Chapter 54 : Biologically Active Secondary Metabolites from the Fungi

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

Preview this chapter:
Zoom in

Biologically Active Secondary Metabolites from the Fungi, Page 1 of 2

| /docserver/preview/fulltext/10.1128/9781555819583/9781555819576_Chap54-1.gif /docserver/preview/fulltext/10.1128/9781555819583/9781555819576_Chap54-2.gif


Fungi, plants, and bacteria are the major kingdoms of life with well-developed secondary metabolism. About 500,000 secondary metabolites (also referred to as natural products) have been described to date. About 100,000 of these are derived from animals, 350,000 are from plants, and 70,000 are from microbes ( ). Roughly 33,500 bioactive microbial metabolites have been described ( ). Of these 33,500 microbial metabolites, about 12.5% (4,200) are metabolites of unicellular bacteria and cyanobacteria, 41% (13,700) are products of Actinomycete fermentations, and about 47% (15,600) are of fungal origin ( ). Furthermore, the rate of discovery of new fungal metabolites has accelerated significantly in the past two decades relative to the rate of discovery in the actinomycetes, filamentous bacteria that traditionally have been the richest source of microbial natural products ( ). This complex and rich secondary metabolism is highly developed in the filamentous Ascomycota and Basidiomycota, while it is underdeveloped in the unicellular forms of the Ascomycota and Basidiomycota and in the Zygomycota, Blastocladiomycota, and Chytridiomycota ( Fig. 1 ). The diversity of fungal species, particularly in the Ascomycota and Basidiomycota, and the accompanying diversification of biosynthetic genes and gene clusters points to an almost limitless potential for metabolic variation. In fact, one can argue that much of the ecological success of the filamentous fungi in colonizing virtually all habitats on the planet is owed to their ability to deploy arrays of secondary metabolites in concert with their penetrative and absorptive life forms. This dependence of the fungi on secondary metabolites to conquer diverse habitats and sustain their existence within them is evidenced by the facts that most species make multiple types of secondary metabolites, their expression is orchestrated with the life cycle and environment, and significant portions of their genomes are devoted to encoding and regulating the production of these products.

Citation: Bills G, Gloer J. 2017. Biologically Active Secondary Metabolites from the Fungi, p 1087-1119. In Heitman J, Howlett B, Crous P, Stukenbrock E, James T, Gow N (ed), The Fungal Kingdom. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.FUNK-0009-2016
Highlighted Text: Show | Hide
Loading full text...

Full text loading...


Image of Figure 1
Figure 1

Simplified phylogeny of the phyla and classes of the Fungi. Numbers after phylum or class indicate the average number of secondary metabolite, transport, and catabolism genes recognized by the Clusters of Orthologous Groups of Proteins Classification (KOGs) from sequenced genomes (number in parentheses) of fungi at the Joint Genome Institute’s Mycosm Project (January 15, 2016). Taxa shaded in gray are known to produce secondary metabolites with high frequency. Branch length reflects relatedness of taxa.

Citation: Bills G, Gloer J. 2017. Biologically Active Secondary Metabolites from the Fungi, p 1087-1119. In Heitman J, Howlett B, Crous P, Stukenbrock E, James T, Gow N (ed), The Fungal Kingdom. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.FUNK-0009-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 2
Figure 2

Structures of mycophenolic acid and gibberellic acid.

Citation: Bills G, Gloer J. 2017. Biologically Active Secondary Metabolites from the Fungi, p 1087-1119. In Heitman J, Howlett B, Crous P, Stukenbrock E, James T, Gow N (ed), The Fungal Kingdom. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.FUNK-0009-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 3
Figure 3

Some rudimentary fungal metabolites. Hadicidin. Cyclo (-leucine--proline). Cyclo (-proline--phenylalanine). Dipicolinic acid. -DOPA. Tyrosol. 3-Nitropropionic acid. Mycosporine serinol. Farnesol. Cordycepin. Kojic acid.

Citation: Bills G, Gloer J. 2017. Biologically Active Secondary Metabolites from the Fungi, p 1087-1119. In Heitman J, Howlett B, Crous P, Stukenbrock E, James T, Gow N (ed), The Fungal Kingdom. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.FUNK-0009-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 4
Figure 4

Schematic representation of a cyclodipeptide synthase biosynthetic pathway. A cyclodipeptide synthase (red) binds aa-tRNAs (black) via a serine residue (Ser) to produce cyclodipeptides. aa-tRNAs are generated from an amino acid, ATP, and tRNAs.

Citation: Bills G, Gloer J. 2017. Biologically Active Secondary Metabolites from the Fungi, p 1087-1119. In Heitman J, Howlett B, Crous P, Stukenbrock E, James T, Gow N (ed), The Fungal Kingdom. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.FUNK-0009-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 5
Figure 5

Some fungal metabolites derived from the shikimic acid pathway and ribosomally synthesized and posttranslationally modified peptides (RiPPs). Involutin. α-Amanitin. Phalloidin. Ustiloxin A. Phomopsin A. Epichloëcyclin A.

Citation: Bills G, Gloer J. 2017. Biologically Active Secondary Metabolites from the Fungi, p 1087-1119. In Heitman J, Howlett B, Crous P, Stukenbrock E, James T, Gow N (ed), The Fungal Kingdom. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.FUNK-0009-2016
Permissions and Reprints Request Permissions
Download as Powerpoint
Image of Figure 6
Figure 6

Some fungal polyketides, nonribosomal peptides, and terpenoids. Griseofulvin. 6-Methyl salicylic acid. (R)-Mellein. Lovastatin. Cyclosporine A. Pneumocandin A. Pleuromutilin. Fusidic acid.

Citation: Bills G, Gloer J. 2017. Biologically Active Secondary Metabolites from the Fungi, p 1087-1119. In Heitman J, Howlett B, Crous P, Stukenbrock E, James T, Gow N (ed), The Fungal Kingdom. ASM Press, Washington, DC. doi: 10.1128/microbiolspec.FUNK-0009-2016
Permissions and Reprints Request Permissions
Download as Powerpoint


