Skip to main content
Log in

Strategies for mining fungal natural products

  • Review
  • Published:
Journal of Industrial Microbiology & Biotechnology

Abstract

Fungi are well known for their ability to produce a multitude of natural products. On the one hand their potential to provide beneficial antibiotics and immunosuppressants has been maximized by the pharmaceutical industry to service the market with cost-efficient drugs. On the other hand identification of trace amounts of known mycotoxins in food and feed samples is of major importance to ensure consumer health and safety. Although several fungal natural products, their biosynthesis and regulation are known today, recent genome sequences of hundreds of fungal species illustrate that the secondary metabolite potential of fungi has been substantially underestimated. Since expression of genes and subsequent production of the encoded metabolites are frequently cryptic or silent under standard laboratory conditions, strategies for activating these hidden new compounds are essential. This review will cover the latest advances in fungal genome mining undertaken to unlock novel products.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Ahuja M, Chiang YM, Chang SL, Praseuth MB, Entwistle R, Sanchez JF, Lo HC, Yeh HH, Oakley BR, Wang CC (2012) Illuminating the diversity of aromatic polyketide synthases in Aspergillus nidulans. J Am Chem Soc 134:8212–8221

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Amaike S, Keller NP (2009) Distinct roles for VeA and LaeA in development and pathogenesis of Aspergillus flavus. Eukaryot Cell 8:1051–1060

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Amselem J, Cuomo CA, van Kan JA, Viaud M, Benito EP, Couloux A, Coutinho PM, de Vries RP, Dyer PS, Fillinger S, Fournier E, Gout L, Hahn M, Kohn L, Lapalu N, Plummer KM, Pradier JM, Quevillon E, Sharon A, Simon A, ten Have A, Tudzynski B, Tudzynski P, Wincker P, Andrew M, Anthouard V, Beever RE, Beffa R, Benoit I, Bouzid O, Brault B, Chen Z, Choquer M, Collemare J, Cotton P, Danchin EG, Da Silva C, Gautier A, Giraud C, Giraud T, Gonzalez C, Grossetete S, Guldener U, Henrissat B, Howlett BJ, Kodira C, Kretschmer M, Lappartient A, Leroch M, Levis C, Mauceli E, Neuveglise C, Oeser B, Pearson M, Poulain J, Poussereau N, Quesneville H, Rascle C, Schumacher J, Segurens B, Sexton A, Silva E, Sirven C, Soanes DM, Talbot NJ, Templeton M, Yandava C, Yarden O, Zeng Q, Rollins JA, Lebrun MH, Dickman M (2011) Genomic analysis of the necrotrophic fungal pathogens Sclerotinia sclerotiorum and Botrytis cinerea. PLoS Genet 7:e1002230

    CAS  PubMed Central  PubMed  Google Scholar 

  4. Andersen MR, Nielsen JB, Klitgaard A, Petersen LM, Zachariasen M, Hansen TJ, Blicher LH, Gotfredsen CH, Larsen TO, Nielsen KF, Mortensen UH (2013) Accurate prediction of secondary metabolite gene clusters in filamentous fungi. Proc Natl Acad Sci U S A 110:E99–E107

    CAS  PubMed Central  PubMed  Google Scholar 

  5. Asami Y, Kakeya H, Onose R, Yoshida A, Matsuzaki H, Osada H (2002) Azaspirene: a novel angiogenesis inhibitor containing a 1-oxa-7-azaspiro[4.4]non-2-ene-4,6-dione skeleton produced by the fungus Neosartorya sp. Org Lett 4:2845–2848

    CAS  PubMed  Google Scholar 

  6. Austin MB, Noel JP (2003) The chalcone synthase superfamily of type III polyketide synthases. Nat Prod Rep 20:79–110

    CAS  PubMed  Google Scholar 

  7. Avalos J, Prado-Cabrero A, Estrada AF (2012) Neurosporaxanthin production by Neurospora and Fusarium. Methods Mol Biol 898:263–274

    CAS  PubMed  Google Scholar 

  8. Baba S, Kinoshita H, Nihira T (2012) Identification and characterization of Penicillium citrinum VeA and LaeA as global regulators for ML-236B production. Curr Genet 58:1–11

