, N. D. Fedorova,, J. W. Bok,, R. A. Cramer,, J. R. Wortman,, H. S. Kim,, W. C. Nierman, and, N. P. Keller. 2007. Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog. 3:508517.
126. Rodriguez-Carres, M.,, G. White,, D. Tsuchiya,, M. Taga, and, H. D. VanEtten. 2008. The supernumerary chromosome of Nectria haematococca that carries pea-pathogenicity-related genes also carries a trait for pea rhizosphere competitiveness. Appl. Environ. Microbiol. 74:38493856.
127. Roncal, T.,, S. Cordobes,, O. Sterner, and, U. Ugalde. 2002. Conidiation in Penicillium cyclopium is induced by conidiogenone, an endogenous diterpene. Eukaryot. Cell 1:823829.
128. Rose, M. S.,, S. H. Yun,, T. Asvarak,, S. W. Lu,, O. C. Yoder, and, B. G. Turgeon. 2002. A decarboxylase encoded at the Cochliobolus heterostrophus translocation-associated Tox1B locus is required for polyketide biosynthesis and high virulence on maize. Mol. Plant-Microbe Interact. 15:883893.
129. Saikia, S.,, M. J. Nicholson,, C. Young,, E. J. Parker, and, B. Scott. 2008. The genetic basis for indole-diterpene chemical diversity in filamentous fungi. Mycol. Res. 112:184199.
130. Saikia, S.,, E. J. Parker,, A. Koulman, and, B. Scott. 2007. Defining paxilline biosynthesis in Penicillium paxilli: functional characterization of two cytochrome P450 monooxygenases. J. Biol. Chem. 282:1682916837.
131. Saikia, S.,, E. J. Parker,, A. Koulman, and, B. Scott. 2006. Four gene products are required for the fungal synthesis of the indole-diterpene, paspaline. FEBS Lett. 580:16251630.
132. Saikkonen, K.,, P. Wali,, M. Helander, and, S. H. Faeth. 2004. Evolution of endophyte-plant symbioses. Trends Plant Sci. 9:275280.
133. Sattely, E. S.,, M. A. Fischbach, and, C. T. Walsh. 2008. Total biosynthesis: in vitro reconstitution of polyketide and nonribosomal peptide pathways. Nat. Prod. Rep. 25:757793.
134. Schardl, C. L. 2001. Epichloe festucae and related mutualistic symbionts of grasses. Fungal Genet. Biol. 33:6982.
135. Schardl, C. L. 2006. A global view of metabolites. Chem. Biol. 13:56.
136. Schardl, C. L.,, R. B. Grossman,, P. Nagabhyru,, J. R. Faulkner, and, U. P. Mallik. 2007. Loline alkaloids: currencies of mutualism. Phytochemistry 68:980996.
137. Scheffer, R. P.,, R. R. Nelson, and, A. J. Ullstrup. 1967. Inheritance of toxin production and pathogenicity in Cochliobolus carbonum and Cochliobolus victoriae. Phytopathology 57:12881291.
138. Scheffer, R. P., and, A. J. Ullstrup. 1965. A host-specific toxic metabolite from Helminthosporium carbonum. Phytopathology 55:10371038.
139. Schimmel, T. G.,, A. D. Coffman, and, S. J. Parsons. 1998. Effect of butyrolactone I on the producing fungus, Aspergillus terreus. Appl. Environ. Microbiol. 64:37073712.
140. Schrettl, M.,, E. Bignell,, C. Kragl,, Y. Sabiha,, O. Loss,, M. Eisendle,, A. Wallner,, H. N. Arst,, K. Haynes, and, H. Haas. 2007. Distinct roles for intra- and extracellular siderophores during Aspergillus fumigatus infection. PLoS Pathog. 3:e128.
141. Schrettl, M.,, H. S. Kim,, M. Eisendle,, C. Kragl,, W. C. Nierman,, T. Heinekamp,, E. R. Werner,, I. Jacobsen,, P. Illmer,, H. Yi,, A. A. Brakhage, and, H. Haas. 2008. SreA-mediated iron regulation in Aspergillus fumigatus. Mol. Microbiol. 70:2743.
142. Schwarzer, D.,, R. Finking, and, M. A. Marahiel. 2003. Nonribosomal peptides: from genes to products. Nat. Prod. Rep. 20:275287.
143. Schwarzer, D., and, M. A. Marahiel. 2001. Multimodular bio-catalysts for natural product assembly. Naturwissenschaften 88:93101.