1. Bérdy J . 2012. Thoughts and facts about antibiotics: where we are now and where we are heading. J Antibiot (Tokyo) 65 : 385395.[CrossRef]
2. Nett M,, Ikeda H,, Moore BS . 2009. Genomic basis for natural product biosynthetic diversity in the actinomycetes. Nat Prod Rep 26 : 13621384.[CrossRef]
3. Bräse S,, Gläser F,, Kramer C,, Lindner S,, Linsenmeier AM,, Masters K-S,, Meister AC,, Ruff BM,, Zhong S . 2013. The Chemistry of Mycotoxins. Springer Verlag, Vienna, Austria.[CrossRef]
4. Bräse S,, Encinas A,, Keck J,, Nising CF . 2009. Chemistry and biology of mycotoxins and related fungal metabolites. Chem Rev 109 : 39033990.[CrossRef]
5. Miller JD,, McMullin DR . 2014. Fungal secondary metabolites as harmful indoor air contaminants: 10 years on. Appl Microbiol Biotechnol 98 : 99539966.[CrossRef]
6. Pusztahelyi T,, Holb IJ,, Pócsi I . 2015. Secondary metabolites in fungus-plant interactions. Front Plant Sci 6 : 573.[CrossRef]
7. Newman DJ,, Cragg GM . 2016. Natural products as sources of new drugs from 1981 to 2014. J Nat Prod 79 : 629661.[CrossRef]
8. Asolkar RN,, Cordova-Kreylos AL,, Himmel P,, Marrone PG . 2013. Discovery and development of natural products for pest management. ACS Symp Ser 1141 : 1730.[CrossRef]
9. Rimando AM,, Duke SO . 2006. Natural products for pest management. ACS Symp Ser 927 : 221.[CrossRef]
10. Peláez F, . 2005. Biological activities of fungal metabolites, p 4992. In An Z (ed), Handbook of Industrial Mycology. Marcel Dekker, New York, NY.
11. Miyamoto KT,, Komatsu M,, Ikeda H . 2014. Discovery of gene cluster for mycosporine-like amino acid biosynthesis from Actinomycetales microorganisms and production of a novel mycosporine-like amino acid by heterologous expression. Appl Environ Microbiol 80 : 50285036.[CrossRef]
12. CRC Press . 2016. The Chapman & Hall/CRC Dictionary of Natural Products version 25.1. http://dnp.chemnetbase.com.
13. Katz L,, Baltz RH . 2016. Natural product discovery: past, present, and future. J Ind Microbiol Biotechnol 43 : 155176.[CrossRef]
14. Dreyfuss M,, Chapela I, . 1994. The potential of fungi in the discovery of novel, low-weight pharmaceuticals, p 4980. In Gullo VP (ed), The Discovery of Natural Products with Therapeutic Potential. Butterworth-Heinemann, Boston, MA.[CrossRef]
15. Nielsen KF,, Larsen TO . 2015. The importance of mass spectrometric dereplication in fungal secondary metabolite analysis. Front Microbiol 6 : 71.[CrossRef]
16. Gaudêncio SP,, Pereira F . 2015. Dereplication: racing to speed up the natural products discovery process. Nat Prod Rep 32 : 779810.[CrossRef]
17. Bills GF,, Martín J,, Collado J,, Platas G,, Overy D,, Tormo JR,, Vicente F,, Verkleij G,, Crous P . 2009. Measuring the distribution and diversity of antibiosis and secondary metabolites in the filamentous fungi. Soc Indus Microbiol News 59 : 133147.
18. Bentley R . 2000. Mycophenolic acid: a one hundred year odyssey from antibiotic to immunosuppressant. Chem Rev 100 : 38013826.[CrossRef]
19. Bentley R . 2001. Bartolomeo Gosio, 1863-1944: an appreciation. Adv Appl Microbiol 48 : 229250.[CrossRef]
20. Alsberg CL,, Black OF . 1913. Contribution to the study of maize deterioration: biochemical and toxicological investigations of Penicillium puberulum and Penicillium stoloniferum . USDA Bur Plant Indust Bull 270 : 1270.
21. Florey HW,, Jennings MA,, Gilliver K,, Sanders AG . 1946. Mycophenolic acid: an antibiotic from Penicillium brevicompactum Dlerckx. Lancet 247 : 4649.[CrossRef]
22. Epinette WW,, Parker CM,, Jones EL,, Greist MC . 1987. Mycophenolic acid for psoriasis: a review of pharmacology, long-term efficacy, and safety. J Am Acad Dermatol 17 : 962971.[CrossRef]
23. Hansen BG,, Salomonsen B,, Nielsen MT,, Nielsen JB,, Hansen NB,, Nielsen KF,, Regueira TB,, Nielsen J,, Patil KR,, Mortensen UH . 2011. Versatile enzyme expression and characterization system for Aspergillus nidulans, with the Penicillium brevicompactum polyketide synthase gene from the mycophenolic acid gene cluster as a test case. Appl Environ Microbiol 77 : 30443051.[CrossRef]
24. Hansen BG,, Genee HJ,, Kaas CS,, Nielsen JB,, Regueira TB,, Mortensen UH,, Frisvad JC,, Patil KR . 2011. A new class of IMP dehydrogenase with a role in self-resistance of mycophenolic acid producing fungi. BMC Microbiol 11 : 202.[CrossRef]
25. Del-Cid A,, Gil-Durán C,, Vaca I,, Rojas-Aedo JF,, García-Rico RO,, Levicán G,, Chávez R . 2016. Identification and functional analysis of the mycophenolic acid gene cluster of Penicillium roqueforti . PLoS One 11 : e0147047.[CrossRef]
26. Quin MB,, Flynn CM,, Schmidt-Dannert C . 2014. Traversing the fungal terpenome. Nat Prod Rep 31 : 14491473.[CrossRef]
27. Turner WB,, Aldridge DC . 1983. Fungal Metabolites, vol II. Academic Press, New York, NY.
28. Bräse S,, Gläser F,, Kramer CS,, Lindner S,, Linsenmeier AM,, Masters K-S,, Meister AC,, Ruff BM,, Zhong S . 2013. The Chemistry of Mycotoxins. Springer-Verlag, Vienna, Austria.[CrossRef]
29. Hansen JR . 2008. The Chemistry of Fungi. Royal Society of Chemistry, Cambridge, United Kingdom.
30. Chooi Y-H,, Tang Y . 2012. Navigating the fungal polyketide chemical space: from genes to molecules. J Org Chem 77 : 99339953.[CrossRef]
31. Matsuda Y,, Abe I . 2016. Biosynthesis of fungal meroterpenoids. Nat Prod Rep 33 : 2653.[CrossRef]
32. Li YF,, Tsai KJS,, Harvey CJB,, Li JJ,, Ary BE,, Berlew EE,, Boehman BL,, Findley DM,, Friant AG,, Gardner CA,, Gould MP,, Ha JH,, Lilley BK,, McKinstry EL,, Nawal S,, Parry RC,, Rothchild KW,, Silbert SD,, Tentilucci MD,, Thurston AM,, Wai RB,, Yoon Y,, Aiyar RS,, Medema MH,, Hillenmeyer ME,, Charkoudian LK . 2016. Comprehensive curation and analysis of fungal biosynthetic gene clusters of published natural products. Fungal Genet Biol 89 : 1828.[CrossRef]
33. Wilkinson HH,, Ramaswamy A,, Sim SC,, Keller NP . 2004. Increased conidiation associated with progression along the sterigmatocystin biosynthetic pathway. Mycologia 96 : 11901198.[CrossRef]