    CAS  PubMed  Google Scholar 

  9. Baker SE, Kroken S, Inderbitzin P, Asvarak T, Li BY, 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 19:139–149

    CAS  PubMed  Google Scholar 

  10. Baltz RH (2010) Streptomyces and Saccharopolyspora hosts for heterologous expression of secondary metabolite gene clusters. J Ind Microbiol Biotechnol 37:759–772

    CAS  PubMed  Google Scholar 

  11. Baltz RH (2011) Strain improvement in actinomycetes in the postgenomic era. J Ind Microbiol Biotechnol 38:657–666

    CAS  PubMed  Google Scholar 

  12. Bannister AJ, Kouzarides T (2011) Regulation of chromatin by histone modifications. Cell Res 21:381–395

    CAS  PubMed  Google Scholar 

  13. Bayram O, Braus GH (2012) Coordination of secondary metabolism and development in fungi: the velvet family of regulatory proteins. FEMS Microbiol Rev 36:1–24

    CAS  PubMed  Google Scholar 

  14. Bayram O, Krappmann S, Ni M, Bok JW, Helmstaedt K, Valerius O, Braus-Stromeyer S, Kwon NJ, Keller NP, Yu JH, Braus GH (2008) VelB/VeA/LaeA complex coordinates light signal with fungal development and secondary metabolism. Science 320:1504–1506

    CAS  PubMed  Google Scholar 

  15. Benny O, Fainaru O, Adini A, Cassiola F, Bazinet L, Adini I, Pravda E, Nahmias Y, Koirala S, Corfas G, D’Amato RJ, Folkman J (2008) An orally delivered small-molecule formulation with antiangiogenic and anticancer activity. Nat Biotechnol 26:799–807

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Bentley SD, Chater KF, Cerdeno-Tarraga AM, Challis GL, Thomson NR, James KD, Harris DE, Quail MA, Kieser H, Harper D, Bateman A, Brown S, Chandra G, Chen CW, Collins M, Cronin A, Fraser A, Goble A, Hidalgo J, Hornsby T, Howarth S, Huang CH, Kieser T, Larke L, Murphy L, Oliver K, O’Neil S, Rabbinowitsch E, Rajandream MA, Rutherford K, Rutter S, Seeger K, Saunders D, Sharp S, Squares R, Squares S, Taylor K, Warren T, Wietzorrek A, Woodward J, Barrell BG, Parkhill J, Hopwood DA (2002) Complete genome sequence of the model actinomycete Streptomyces coelicolor A3(2). Nature 417:141–147

    PubMed  Google Scholar 

  17. Berdy J (2005) Bioactive microbial metabolites. J Antibiot (Tokyo) 58:1–26

    CAS  Google Scholar 

  18. Berdy J (2012) Thoughts and facts about antibiotics: where we are now and where we are heading. J Antibiot (Tokyo) 65:385–395

    CAS  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  20. Blin K, Medema MH, Kazempour D, Fischbach MA, Breitling R, Takano E, Weber T (2013) antiSMASH 2.0—a versatile platform for genome mining of secondary metabolite producers. Nucleic Acids Res 41:W204–W212

    PubMed Central  PubMed  Google Scholar 

  21. Boettger D, Hertweck C (2013) Molecular diversity sculpted by fungal PKS-NRPS hybrids. ChemBioChem 14:28–42

    CAS  PubMed  Google Scholar 

  22. Bok JW, Balajee SA, Marr KA, Andes D, Nielsen KF, Frisvad JC, Keller NP (2005) LaeA, a regulator of morphogenetic fungal virulence factors. Eukaryot Cell 4:1574–1582

    CAS  PubMed Central  PubMed  Google Scholar 

  23. Bok JW, Chiang YM, Szewczyk E, Reyes-Dominguez Y, Davidson AD, Sanchez JF, Lo HC, Watanabe K, Strauss J, Oakley BR, Wang CC, Keller NP (2009) Chromatin-level regulation of biosynthetic gene clusters. Nat Chem Biol 5:462–464