144. Scottcraig, J. S.,, D. G. Panaccione,, J. A. Pocard, and, J. D. Walton. 1992. The cyclic peptide synthetase catalyzing HCtoxin production in the filamentous fungus Cochliobolus carbonum is encoded by a 15.7-kilobase open reading frame. J. Biol. Chem. 267:2604426049.
145. Shwab, E. K.,, J. W. Bok,, M. Tribus,, J. Galehr,, S. Graessle, and, N. P. Keller. 2007. Histone deacetylase activity regulates chemical diversity in Aspergillus. Eukaryot. Cell 6:16561664.
146. Shwab, E. K., and, N. P. Keller. 2008. Regulation of secondary metabolite production in filamentous ascomycetes. Mycol. Res. 112:225230.
147. Siewers, V.,, M. Viaud,, D. Jimenez-Teja,, I. G. Collado,, C. S. Gronover,, J. M. Pradier,, B. Tudzynski, and, P. Tudzynski. 2005. Functional analysis of the cytochrome P450 monooxygenase gene bcbot1 of Botrytis cinerea indicates that botrydial is a strain-specific virulence factor. Mol. Plant-Microbe Interact. 18:602612.
148. Sims, J. W., and, E. W. Schmidt. 2008. Thioesterase-like role for fungal PKS-NRPS hybrid reductive domains. J. Am. Chem. Soc. 130:1114911155.
149. Spikes, S.,, R. Xu,, C. K. Nguyen,, G. Chamilos,, D. P. Kontoyiannis,, R. H. Jacobson,, D. E. Ejzykowicz,, L. Y. Chiang,, S. G. Filler, and, G. S. May. 2008. Gliotoxin production in Aspergillus fumigatus contributes to host-specific differences in virulence. J. Infect. Dis. 197:479486.
150. Stack, D.,, C. Neville, and, S. Doyle. 2007. Nonribosomal peptide synthesis in Aspergillus fumigatus and other fungi. Microbiology 153:12971306.
151. Stocker-Wörgötter, E. 2008. Metabolic diversity of lichen-forming ascomycetous fungi: culturing, polyketide and shiki-mate metabolite production, and PKS genes. Nat. Prod. Rep. 25:188200.
152. 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.
153. Sugui, J. A.,, J. Pardo,, Y. C. Chang,, K. A. Zarember,, G. Nar-done,, E. M. Galvez,, A. Mullbacher,, J. I. Gallin,, M. M. Simon, and, K. J. Kwon-Chung. 2007. Gliotoxin is a virulence factor of Aspergillus fumigatus: gliP deletion attenuates virulence in mice immunosuppressed with hydrocortisone. Eukaryot. Cell 6:15621569.
154. Takano, Y.,, Y. Kubo,, K. Shimizu,, K. Mise,, T. Okuno, and, I. Furusawa. 1995. Structural analysis of PKS1, a polyketide synthase gene involved in melanin biosynthesis in Colletotrichum lagenarium. Mol. Gen. Genet. 249:162167.
155. Tanaka, A.,, B. A. Tapper,, A. Popay,, E. J. Parker, and, B. Scott. 2005. A symbiosis expressed non-ribosomal peptide synthetase from a mutualistic fungal endophyte of perennial ryegrass confers protection to the symbiotum from insect herbivory. Mol. Microbiol. 57:10361050.
156. Tanaka, S. 1933. Studies on black spot disease of the Japanese pears (Pyrus serotina). Mem. College Agric. Kyoto Imp. Univ. 28:131.
157. Temporini, E. D., and, H. D. VanEtten. 2004. An analysis of the phylogenetic distribution of the pea pathogenicity genes of Nectria haematococca MPVI supports the hypothesis of their origin by horizontal transfer and uncovers a potentially new pathogen of garden pea: Neocosmospora boniensis. Curr. Genet. 46:2936.
158. Toyomasu, T. 2008. Recent advances regarding diterpene cyclase genes in higher plants and fungi. Biosci. Biotechnol. Biochem. 72:11681175.
159. Tran, L.,, M. Tosin,, J. B. Spencer,, P. F. Leadlay, and, K. J. Weissman. 2008. Covalent linkage mediates communication between ACP and TE domains in modular polyketide synthases. Chembiochem 9:905915.
160. Tudzynski, B. 2005. Gibberellin biosynthesis in fungi: genes, enzymes, evolution, and impact on biotechnology. Appl. Microbiol. Biotechnol. 66:597611.
161. Tudzynski, B., and, K. Holter. 1998. Gibberellin biosynthetic pathway in Gibberella fujikuroi: evidence for a gene cluster. Fungal Genet. Biol. 25:15770.
162. Tudzynski, P.,, T. Correia, and, U. Keller. 2001. Biotechnology and genetics of ergot alkaloids. Appl. Microbiol. Biotechnol. 57:593605.