34. Gaffoor I,, Brown DW,, Plattner R,, Proctor RH,, Qi W,, Trail F . 2005. Functional analysis of the polyketide synthase genes in the filamentous fungus Gibberella zeae (anamorph Fusarium graminearum). Eukaryot Cell 4 : 19261933.[CrossRef]
35. Chiang Y-M,, Ahuja M,, Oakley CE,, Entwistle R,, Asokan A,, Zutz C,, Wang CCC,, Oakley BR . 2016. Development of genetic dereplication strains in Aspergillus nidulans results in the discovery of aspercryptin. Angew Chem Int Ed Engl 55 : 16621665.[CrossRef]
36. Schreiber SL . 2005. Small molecules: the missing link in the central dogma. Nat Chem Biol 1 : 6466.[CrossRef]
37. Dutton MV,, Evans CS . 1996. Oxalate production by fungi: its role in pathogenicity and ecology in the soil environment. Can J Microbiol 42 : 881895.[CrossRef]
38. de Oliveira Ceita G,, Macêdo JNA,, Santos TB,, Alemanno L,, da Silva Gesteira A,, Micheli F,, Mariano AC,, Gramacho KP,, da Costa Silva D,, Meinhardt L,, Mazzafera P,, Pereira GAG,, de Mattos Cascardo JC . 2007. Involvement of calcium oxalate degradation during programmed cell death in Theobroma cacao tissues triggered by the hemibiotrophic fungus Moniliophthora perniciosa . Plant Sci 173 : 106117.[CrossRef]
39. Schmalenberger A,, Duran AL,, Bray AW,, Bridge J,, Bonneville S,, Benning LG,, Romero-Gonzalez ME,, Leake JR,, Banwart SA . 2015. Oxalate secretion by ectomycorrhizal Paxillus involutus is mineral-specific and controls calcium weathering from minerals. Sci Rep 5 : 12187.[CrossRef]
40. Albuquerque P,, Casadevall A . 2012. Quorum sensing in fungi: a review. Med Mycol 50 : 337345.[CrossRef]
41. Frisvad JC,, Larsen TO . 2015. Chemodiversity in the genus Aspergillus . Appl Microbiol Biotechnol 99 : 78597877.[CrossRef]
42. Gill M,, Steglich W . 1987. Pigments of fungi (Macromycetes). Fortschr Chem Org Naturst 51 : 1317.[CrossRef]
43. Röhrich CR,, Jaklitsch WM,, Voglmayr H,, Iversen A,, Vilcinskas A,, Nielsen KF,, Thrane U,, von Döhren H,, Brückner H,, Degenkolb T . 2014. Front line defenders of the ecological niche! Screening the structural diversity of peptaibiotics from saprotrophic and fungicolous Trichoderma/Hypocrea species. Fungal Divers 69 : 117146.[CrossRef]
44. Schardl CL , , et al . 2013. Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the clavicipitaceae reveals dynamics of alkaloid loci. PLoS Genet 9 : e1003323.[CrossRef]
45. Frisvad JC,, Andersen B,, Thrane U . 2008. The use of secondary metabolite profiling in chemotaxonomy of filamentous fungi. Mycol Res 112 : 231240.[CrossRef]
46. Stadler M,, Læssøe T,, Fournier J,, Decock C,, Schmieschek B,, Tichy HV,, Peršoh D . 2014. A polyphasic taxonomy of Daldinia (Xylariaceae). Stud Mycol 77 : 1143.[CrossRef]
47. Bömke C,, Tudzynski B . 2009. Diversity, regulation, and evolution of the gibberellin biosynthetic pathway in fungi compared to plants and bacteria. Phytochemistry 70 : 18761893.[CrossRef]
48. Rodrigues C,, Vandenberghe LPDS,, de Oliveira J,, Soccol CR . 2012. New perspectives of gibberellic acid production: a review. Crit Rev Biotechnol 32 : 263273.[CrossRef]
49. Schardl CL,, Young CA,, Pan J,, Florea S,, Takach JE,, Panaccione DG,, Farman ML,, Webb JS,, Jaromczyk J,, Charlton ND,, Nagabhyru P,, Chen L,, Shi C,, Leuchtmann A . 2013. Currencies of mutualisms: sources of alkaloid genes in vertically transmitted epichloae . Toxins (Basel) 5 : 10641088.[CrossRef]
50. Cook D,, Gardner DR,, Pfister JA . 2014. Swainsonine-containing plants and their relationship to endophytic fungi. J Agric Food Chem 62 : 73267334.[CrossRef]
51. Lu MYJ,, Fan WL,, Wang WF,, Chen T,, Tang YC,, Chu FH,, Chang TT,, Wang SY,, Li MY,, Chen YH,, Lin ZS,, Yang KJ,, Chen SM,, Teng YC,, Lin YL,, Shaw JF,, Wang TF,, Li WH . 2014. Genomic and transcriptomic analyses of the medicinal fungus Antrodia cinnamomea for its metabolite biosynthesis and sexual development. Proc Natl Acad Sci USA 111 : E4743E4752.[CrossRef]
52. Calvo AM,, Cary JW . 2015. Association of fungal secondary metabolism and sclerotial biology. Front Microbiol 6 : 62.[CrossRef]
53. Brakhage AA . 2013. Regulation of fungal secondary metabolism. Nat Rev Microbiol 11 : 2132.[CrossRef]
54. Stadler M,, Quang DN,, Tomita A,, Hashimoto T,, Asakawa Y . 2006. Changes in secondary metabolism during stromatal ontogeny of Hypoxylon fragiforme . Mycol Res 110 : 811820.[CrossRef]
55. Minerdi D,, Moretti M,, Gilardi G,, Barberio C,, Gullino ML,, Garibaldi A . 2008. Bacterial ectosymbionts and virulence silencing in a Fusarium oxysporum strain. Environ Microbiol 10 : 17251741.[CrossRef]
56. Lamacchia M,, Dyrka W,, Breton A,, Saupe SJ,, Paoletti M . 2016. Overlapping Podospora anserina transcriptional responses to bacterial and fungal non self indicate a multilayered innate immune response. Front Microbiol 7 : 471.[CrossRef]
57. Yarbrough GG,, Taylor DP,, Rowlands RT,, Crawford MS,, Lasure LL . 1993. Screening microbial metabolites for new drugs: theoretical and practical issues. J Antibiot (Tokyo) 46 : 535544.[CrossRef]
58. Moyer AJ,, Coghill RD . 1946. Penicillin. VIII. Production of penicillin in surface cultures. J Bacteriol 51 : 5778.
59. Schroeder HW . 1966. Effect of corn steep liquor on mycelial growth and aflatoxin production in Aspergillus parasiticus . Appl Microbiol 14 : 381385.
60. Overy DP,, Smedsgaard J,, Frisvad JC,, Phipps RK,, Thrane U . 2006. Host-derived media used as a predictor for low abundant, in planta metabolite production from necrotrophic fungi. J Appl Microbiol 101 : 12921300.[CrossRef]
61. Bills GF,, Dombrowski AW,, Goetz MA . 2012. The “FERMEX” method for metabolite-enriched fungal extracts. Methods Mol Biol 944 : 7996.[CrossRef]
62. Rastogi S,, Liberles DA . 2005. Subfunctionalization of duplicated genes as a transition state to neofunctionalization. BMC Evol Biol 5 : 28.[CrossRef]
63. Fitzpatrick DA . 2012. Horizontal gene transfer in fungi. FEMS Microbiol Lett 329 : 18.[CrossRef]