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Bok JW, Chung D, Balajee SA, Marr KA, Andes D, Nielsen KF, Frisvad JC, Kirby KA, Keller NP (2006) GliZ, a transcriptional regulator of gliotoxin biosynthesis, contributes to Aspergillus fumigatus virulence. Infect Immun 74:6761–6768

    CAS  PubMed Central  PubMed  Google Scholar 

  25. Bok JW, Hoffmeister D, Maggio-Hall LA, Murillo R, Glasner JD, Keller NP (2006) Genomic mining for Aspergillus natural products. Chem Biol 13:31–37

    CAS  PubMed  Google Scholar 

  26. Bok JW, Keller NP (2004) LaeA, a regulator of secondary metabolism in Aspergillus spp. Eukaryot Cell 3:527–535

    CAS  PubMed Central  PubMed  Google Scholar 

  27. Bomke C, Tudzynski B (2009) Diversity, regulation, and evolution of the gibberellin biosynthetic pathway in fungi compared to plants and bacteria. Phytochemistry 70:1876–1893

    PubMed  Google Scholar 

  28. Bouhired S, Weber M, Kempf-Sontag A, Keller NP, Hoffmeister D (2007) Accurate prediction of the Aspergillus nidulans terrequinone gene cluster boundaries using the transcriptional regulator LaeA. Fungal Genet Biol 44:1134–1145

    CAS  PubMed  Google Scholar 

  29. Bradshaw RE, Slot JC, Moore GG, Chettri P, de Wit PJ, Ehrlich KC, Ganley AR, Olson MA, Rokas A, Carbone I, Cox MP (2013) Fragmentation of an aflatoxin-like gene cluster in a forest pathogen. New Phytol 198:525–535

    CAS  PubMed  Google Scholar 

  30. Brakhage AA (2013) Regulation of fungal secondary metabolism. Nat Rev Microbiol 11:21–32

    CAS  PubMed  Google Scholar 

  31. Brakhage AA, Thon M, Sprote P, Scharf DH, Al-Abdallah Q, Wolke SM, Hortschansky P (2009) Aspects on evolution of fungal beta-lactam biosynthesis gene clusters and recruitment of trans-acting factors. Phytochemistry 70:1801–1811

    CAS  PubMed  Google Scholar 

  32. Bromann K, Toivari M, Viljanen K, Vuoristo A, Ruohonen L, Nakari-Setala T (2012) Identification and characterization of a novel diterpene gene cluster in Aspergillus nidulans. PLoS ONE 7:e35450

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Brown DW, Butchko RA, Busman M, Proctor RH (2007) The Fusarium verticillioides FUM gene cluster encodes a Zn(II)2Cys6 protein that affects FUM gene expression and fumonisin production. Eukaryot Cell 6:1210–1218

    CAS  PubMed Central  PubMed  Google Scholar 

  34. Brown DW, Butchko RA, Busman M, Proctor RH (2012) Identification of gene clusters associated with fusaric acid, fusarin, and perithecial pigment production in Fusarium verticillioides. Fungal Genet Biol 49:521–532

    CAS  PubMed  Google Scholar 

  35. Brown DW, Yu JH, Kelkar HS, Fernandes M, Nesbitt TC, Keller NP, Adams TH, Leonard TJ (1996) Twenty-five coregulated transcripts define a sterigmatocystin gene cluster in Aspergillus nidulans. Proc Natl Acad Sci U S A 93:1418–1422

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Butchko RA, Brown DW, Busman M, Tudzynski B, Wiemann P (2012) Lae1 regulates expression of multiple secondary metabolite gene clusters in Fusarium verticillioides. Fungal Genet Biol 49:602–612

    CAS  PubMed  Google Scholar 

  37. Cantwell C, Beckmann R, Whiteman P, Queener SW, Abraham EP (1992) Isolation of deacetoxycephalosporin C from fermentation broths of Penicillium chrysogenum transformants: construction of a new fungal biosynthetic pathway. In: Proceedings of the biological sciences, pp 283–289

  38. Chang PK, Ehrlich KC (2013) Genome-wide analysis of the Zn(II)(2)Cys(6) zinc cluster-encoding gene family in Aspergillus flavus. Appl Microbiol Biotechnol 97:4289–4300