163. Tudzynski, P.,, K. Hoelter,, T. Correia,, C. Arntz,, N. Gram-mel, and, U. Keller. 1999. Evidence for an ergot alkaloid gene cluster in Claviceps purpurea. Mol. Gen. Genet. 261:133141.
164. Turgeon, B. G., and, S. E. Baker. 2007. Genetic and genomic dissection of the Cochliobolus heterostrophus Tox1 locus controlling biosynthesis of the polyketide virulence factor T-toxin. Adv. Genet. 57:219261.
165. Turgeon, B. G.,, M. Kodama,, G. Yang,, M. S. Rose,, S. W. Lu, and, O. C. Yoder. 1995. Function and chromosomal location of the Cochliobolus heterostrophus Tox1 locus. Can. J. Bot. 73:S1071S1076.
166. Turgeon, B. G., and, S.-W. Lu. 2000. Evolution of host specific virulence in Cochliobolus heterostrophus, p. 9–126. In J. W. Kronstad (ed.), Fungal Pathology. Kluwer, Dordrecht, The Netherlands.
167. Turgeon, B. G.,, S. Oide, and, K. Bushley. 2008. Creating and screening Cochliobolus heterostrophus non-ribosomal peptide synthetase mutants. Mycol. Res. 112:200206.
168. Ullan, R. V.,, J. Casqueiro,, O. Banuelos,, F. J. Fernandez,, S. Gutierrez, and, J. F. Martin. 2002. A novel epimerization system in fungal secondary metabolism involved in the conversion of isopenicillin N into penicillin N in Acremonium chrysogenum. J. Biol. Chem. 277:4621646225.
169. Umezawa, H. 1972. Enzyme inhibitors of microbial origin. University of Tokyo Press, Tokyo, Japan.
170. von Dohren, H. 2004. Biochemistry and general genetics of nonribosomal peptide synthetases in fungi, p. 217–264. In A. A. Brakhage (ed.), Molecular Biotechnology of Fungal Beta-Lactam Antibiotics and Related Peptide Synthetases. Advances in Biochemical Engineering/Biotechnology, vol. 88. Springer, Berlin, Germany.
171. Walton, J. D. 2000. Horizontal gene transfer and the evolution of secondary metabolite gene clusters in fungi: an hypothesis. Fungal Genet. Biol. 30:167171.
172. Walton, J. D. 1996. Host-selective toxins: agents of compatibility. Plant Cell 8:17231733.
173. Walton, J. D., and, D. C. Panaccione. 1993. Host-selective toxins and disease specificity: perspectives and progress. Annu. Rev. Phytopathol. 31:275303.
174. Wang, H. J.,, J. B. Gloer,, D. T. Wicklow, and, P. F. Dowd. 1995. Aflavinines and other antiinsectan metabolites from the ascostromata of Eupenicillium crustaceum and related species. Appl. Environ. Microbiol. 61:44294435.
175. Weissman, K. J. 2008. Biochemistry. Anatomy of a fungal polyketide synthase. Science 320:186187.
176. Woloshuk, C. P.,, K. R. Foutz,, 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.
177. Wolpert, T. J.,, L. D. Dunkle, and, L. M. Ciuffetti. 2002. Host-selective toxins and avirulence determinants: what’s in a name? Annu. Rev. Phytopathol. 40:251285.
178. Wong, S., and, K. H. Wolfe. 2005. Birth of a metabolic gene cluster in yeast by adaptive gene relocation. Nat. Genet. 37:777782.