64. Kroken S,, Glass NL,, Taylor JW,, Yoder OC,, Turgeon BG . 2003. Phylogenomic analysis of type I polyketide synthase genes in pathogenic and saprobic ascomycetes. Proc Natl Acad Sci USA 100 : 1567015675.[CrossRef]
65. Slot JC,, Rokas A . 2011. Horizontal transfer of a large and highly toxic secondary metabolic gene cluster between fungi. Curr Biol 21 : 134139.[CrossRef]
66. Koczyk G,, Dawidziuk A,, Popiel D . 2015. The distant siblings: a phylogenomic roadmap illuminates the origins of extant diversity in fungal aromatic polyketide biosynthesis. Genome Biol Evol 7 : 31323154.[CrossRef]
67. Rank C,, Nielsen KF,, Larsen TO,, Varga J,, Samson RA,, Frisvad JC . 2011. Distribution of sterigmatocystin in filamentous fungi. Fungal Biol 115 : 406420.[CrossRef]
68. Kornsakulkarn J,, Saepua S,, Srichomthong K,, Supothina S,, Thongpanchang C . 2012. New mycotoxins from the scale insect fungus Aschersonia coffeae Henn. BCC 28712. Tetrahedron 68 : 84808486.[CrossRef]
69. Ayer WA,, Lee SP,, Tsuneda A,, Hiratsuka Y . 1980. The isolation, identification, and bioassay of the antifungal metabolites produced by Monocillium nordinii . Can J Microbiol 26 : 766773.[CrossRef]
70. Ayer WA,, Pena-Rodriguez L,, Vederas JC . 1981. Identification of sterigmatocystin as a metabolite of Monocillium nordinii . Can J Microbiol 27 : 846847.[CrossRef]
71. Mao XM,, Xu W,, Li D,, Yin WB,, Chooi YH,, Li YQ,, Tang Y,, Hu Y . 2015. Epigenetic genome mining of an endophytic fungus leads to the pleiotropic biosynthesis of natural products. Angew Chem Int Ed Engl 54 : 75927596.[CrossRef]
72. Almeida C,, Ortega H,, Higginbotham S,, Spadafora C,, Arnold AE,, Coley PD,, Kursar TA,, Gerwick WH,, Cubilla-Rios L . 2014. Chemical and bioactive natural products from Microthyriaceae sp., an endophytic fungus from a tropical grass. Lett Appl Microbiol 59 : 5864.[CrossRef]
73. Cornman RS,, Bennett AK,, Murray KD,, Evans JD,, Elsik CG,, Aronstein K . 2012. Transcriptome analysis of the honey bee fungal pathogen, Ascosphaera apis: implications for host pathogenesis. BMC Genomics 13 : 285.[CrossRef]
74. Yew SM,, Chan CL,, Kuan CS,, Toh YF,, Ngeow YF,, Na SL,, Lee KW,, Hoh C-C,, Yee W-Y,, Ng KP . 2016. The genome of newly classified Ochroconis mirabilis: insights into fungal adaptation to different living conditions. BMC Genomics 17 : 91.[CrossRef]
75. de Wit PJGM,, van der Burgt A,, Ökmen B,, Stergiopoulos I,, Abd-Elsalam KA,, Aerts AL,, Bahkali AH,, Beenen HG,, Chettri P,, Cox MP,, Datema E,, de Vries RP,, Dhillon B,, Ganley AR,, Griffiths SA,, Guo Y,, Hamelin RC,, Henrissat B,, Kabir MS,, Jashni MK,, Kema G,, Klaubauf S,, Lapidus A,, Levasseur A,, Lindquist E,, Mehrabi R,, Ohm RA,, Owen TJ,, Salamov A,, Schwelm A,, Schijlen E,, Sun H,, van den Burg HA,, van Ham RCHJ,, Zhang S,, Goodwin SB,, Grigoriev IV,, Collemare J,, Bradshaw RE . 2012. The genomes of the fungal plant pathogens Cladosporium fulvum and Dothistroma septosporum reveal adaptation to different hosts and lifestyles but also signatures of common ancestry. PLoS Genet 8 : e1003088. [Erratum, 11:e1005775 doi:10.1371/journal.pgen.1005775.][CrossRef]
76. Fischbach MA,, Walsh CT,, Clardy J . 2008. The evolution of gene collectives: how natural selection drives chemical innovation. Proc Natl Acad Sci USA 105 : 46014608. [Erratum, 106:1679.][CrossRef]
77. Scharf DH,, Heinekamp T,, Brakhage AA . 2014. Human and plant fungal pathogens: the role of secondary metabolites. PLoS Pathog 10 : e1003859.[CrossRef]
78. Flórez LV,, Biedermann PHW,, Engl T,, Kaltenpoth M . 2015. Defensive symbioses of animals with prokaryotic and eukaryotic microorganisms. Nat Prod Rep 32 : 904936.[CrossRef]
79. Bills GF,, Overy D,, Genilloud O,, Peláez F, . 2009. Contributions of pharmaceutical antibiotic and secondary metabolite discovery to the understanding of microbial defense and antagonism, p 257297. In White JF,, Torres MS (ed), Defensive Mutualism in Microbial Symbiosis. CRC Press, Boca Raton, FL.[CrossRef]
80. Kaspari M,, Stevenson B . 2008. Evolutionary ecology, antibiosis, and all that rot. Proc Natl Acad Sci USA 105 : 1902719028.[CrossRef]
81. Davies J . 2013. Specialized microbial metabolites: functions and origins. J Antibiot (Tokyo) 66 : 361364.[CrossRef]
82. Challis GL,, Hopwood DA . 2003. Synergy and contingency as driving forces for the evolution of multiple secondary metabolite production by Streptomyces species. Proc Natl Acad Sci USA 100(Suppl 2): 1455514561.[CrossRef]
83. Gloer JB . 1995. The chemistry of fungal antagonism and defense. Can J Bot 73(S1): 12651274.[CrossRef]
84. O’Brien J,, Wright GD . 2011. An ecological perspective of microbial secondary metabolism. Curr Opin Biotechnol 22 : 552558.[CrossRef]
85. Wicklow DT, . 1981. Interference competition and the organization of fungal communities, p 351375. In Wicklow DT,, Carroll GC (ed), The Fungal Community. Marcel Dekker, New York, NY.
86. Czárán TL,, Hoekstra RF,, Pagie L . 2002. Chemical warfare between microbes promotes biodiversity. Proc Natl Acad Sci USA 99 : 786790.[CrossRef]
87. Hopwood DA . 2007. How do antibiotic-producing bacteria ensure their self-resistance before antibiotic biosynthesis incapacitates them? Mol Microbiol 63 : 937940.[CrossRef]
88. D’Costa VM,, King CE,, Kalan L,, Morar M,, Sung WWL,, Schwarz C,, Froese D,, Zazula G,, Calmels F,, Debruyne R,, Golding GB,, Poinar HN,, Wright GD . 2011. Antibiotic resistance is ancient. Nature 477 : 457461.[CrossRef]
89. Keller NP . 2015. Translating biosynthetic gene clusters into fungal armor and weaponry. Nat Chem Biol 11 : 671677.[CrossRef]
90. Abe Y,, Suzuki T,, Mizuno T,, Ono C,, Iwamoto K,, Hosobuchi M,, Yoshikawa H . Effect of increased dosage of the ML-236B (compactin) biosynthetic gene cluster on ML-236B production in Penicillium citrinum . Mol Genet Genomics 268 : 130137.
91. Chen Y-P,, Tseng C-P,, Liaw L-L,, Wang C-L,, Chen IC,, Wu W-J,, Wu M-D,, Yuan G-F . 2008. Cloning and characterization of monacolin K biosynthetic gene cluster from Monascus pilosus . J Agric Food Chem 56 : 56395646.[CrossRef]