    CAS  PubMed  Google Scholar 

  39. Chang PK, Ehrlich KC, Yu J, Bhatnagar D, Cleveland TE (1995) Increased expression of Aspergillus parasiticus aflR, encoding a sequence-specific DNA-binding protein, relieves nitrate inhibition of aflatoxin biosynthesis. Appl Environ Microbiol 61:2372–2377

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Chen H, Lee MH, Daub ME, Chung KR (2007) Molecular analysis of the cercosporin biosynthetic gene cluster in Cercospora nicotianae. Mol Microbiol 64:755–770

    CAS  PubMed  Google Scholar 

  41. Chiang YM, Oakley CE, Ahuja M, Entwistle R, Schultz A, Chang SL, Sung CT, Wang CC, Oakley BR (2013) An efficient system for heterologous expression of secondary metabolite genes in Aspergillus nidulans. J Am Chem Soc 135:7720–7731

    CAS  PubMed  Google Scholar 

  42. Chiang YM, Szewczyk E, Davidson AD, Entwistle R, Keller NP, Wang CC, Oakley BR (2010) Characterization of the Aspergillus nidulans monodictyphenone gene cluster. Appl Environ Microbiol 76:2067–2074

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Chiang YM, Szewczyk E, Davidson AD, Keller N, Oakley BR, Wang CC (2009) A gene cluster containing two fungal polyketide synthases encodes the biosynthetic pathway for a polyketide, asperfuranone, in Aspergillus nidulans. J Am Chem Soc 131:2965–2970

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Chiang YM, Szewczyk E, Nayak T, Davidson AD, Sanchez JF, Lo HC, Ho WY, Simityan H, Kuo E, Praseuth A, Watanabe K, Oakley BR, Wang CC (2008) Molecular genetic mining of the Aspergillus secondary metabolome: discovery of the emericellamide biosynthetic pathway. Chem Biol 15:527–532

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Chooi YH, Fang J, Liu H, Filler SG, Wang P, Tang Y (2013) Genome mining of a prenylated and immunosuppressive polyketide from pathogenic fungi. Org Lett 15:780–783

    CAS  PubMed  Google Scholar 

  46. Chooi YH, Wang P, Fang J, Li Y, Wu K, Wang P, Tang Y (2012) Discovery and characterization of a group of fungal polycyclic polyketide prenyltransferases. J Am Chem Soc 134:9428–9437

    CAS  PubMed  Google Scholar 

  47. Choquer M, Dekkers KL, Chen HQ, Cao L, Ueng PP, Daub ME, Chung KR (2005) The CTB1 gene encoding a fungal polyketide synthase is required for cercosporin biosynthesis and fungal virulence of Cercospora nicotianae. Mol Plant Microbe Interact 18:468–476

    CAS  PubMed  Google Scholar 

  48. Cichewicz RH (2010) Epigenome manipulation as a pathway to new natural product scaffolds and their congeners. Nat Prod Rep 27:11–22

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Condon BJ, Leng Y, Wu D, Bushley KE, Ohm RA, Otillar R, Martin J, Schackwitz W, Grimwood J, MohdZainudin N, Xue C, Wang R, Manning VA, Dhillon B, Tu ZJ, Steffenson BJ, Salamov A, Sun H, Lowry S, LaButti K, Han J, Copeland A, Lindquist E, Barry K, Schmutz J, Baker SE, Ciuffetti LM, Grigoriev IV, Zhong S, Turgeon BG (2013) Comparative genome structure, secondary metabolite, and effector coding capacity across Cochliobolus pathogens. PLoS Genet 9:e1003233

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Cox RJ, Glod F, Hurley D, Lazarus CM, Nicholson TP, Rudd BA, Simpson TJ, Wilkinson B, Zhang Y (2004) Rapid cloning and expression of a fungal polyketide synthase gene involved in squalestatin biosynthesis. Chem Commun (Camb) 2260–2261