179. Wood, V.,, R. Gwilliam,, M. A. Rajandream,, M. Lyne,, R. Lyne,, A. Stewart,, J. Sgouros,, N. Peat,, J. Hayles,, S. Baker,, D. Basham,, S. Bowman,, K. Brooks,, D. Brown,, S. Brown,, T. Chillingworth,, C. Churcher,, M. Collins,, R. Connor,, A. Cronin,, P. Davis,, T. Feltwell,, A. Fraser,, S. Gentles,, A. Goble,, N. Hamlin,, D. Harris,, J. Hidalgo,, G. Hodgson,, S. Holroyd,, T. Hornsby,, S. Howarth,, E. J. Huckle,, S. Hunt,, K. Jagels,, K. James,, L. Jones,, M. Jones,, S. Leather,, S. McDonald,, J. McLean,, P. Mooney,, S. Moule,, K. Mungall,, L. Murphy,, D. Niblett,, C. Odell,, K. Oliver,, S. O’Neil,, D. Pearson,, M. A. Quail,, E. Rabbinowitsch,, K. Rutherford,, S. Rutter,, D. Saunders,, K. Seeger,, S. Sharp,, J. Skelton,, M. Simmonds,, R. Squares,, S. Squares,, K. Stevens,, K. Taylor,, R. G. Taylor,, A. Tivey,, S. Walsh,, T. Warren,, S. Whitehead,, J. Woodward,, G. Volckaert,, R. Aert,, J. Robben,, B. Grymonprez,, I. Weltjens,, E. Vanstreels,, M. Rieger,, M. Schafer,, S. Muller-Auer,, C. Gabel,, M. Fuchs,, A. Dusterhoft,, C. Fritzc,, E. Holzer,, D. Moestl,, H. Hilbert,, K. Borzym,, I. Langer,, A. Beck,, H. Lehrach,, R. Reinhardt,, T. M. Pohl,, P. Eger,, W. Zimmermann,, H. Wedler,, R. Wambutt,, B. Purnelle,, A. Goffeau,, E. Cadieu,, S. Dreano,, S. Gloux,, V. Lelaure,, S. Mottier,, F. Galibert,, S. J. Aves,, Z. Xiang,, C. Hunt,, K. Moore,, S. M. Hurst,, M. Lucas,, M. Rochet,, C. Gaillardin,, V. A. Tallada,, A. Garzon,, G. Thode,, R. R. Daga,, L. Cruzado,, J. Jimenez,, M. Sánchez,, F. del Rey,, J. Benito,, A. Domínguez,, J. L. Revuelta,, S. Moreno,, J. Armstrong,, S. L. Forsburg,, L. Cerrutti,, T. Lowe,, W. R. McCombie,, I. Paulsen,, J. Potashkin,, G. V. Shpakovski,, D. Ussery,, B. G. Barrell, and, P. Nurse. 2002. The genome sequence of Schizosaccharomyces pombe. Nature 415:871880.
180. Yang, G.,, M. S. Rose,, B. G. Turgeon, and, O. C. Yoder. 1996. A polyketide synthase is required for fungal virulence and production of the polyketide T-toxin. Plant Cell 11:21392150.
181. Yoder, O., and, D. Mukunya. 1972. A host-specific toxic metabolite produced by Phyllosticta maydis. Phytopathology 62:799.
182. Yoder, O. C. 1973. A selective toxin produced by Phyllosticta maydis. Phytopathology 63:13611365.
183. Yoder, O. C., and, B. G. Turgeon. 2001. Fungal genomics and pathogenicity. Curr. Opin. Plant Biol. 4:315321.
184. Yonus, H.,, P. Neumann,, S. Zimmermann,, J. J. May,, M. A. Marahiel, and, M. T. Stubbs. 2008. Crystal structure of DltA: implications for the reaction mechanism of non-ribosomal peptide synthetase (NRPS) adenylation domains. J. Biol. Chem. 283:3248432491.
185. Young, C.,, L. McMillan,, E. Telfer, and, B. Scott. 2001. Molecular cloning and genetic analysis of an indole-diterpene gene cluster from Penicillium paxilli. Mol. Microbiol. 39:754764.
186. Young, C. A.,, M. K. Bryant,, M. J. Christensen,, B. A. Tapper,, G. T. Bryan, and, B. Scott. 2005. Molecular cloning and genetic analysis of a symbiosis-expressed gene cluster for lolitrem biosynthesis from a mutualistic endophyte of perennial ryegrass. Mol. Genet. Genomics 274:1329.
187. 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.
188. Yue, Q.,, J. Johnson-Cicalese,, T. Gianfagna, and, W. Meyer. 2000. Alkaloid production and chinch bug resistance in endophyte-inoculated chewings and strong creeping red fescues. J. Chem. Ecol. 26:279292.
189. Zhang, S.,, A. Schwelm,, H. Jin,, L. J. Collins, and, R. E. Bradshaw. 2007. A fragmented aflatoxin-like gene cluster in the forest pathogen Dothistroma septosporum. Fungal Genet. Biol. 44:13421354.
190. Zhou, H.,, J. Zhan,, K. Watanabe,, X. Xie, and, Y. Tang. 2008. A polyketide macrolactone synthase from the filamentous fungus Gibberella zeae. Proc. Natl. Acad. Sci. USA 105:62496254.


Generic image for table

PKS and NPS locations

Citation: Turgeon B, Bushley K. 2010. Secondary Metabolism, p 376-395. In Borkovich K, Ebbole D (ed), Cellular and Molecular Biology of Filamentous Fungi. ASM Press, Washington, DC. doi: 10.1128/9781555816636.ch26

This is a required field
Please enter a valid email address
Please check the format of the address you have entered.
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error