92. Scharf DH,, Heinekamp T,, Remme N,, Hortschansky P,, Brakhage AA,, Hertweck C . 2012. Biosynthesis and function of gliotoxin in Aspergillus fumigatus . Appl Microbiol Biotechnol 93 : 467472.[CrossRef]
93. Schrettl M,, Carberry S,, Kavanagh K,, Haas H,, Jones GW,, O’Brien J,, Nolan A,, Stephens J,, Fenelon O,, Doyle S . 2010. Self-protection against gliotoxin—a component of the gliotoxin biosynthetic cluster, GliT, completely protects Aspergillus fumigatus against exogenous gliotoxin. PLoS Pathog 6 : e1000952.[CrossRef]
94. Kistler HC,, Broz K . 2015. Cellular compartmentalization of secondary metabolism. Front Microbiol 6 : 68.[CrossRef]
95. Davies J . 1990. What are antibiotics? Archaic functions for modern activities. Mol Microbiol 4 : 12271232.[CrossRef]
96. Davies J,, Ryan KS . 2012. Introducing the parvome: bioactive compounds in the microbial world. ACS Chem Biol 7 : 252259.[CrossRef]
97. Strachan CR,, Davies J . 2016. Antibiotics and evolution: food for thought. J Ind Microbiol Biotechnol 43 : 149153.[CrossRef]
98. Bellezza I,, Peirce MJ,, Minelli A . 2014. Cyclic dipeptides: from bugs to brain. Trends Mol Med 20 : 551558.[CrossRef]
99. Dulaney EL,, Gray RA . 1962. Penicillia that make n-formyl hydroxyaminoacetic acid, a new fungal product. Mycologia 54 : 476480.[CrossRef]
100. Shigeura HT,, Gordon CN . 1962. Hadacidin, a new inhibitor of purine biosynthesis. J Biol Chem 237 : 19321936.
101. Kaczka EA,, Gitterman CO,, Dulaney EL,, Folkers K . 1962. Hadacidin, a new growth-inhibitory substance in human tumor systems. Biochemistry 1 : 340343.[CrossRef]
102. Gray RA,, Gauger GW,, Dulaney EL,, Kaczka EA,, Woodruff HB . 1964. Hadacidin, a new plant-growth inhibitor produced by fermentation. Plant Physiol 39 : 204207.[CrossRef]
103. Shimoyama A,, Ogasawara R . 2002. Dipeptides and diketopiperazines in the Yamato-791198 and Murchison carbonaceous chondrites. Orig Life Evol Biosph 32 : 165179.[CrossRef]
104. Jacques IB,, Moutiez M,, Witwinowski J,, Darbon E,, Martel C,, Seguin J,, Favry E,, Thai R,, Lecoq A,, Dubois S,, Pernodet J-L,, Gondry M,, Belin P . 2015. Analysis of 51 cyclodipeptide synthases reveals the basis for substrate specificity. Nat Chem Biol 11 : 721727.[CrossRef]
105. Belin P,, Moutiez M,, Lautru S,, Seguin J,, Pernodet JL,, Gondry M . 2012. The nonribosomal synthesis of diketopiperazines in tRNA-dependent cyclodipeptide synthase pathways. Nat Prod Rep 29 : 961979.[CrossRef]
106. Arnison PG , , et al . 2013. Ribosomally synthesized and post-translationally modified peptide natural products: overview and recommendations for a universal nomenclature. Nat Prod Rep 30 : 108160.[CrossRef]
107. Chen YU . 1960. Studies on the metabolic products of Rosellinia necatrix Berlese: part I. isolation and characterization of several physiologically active neutral substances. Bull Agric Chem Soc Jpn 24 : 372381.[CrossRef]
108. Walter R,, Ritzmann RF,, Bhargava HN,, Flexner LB . 1979. Prolyl-leucyl-glycinamide, cyclo(leucylglycine), and derivatives block development of physical dependence on morphine in mice. Proc Natl Acad Sci USA 76 : 518520.[CrossRef]
109. Kalle GP,, Khandekar PS . 1983. Dipicolinic acid as a secondary metabolite in Penicillium citreoviride . J Biosci 5 : 4352.[CrossRef]
110. Tanenbaum SW,, Kaneko K . 1964. Biosynthesis of dipicolinic acid and of lysine in Penicillium citreo-viride . Biochemistry 3 : 13141322.[CrossRef]
111. Asaff A,, Cerda-García-Rojas C,, de la Torre M . 2005. Isolation of dipicolinic acid as an insecticidal toxin from Paecilomyces fumosoroseus . Appl Microbiol Biotechnol 68 : 542547.[CrossRef]
112. Eisenman HC,, Mues M,, Weber SE,, Frases S,, Chaskes S,, Gerfen G,, Casadevall A . 2007. Cryptococcus neoformans laccase catalyses melanin synthesis from both D- and L-DOPA. Microbiology 153 : 39543962.[CrossRef]
113. Casadevall A,, Rosas AL,, Nosanchuk JD . 2000. Melanin and virulence in Cryptococcus neoformans . Curr Opin Microbiol 3 : 354358.[CrossRef]
114. Nosanchuk JD,, Stark RE,, Casadevall A . 2015. Fungal melanin: what do we know about structure? Front Microbiol 6 : 1463.[CrossRef]
115. Chen H,, Fujita M,, Feng Q,, Clardy J,, Fink GR . 2004. Tyrosol is a quorum-sensing molecule in Candida albicans . Proc Natl Acad Sci USA 101 : 50485052.[CrossRef]
116. James LF,, Hartley WJ,, Van Kampen KR . 1981. Syndromes of astragalus poisoning in livestock. J Am Vet Med Assoc 178 : 146150.
117. Hylin JW,, Matsumoto H . 1961. The biosynthesis of 3-nitropropanoic acid by Penicillium atrovenetum . Arch Biochem Biophys 93 : 542545.[CrossRef]
118. Bush MT,, Touster O,, Brockman JE . 1951. The production of β-nitropropionic acid by a strain of Aspergillus flavus . J Biol Chem 188 : 685693.
119. Hershenhorn J,, Vurro M,, Zonno MC,, Stierle A,, Strobel G . 1993. Septoria cirsii, a potential biocontrol agent of Canada thistle and its phytotoxin: ß-nitropropionic acid. Plant Sci 94 : 227234.[CrossRef]
120. Fu Y,, He F,, Zhang S,, Jiao X . 1995. Consistent striatal damage in rats induced by 3-nitropropionic acid and cultures of Arthrinium fungus. Neurotoxicol Teratol 17 : 413418.[CrossRef]
121. Ming L . 1995. Moldy sugarcane poisoning: a case report with a brief review. J Toxicol Clin Toxicol 33 : 363367.[CrossRef]
122. Francis K,, Smitherman C,, Nishino SF,, Spain JC,, Gadda G . 2013. The biochemistry of the metabolic poison propionate 3-nitronate and its conjugate acid, 3-nitropropionate. IUBMB Life 65 : 759768.[CrossRef]
123. Chomcheon P,, Wiyakrutta S,, Sriubolmas N,, Ngamrojanavanich N,, Isarangkul D,, Kittakoop P . 2005. 3-Nitropropionic acid (3-NPA), a potent antimycobacterial agent from endophytic fungi: is 3-NPA in some plants produced by endophytes? J Nat Prod 68 : 11031105.[CrossRef]
124. Bhatia S,, Garg A,, Sharma K,, Kumar S,, Sharma A,, Purohit AP . 2011. Mycosporine and mycosporine-like amino acids: a paramount tool against ultra violet irradiation. Pharmacogn Rev 5 : 138146.[CrossRef]