  51. Davis C, Carberry S, Schrettl M, Singh I, Stephens JC, Barry SM, Kavanagh K, Challis GL, Brougham D, Doyle S (2011) The role of glutathione S-transferase GliG in gliotoxin biosynthesis in Aspergillus fumigatus. Chem Biol 18:542–552

    CAS  PubMed  Google Scholar 

  52. Demain AL (1991) Production of beta-lactam antibiotics and its regulation. Proc Natl Sci Counc Repub China B 15:251–265

    CAS  PubMed  Google Scholar 

  53. Desjardins AE, Plattner RD, Proctor RH (1996) Linkage among genes responsible for fumonisin biosynthesis in Gibberella fujikuroi mating population A. Appl Environ Microbiol 62:2571–2576

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Diez B, Gutierrez S, Barredo JL, van Solingen P, van der Voort LH, Martin JF (1990) The cluster of penicillin biosynthetic genes. Identification and characterization of the pcbAB gene encoding the alpha-aminoadipyl-cysteinyl-valine synthetase and linkage to the pcbC and penDE genes. J Biol Chem 265:16358–16365

    CAS  PubMed  Google Scholar 

  55. Eisenman HC, Casadevall A (2012) Synthesis and assembly of fungal melanin. Appl Microbiol Biotechnol 93:931–940

    CAS  PubMed  Google Scholar 

  56. Fedorova ND, Moktali V, Medema MH (2012) Bioinformatics approaches and software for detection of secondary metabolic gene clusters. Methods Mol Biol 944:23–45

    CAS  PubMed  Google Scholar 

  57. Fernandes M, Keller NP, Adams TH (1998) Sequence-specific binding by Aspergillus nidulans AflR, a C6 zinc cluster protein regulating mycotoxin biosynthesis. Mol Microbiol 28:1355–1365

    CAS  PubMed  Google Scholar 

  58. Fisch KM, Bakeer W, Yakasai AA, Song Z, Pedrick J, Wasil Z, Bailey AM, Lazarus CM, Simpson TJ, Cox RJ (2011) Rational domain swaps decipher programming in fungal highly reducing polyketide synthases and resurrect an extinct metabolite. J Am Chem Soc 133:16635–16641

    CAS  PubMed  Google Scholar 

  59. Forseth RR, Amaike S, Schwenk D, Affeldt KJ, Hoffmeister D, Schroeder FC, Keller NP (2013) Homologous NRPS-like gene clusters mediate redundant small-molecule biosynthesis in Aspergillus flavus. Angew Chem Int Ed Engl 52:1590–1594

    CAS  PubMed  Google Scholar 

  60. Forseth RR, Fox EM, Chung D, Howlett BJ, Keller NP, Schroeder FC (2011) Identification of cryptic products of the gliotoxin gene cluster using NMR-based comparative metabolomics and a model for gliotoxin biosynthesis. J Am Chem Soc 133:9678–9681

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Fox EM, Gardiner DM, Keller NP, Howlett BJ (2008) A Zn(II)2Cys6 DNA binding protein regulates the sirodesmin PL biosynthetic gene cluster in Leptosphaeria maculans. Fungal Genet Biol 45:671–682

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Frandsen RJ, Nielsen NJ, Maolanon N, Sorensen JC, Olsson S, Nielsen J, Giese H (2006) The biosynthetic pathway for aurofusarin in Fusarium graminearum reveals a close link between the naphthoquinones and naphthopyrones. Mol Microbiol 61:1069–1080

    CAS  PubMed  Google Scholar 

  63. Fujii I, Ono Y, Tada H, Gomi K, Ebizuka Y, Sankawa U (1996) Cloning of the polyketide synthase gene atX from Aspergillus terreus and its identification as the 6-methylsalicylic acid synthase gene by heterologous expression. Mol Gen Genet 253:1–10

    CAS  PubMed  Google Scholar 

  64. Fujii R, Minami A, Tsukagoshi T, Sato N, Sahara T, Ohgiya S, Gomi K, Oikawa H (2011) Total biosynthesis of diterpene aphidicolin, a specific inhibitor of DNA polymerase alpha: heterologous expression of four biosynthetic genes in Aspergillus oryzae. Biosci Biotechnol Biochem 75:1813–1817