125. Bandaranayake WM . 1998. Mycosporines: are they nature’s sunscreens? Nat Prod Rep 15 : 159172.[CrossRef]
126. Leach CM . 1965. Ultraviolet-absorbing substances associated with light-induced sporulation in fung. Can J Bot 43 : 185200.[CrossRef]
127. Oren A,, Gunde-Cimerman N . 2007. Mycosporines and mycosporine-like amino acids: UV protectants or multipurpose secondary metabolites? FEMS Microbiol Lett 269 : 110.[CrossRef]
128. Balskus EP,, Walsh CT . 2010. The genetic and molecular basis for sunscreen biosynthesis in cyanobacteria. Science 329 : 16531656.[CrossRef]
129. Hornby JM,, Jensen EC,, Lisec AD,, Tasto JJ,, Jahnke B,, Shoemaker R,, Dussault P,, Nickerson KW . 2001. Quorum sensing in the dimorphic fungus Candida albicans is mediated by farnesol. Appl Environ Microbiol 67 : 29822992.[CrossRef]
130. Leonhardt I,, Spielberg S,, Weber M,, Albrecht-Eckardt D,, Bläss M,, Claus R,, Barz D,, Scherlach K,, Hertweck C,, Löffler J,, Hünniger K,, Kurzai O . 2015. The fungal quorum-sensing molecule farnesol activates innate immune cells but suppresses cellular adaptive immunity. MBio 6 : e00143-15.[CrossRef]
131. McAlester G,, O’Gara F,, Morrissey JP . 2008. Signal-mediated interactions between Pseudomonas aeruginosa and Candida albicans . J Med Microbiol 57 : 563569.[CrossRef]
132. Cugini C,, Calfee MW,, Farrow JM III,, Morales DK,, Pesci EC,, Hogan DA . 2007. Farnesol, a common sesquiterpene, inhibits PQS production in Pseudomonas aeruginosa . Mol Microbiol 65 : 896906.[CrossRef]
133. de Salas F,, Martínez MJ,, Barriuso J . 2015. Quorum-sensing mechanisms mediated by farnesol in Ophiostoma piceae: effect on secretion of sterol esterase. Appl Environ Microbiol 81 : 43514357.[CrossRef]
134. Hornby JM,, Kebaara BW,, Nickerson KW . 2003. Farnesol biosynthesis in Candida albicans: cellular response to sterol inhibition by zaragozic acid B. Antimicrob Agents Chemother 47 : 23662369.[CrossRef]
135. Cunningham KG,, Manson W,, Spring FS,, Hutchinson SA . 1950. Cordycepin, a metabolic product isolated from cultures of Cordyceps militaris (Linn.) Link. Nature 166 : 949.[CrossRef]
136. Xie J-W,, Huang L-F,, Hu W,, He Y-B,, Wong KP . 2010. Analysis of the main nucleosides in Cordyceps sinensis by LC/ESI-MS. Molecules 15 : 305314.[CrossRef]
137. Jiang B,, Xu D,, Davison J,, Veillette K,, Sillaots S,, Hu W,, Rodriguez-Suarez R,, Trosok S,, Zhang L,, Li Y,, Rahkhoodaee F,, Ransom T,, Martel N,, Wang H,, Gauvin D,, Parish CA,, Harris G,, Smith S,, Calati K,, Zink D,, Wilson K,, Allocco J,, Nielsen-Kahn J,, Powels M,, Yeung L,, Liberator P,, Youngman P,, Bills G,, Platas G,, Pelaez F,, Diez MT,, Kauffman S,, Becker J,, Roemer T . 2008. PAP inhibitor with in vivo efficacy identified by Candida albicans genetic profiling of natural products. Chem Biol 15 : 363374.[CrossRef]
138. Holbein S,, Wengi A,, Decourty L,, Freimoser FM,, Jacquier A,, Dichtl B . 2009. Cordycepin interferes with 3′ end formation in yeast independently of its potential to terminate RNA chain elongation. RNA 15 : 837849.[CrossRef]
139. Xiang L,, Li Y,, Zhu Y,, Luo H,, Li C,, Xu X,, Sun C,, Song J,, Shi L,, He L,, Sun W,, Chen S . 2014. Transcriptome analysis of the Ophiocordyceps sinensis fruiting body reveals putative genes involved in fruiting body development and cordycepin biosynthesis. Genomics 103 : 154159.[CrossRef]
140. Bentley R . 2006. From miso, saké and shoyu to cosmetics: a century of science for kojic acid. Nat Prod Rep 23 : 10461062.[CrossRef]
141. Morton HE,, Kocholaty W,, Junowicz-Kocholaty R,, Kelner A . 1945. Toxicity and antibiotic activity of kojic acid produced by Aspergillus luteo-virescens . J Bacteriol 50 : 579584.
142. Arnstein HRV,, Bentley R . 1953. The biosynthesis of kojic acid. II. The occurrence of aldolase and triosephosphate isomerase in Aspergillus species and their relationship to kojic acid biosynthesis. Biochem J 54 : 508516.[CrossRef]
143. Arnstein HRV,, Bentley R . 1953. The biosynthesis of kojic acid. III. The incorporation of labelled small molecules into kojic acid. Biochem J 54 : 517522.[CrossRef]
144. Arnstein HRV,, Bentley R . 1953. The biosynthesis of kojic acid. I. production from (1-14C) and (3:4-14C2) glucose and (2-14C)-1:3-dihydroxyacetone. Biochem J 54 : 493508.[CrossRef]
145. Arnstein HRV,, Bentley R . 1956. The biosynthesis of kojic acid. 4. Production from pentoses and methyl pentoses. Biochem J 62 : 403411.[CrossRef]
146. Terabayashi Y,, Sano M,, Yamane N,, Marui J,, Tamano K,, Sagara J,, Dohmoto M,, Oda K,, Ohshima E,, Tachibana K,, Higa Y,, Ohashi S,, Koike H,, Machida M . 2010. Identification and characterization of genes responsible for biosynthesis of kojic acid, an industrially important compound from Aspergillus oryzae . Fungal Genet Biol 47 : 953961.[CrossRef]
147. Knaggs AR . 2003. The biosynthesis of shikimate metabolites. Nat Prod Rep 20 : 119136.[CrossRef]
148. Tohge T,, Watanabe M,, Hoefgen R,, Fernie AR . 2013. Shikimate and phenylalanine biosynthesis in the green lineage. Front Plant Sci 4 : 62.[CrossRef]
149. Herrmann KM,, Weaver LM . 1999. The shikimate pathway. Annu Rev Plant Physiol Plant Mol Biol 50 : 473503.[CrossRef]
150. Maeda H,, Dudareva N . 2012. The shikimate pathway and aromatic amino acid biosynthesis in plants. Annu Rev Plant Biol 63 : 73105.[CrossRef]
151. Braesel J,, Götze S,, Shah F,, Heine D,, Tauber J,, Hertweck C,, Tunlid A,, Stallforth P,, Hoffmeister D . 2015. Three redundant synthetases secure redox-active pigment production in the basidiomycete Paxillus involutus . Chem Biol 22 : 13251334.[CrossRef]
152. Shah F,, Schwenk D,, Nicolás C,, Persson P,, Hoffmeister D,, Tunlid A . 2015. Involutin is an Fe3+ reductant secreted by the ectomycorrhizal fungus Paxillus involutus during Fenton-based decomposition of organic matter. Appl Environ Microbiol 81 : 84278433.[CrossRef]
153. Stocker-Wörgötter E . 2008. Metabolic diversity of lichen-forming ascomycetous fungi: culturing, polyketide and shikimate metabolite production, and PKS genes. Nat Prod Rep 25 : 188200.[CrossRef]
154. Guo C-J,, Knox BP,, Sanchez JF,, Chiang Y-M,, Bruno KS,, Wang CCC . 2013. Application of an efficient gene targeting system linking secondary metabolites to their biosynthetic genes in Aspergillus terreus . Org Lett 15 : 35623565.[CrossRef]
155. Sun W-W,, Guo C-J,, Wang CCC . 2016. Characterization of the product of a nonribosomal peptide synthetase-like (NRPS-like) gene using the doxycycline dependent Tet-on system in Aspergillus terreus . Fungal Genet Biol 89 : 8488.[CrossRef]
156. Craik DJ . 2006. Chemistry. Seamless proteins tie up their loose ends. Science 311 : 15631564.[CrossRef]
157. Ortega Manuel A,, van der Donk WA . 2016. New insights into the biosynthetic logic of ribosomally synthesized and post-translationally modified peptide natural products. Cell Chem Biol 23 : 3144.[CrossRef]
158. Sgambelluri RM,, Epis S,, Sassera D,, Luo H,, Angelos ER,, Walton JD . 2014. Profiling of amatoxins and phallotoxins in the genus Lepiota by liquid chromatography combined with UV absorbance and mass spectrometry. Toxins (Basel) 6 : 23362347.[CrossRef]
159. Muraoka S,, Fukamachi N,, Mizumoto K,, Shinozawa T . 1999. Detection and identification of amanitins in the wood-rotting fungi Galerina fasciculata and Galerina helvoliceps . Appl Environ Microbiol 65 : 42074210.
160. Hallen HE,, Watling R,, Adams GC . 2003. Taxonomy and toxicity of Conocybe lactea and related species. Mycol Res 107 : 969979.[CrossRef]
161. Hallen HE,, Luo H,, Scott-Craig JS,, Walton JD . 2007. Gene family encoding the major toxins of lethal Amanita mushrooms. Proc Natl Acad Sci USA 104 : 1909719101.[CrossRef]
162. Oda T,, Namba K,, Maéda Y . 2005. Position and orientation of phalloidin in F-actin determined by X-ray fiber diffraction analysis. Biophys J 88 : 27272736.[CrossRef]
163. Koiso Y,, Li Y,, Iwasaki S,, Hanaka K,, Kobayashi T,, Sonoda R,, Fujita Y,, Yaegashi H,, Sato Z . 1994. Ustiloxins, antimitotic cyclic peptides from false smut balls on rice panicles caused by Ustilaginoidea virens . J Antibiot (Tokyo) 47 : 765773.[CrossRef]
164. Umemura M,, Koike H,, Nagano N,, Ishii T,, Kawano J,, Yamane N,, Kozone I,, Horimoto K,, Shin-ya K,, Asai K,, Yu J,, Bennett JW,, Machida M . 2013. MIDDAS-M: motif-independent de novo detection of secondary metabolite gene clusters through the integration of genome sequencing and transcriptome data. PLoS One 8 : e84028.[CrossRef]
165. Zhang Y,, Zhang K,, Fang A,, Han Y,, Yang J,, Xue M,, Bao J,, Hu D,, Zhou B,, Sun X,, Li S,, Wen M,, Yao N,, Ma LJ,, Liu Y,, Zhang M,, Huang F,, Luo C,, Zhou L,, Li J,, Chen Z,, Miao J,, Wang S,, Lai J,, Xu JR,, Hsiang T,, Peng YL,, Sun W . 2014. Specific adaptation of Ustilaginoidea virens in occupying host florets revealed by comparative and functional genomics. Nat Commun 5 : 3849.[CrossRef]
166. Umemura M,, Nagano N,, Koike H,, Kawano J,, Ishii T,, Miyamura Y,, Kikuchi M,, Tamano K,, Yu J,, Shin-ya K,, Machida M . 2014. Characterization of the biosynthetic gene cluster for the ribosomally synthesized cyclic peptide ustiloxin B in Aspergillus flavus . Fungal Genet Biol 68 : 2330.[CrossRef]
167. Tsukui T,, Nagano N,, Umemura M,, Kumagai T,, Terai G,, Machida M,, Asai K . 2015. Ustiloxins, fungal cyclic peptides, are ribosomally synthesized in Ustilaginoidea virens . Bioinformatics 31 : 981985.[CrossRef]
168. Battilani P,, Gualla A,, Dall’Asta C,, Pellacani C,, Galaverna G,, Giorni P,, Caglieri A,, Tagliaferri S,, Pietri A,, Dossena A,, Spadaro D,, Marchelli R,, Gullino M,, Costa L . 2011. Phomopsins: an overview of phytopathological and chemical aspects, toxicity, analysis and occurrence. World Mycotoxin J 4 : 345359.[CrossRef]
169. Cormier A,, Marchand M,, Ravelli RBG,, Knossow M,, Gigant B . 2008. Structural insight into the inhibition of tubulin by vinca domain peptide ligands. EMBO Rep 9 : 11011106.[CrossRef]
170. Ding W,, Liu W-Q,, Jia Y,, Li Y,, van der Donk WA,, Zhang Q . 2016. Biosynthetic investigation of phomopsins reveals a widespread pathway for ribosomal natural products in Ascomycetes. Proc Natl Acad Sci USA 113 : 35213526.[CrossRef]
171. Nagano N,, Umemura M,, Izumikawa M,, Kawano J,, Ishii T,, Kikuchi M,, Tomii K,, Kumagai T,, Yoshimi A,, Machida M,, Abe K,, Shin-ya K,, Asai K . 2016. Class of cyclic ribosomal peptide synthetic genes in filamentous fungi. Fungal Genet Biol 86 : 5870.[CrossRef]
172. Johnson RD,, Lane GA,, Koulman A,, Cao M,, Fraser K,, Fleetwood DJ,, Voisey CR,, Dyer JM,, Pratt J,, Christensen M,, Simpson WR,, Bryan GT,, Johnson LJ . 2015. A novel family of cyclic oligopeptides derived from ribosomal peptide synthesis of an in planta-induced gene, gigA, in Epichloë endophytes of grasses. Fungal Genet. Biol. 85 : 1424.[CrossRef]
173. Shen B . 2003. Polyketide biosynthesis beyond the type I, II and III polyketide synthase paradigms. Curr Opin Chem Biol 7 : 285295.[CrossRef]
174. Hertweck C . 2009. The biosynthetic logic of polyketide diversity. Angew Chem Int Ed Engl 48 : 46884716.[CrossRef]
175. Cox RJ,, Simpson TJ . 2009. Fungal type I polyketide synthases. Methods Enzymol 459 : 4978.[CrossRef]
176. Petersen AB,, Rønnest MH,, Larsen TO,, Clausen MH . 2014. The chemistry of griseofulvin. Chem Rev 114 : 1208812107.[CrossRef]
177. Chooi Y-H,, Cacho R,, Tang Y . 2010. Identification of the viridicatumtoxin and griseofulvin gene clusters from Penicillium aethiopicum . Chem Biol 17 : 483494.[CrossRef]
178. Cacho RA,, Chooi Y-H,, Zhou H,, Tang Y . 2013. Complexity generation in fungal polyketide biosynthesis: a spirocycle-forming P450 in the concise pathway to the antifungal drug griseofulvin. ACS Chem Biol 8 : 23222330.[CrossRef]
179. Puel O,, Galtier P,, Oswald IP . 2010. Biosynthesis and toxicological effects of patulin. Toxins (Basel) 2 : 613631.[CrossRef]
180. Moriguchi T,, Ebizuka Y,, Fujii I . 2006. Analysis of subunit interactions in the iterative type I polyketide synthase ATX from Aspergillus terreus . ChemBioChem 7 : 18691874.[CrossRef]
181. Lu P,, Zhang A,, Dennis LM,, Dahl-Roshak AM,, Xia Y-Q,, Arison B,, An Z,, Tkacz JS . 2005. A gene (pks2) encoding a putative 6-methylsalicylic acid synthase from Glarea lozoyensis . Mol Genet Genomics 273 : 207216.[CrossRef]
182. Chooi Y-H,, Krill C,, Barrow RA,, Chen S,, Trengove R,, Oliver RP,, Solomon PS . 2015. An in planta-expressed polyketide synthase produces (R)-mellein in the wheat pathogen Parastagonospora nodorum . Appl Environ Microbiol 81 : 177186.[CrossRef]
183. Sun H,, Ho CL,, Ding F,, Soehano I,, Liu XW,, Liang ZX . 2012. Synthesis of (R)-mellein by a partially reducing iterative polyketide synthase. J Am Chem Soc 134 : 1192411927.[CrossRef]
184. Schmitt I,, Lumbsch HT . 2009. Ancient horizontal gene transfer from bacteria enhances biosynthetic capabilities of fungi. PLoS One 4 : e4437.[CrossRef]
185. Baker SE,, Kroken S,, Inderbitzin P,, Asvarak T,, Li B-Y,, Shi L,, Yoder OC,, Turgeon BG . 2006. Two polyketide synthase-encoding genes are required for biosynthesis of the polyketide virulence factor, T-toxin, by Cochliobolus heterostrophus . Mol Plant Microbe Interact 19 : 139149.[CrossRef]
186. Inderbitzin P,, Asvarak T,, Turgeon BG . 2010. Six new genes required for production of T-toxin, a polyketide determinant of high virulence of Cochliobolus heterostrophus to maize. Mol Plant Microbe Interact 23 : 458472.[CrossRef]
187. Susca A,, Proctor RH,, Butchko RAE,, Haidukowski M,, Stea G,, Logrieco A,, Moretti A . 2014. Variation in the fumonisin biosynthetic gene cluster in fumonisin-producing and nonproducing black aspergilli. Fungal Genet Biol 73 : 3952.[CrossRef]
188. Endo A . 2010. A historical perspective on the discovery of statins. Proc Jpn Acad Ser B Phys Biol Sci 86 : 484493.[CrossRef]
189. Endo A . 1985. Compactin (ML-236B) and related compounds as potential cholesterol-lowering agents that inhibit HMG-CoA reductase. J Med Chem 28 : 401405.[CrossRef]
190. Tobert JA . 2003. Lovastatin and beyond: the history of the HMG-CoA reductase inhibitors. Nat Rev Drug Discov 2 : 517526.[CrossRef]
191. Fisch KM . 2013. Biosynthesis of natural products by microbial iterative hybrid PKS-NRPS. RSC Advances 3 : 1822818247.[CrossRef]
192. Wang H,, Sivonen K,, Fewer DP . 2015. Genomic insights into the distribution, genetic diversity and evolution of polyketide synthases and nonribosomal peptide synthetases. Curr Opin Genet Dev 35 : 7985.[CrossRef]
193. Bushley KE,, Turgeon BG . 2010. Phylogenomics reveals subfamilies of fungal nonribosomal peptide synthetases and their evolutionary relationships. BMC Evol Biol 10 : 26.[CrossRef]
194. Haas H . 2012. Iron: a key nexus in the virulence of Aspergillus fumigatus . Front Microbiol 3 : 28.[CrossRef]
195. Bushley KE,, Ripoll DR,, Turgeon BG . 2008. Module evolution and substrate specificity of fungal nonribosomal peptide synthetases involved in siderophore biosynthesis. BMC Evol Biol 8 : 328.[CrossRef]
196. Johnson L . 2008. Iron and siderophores in fungal-host interactions. Mycol Res 112 : 170183.[CrossRef]
197. Fischbach MA,, Walsh CT . 2006. Assembly-line enzymology for polyketide and nonribosomal peptide antibiotics: logic, machinery, and mechanisms. Chem Rev 106 : 34683496.[CrossRef]
198. Lax E . 2005. The Mold in Dr. Florey’s Coat: The Story of the Penicillin Miracle. Henry Holt and Co., New York, NY.
199. Ozcengiz G,, Demain AL . 2013. Recent advances in the biosynthesis of penicillins, cephalosporins and clavams and its regulation. Biotechnol Adv 31 : 287311.[CrossRef]
200. Unkles SE,, Valiante V,, Mattern DJ,, Brakhage AA . 2014. Synthetic biology tools for bioprospecting of natural products in eukaryotes. Chem Biol 21 : 502508.[CrossRef]
201. Bushley KE,, Raja R,, Jaiswal P,, Cumbie JS,, Nonogaki M,, Boyd AE,, Owensby CA,, Knaus BJ,, Elser J,, Miller D,, Di Y,, McPhail KL,, Spatafora JW . 2013. The genome of tolypocladium inflatum: evolution, organization, and expression of the cyclosporin biosynthetic gene cluster. PLoS Genet 9 : e1003496.[CrossRef]
202. Chen L,, Yue Q,, Zhang X,, Xiang M,, Wang C,, Li S,, Che Y,, Ortiz-López FJ,, Bills GF,, Liu X,, An Z . 2013. Genomics-driven discovery of the pneumocandin biosynthetic gene cluster in the fungus Glarea lozoyensis . BMC Genomics 14 : 339.[CrossRef]
203. Chen L,, Yue Q,, Li Y,, Niu X,, Xiang M,, Wang W,, Bills GF,, Liu X,, An Z . 2015. Engineering of Glarea lozoyensis for exclusive production of the pneumocandin B0 precursor of the antifungal drug caspofungin acetate. Appl Environ Microbiol 81 : 15501558.[CrossRef]
204. Jiang W,, Cacho RA,, Chiou G,, Garg NK,, Tang Y,, Walsh CT . 2013. EcdGHK are three tailoring iron oxygenases for amino acid building blocks of the echinocandin scaffold. J Am Chem Soc 135 : 44574466.[CrossRef]
205. Cacho RA,, Jiang W,, Chooi YH,, Walsh CT,, Tang Y . 2012. Identification and characterization of the echinocandin B biosynthetic gene cluster from Emericella rugulosa NRRL 11440. J Am Chem Soc 134 : 1678116790.[CrossRef]
206. Yue Q,, Chen L,, Zhang X,, Li K,, Sun J,, Liu X,, An Z,, Bills GF . 2015. Evolution of chemical diversity in echinocandin lipopeptide antifungal metabolites. Eukaryot Cell 14 : 698718.[CrossRef]
207. Schmidt-Dannert C . 2014. Biosynthesis of terpenoid natural products in fungi. Adv Biochem Eng Biotechnol 148 : 1961.[CrossRef]
208. Wawrzyn GT,, Bloch SE,, Schmidt-Dannert C . 2012. Discovery and characterization of terpenoid biosynthetic pathways of fungi. Methods Enzymol 515 : 83105.[CrossRef]
209. Miziorko HM . 2011. Enzymes of the mevalonate pathway of isoprenoid biosynthesis. Arch Biochem Biophys 505 : 131143.[CrossRef]
210. Jacobs MR . 2010. Retapamulin: focus on its use in the treatment of uncomplicated superficial skin infections and impetigo. Expert Rev Dermatol 5</