    CAS  PubMed  Google Scholar 

  65. Galagan JE, Calvo SE, Cuomo C, Ma LJ, Wortman JR, Batzoglou S, Lee SI, Basturkmen M, Spevak CC, Clutterbuck J, Kapitonov V, Jurka J, Scazzocchio C, Farman M, Butler J, Purcell S, Harris S, Braus GH, Draht O, Busch S, D’Enfert C, Bouchier C, Goldman GH, Bell-Pedersen D, Griffiths-Jones S, Doonan JH, Yu J, Vienken K, Pain A, Freitag M, Selker EU, Archer DB, Penalva MA, Oakley BR, Momany M, Tanaka T, Kumagai T, Asai K, Machida M, Nierman WC, Denning DW, Caddick M, Hynes M, Paoletti M, Fischer R, Miller B, Dyer P, Sachs MS, Osmani SA, Birren BW (2005) Sequencing of Aspergillus nidulans and comparative analysis with A. fumigatus and A. oryzae. Nature 438:1105–1115

    CAS  PubMed  Google Scholar 

  66. Gao Q, Jin K, Ying SH, Zhang Y, Xiao G, Shang Y, Duan Z, Hu X, Xie XQ, Zhou G, Peng G, Luo Z, Huang W, Wang B, Fang W, Wang S, Zhong Y, Ma LJ, St Leger RJ, Zhao GP, Pei Y, Feng MG, Xia Y, Wang C (2011) Genome sequencing and comparative transcriptomics of the model entomopathogenic fungi Metarhizium anisopliae and M. acridum. PLoS Genet 7:e1001264

  67. Georgianna DR, Fedorova ND, Burroughs JL, Dolezal AL, Bok JW, Horowitz-Brown S, Woloshuk CP, Yu J, Keller NP, Payne GA (2010) Beyond aflatoxin: four distinct expression patterns and functional roles associated with Aspergillus flavus secondary metabolism gene clusters. Mol Plant Pathol 11:213–226

    CAS  PubMed  Google Scholar 

  68. Gerke J, Bayram O, Feussner K, Landesfeind M, Shelest E, Feussner I, Braus GH (2012) Breaking the silence: protein stabilization uncovers silenced biosynthetic gene clusters in the fungus Aspergillus nidulans. Appl Environ Microbiol 78:8234–8244

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Gressler M, Zaehle C, Scherlach K, Hertweck C, Brock M (2011) Multifactorial induction of an orphan PKS-NRPS gene cluster in Aspergillus terreus. Chem Biol 18:198–209

    CAS  PubMed  Google Scholar 

  70. Grigoriev IV, Nordberg H, Shabalov I, Aerts A, Cantor M, Goodstein D, Kuo A, Minovitsky S, Nikitin R, Ohm RA, Otillar R, Poliakov A, Ratnere I, Riley R, Smirnova T, Rokhsar D, Dubchak I (2012) The genome portal of the Department of Energy Joint Genome Institute. Nucleic Acids Res 40:D26–D32

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Grundmann A, Kuznetsova T, Afiyatullov SS, Li SM (2008) FtmPT2, an N-prenyltransferase from Aspergillus fumigatus, catalyses the last step in the biosynthesis of fumitremorgin B. ChemBioChem 9:2059–2063

    CAS  PubMed  Google Scholar 

  72. Grundmann A, Li SM (2005) Overproduction, purification and characterization of FtmPT1, a brevianamide F prenyltransferase from Aspergillus fumigatus. Microbiology 151:2199–2207

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  74. Hansen BG, Mnich E, Nielsen KF, Nielsen JB, Nielsen MT, Mortensen UH, Larsen TO, Patil KR (2012) Involvement of a natural fusion of a cytochrome P450 and a hydrolase in mycophenolic acid biosynthesis. Appl Environ Microbiol 78:4908–4913

    CAS  PubMed Central  PubMed  Google Scholar 

  75. Harris DM, van der Krogt ZA, Klaassen P, Raamsdonk LM, Hage S, van den Berg MA, Bovenberg RA, Pronk JT, Daran JM (2009) Exploring and dissecting genome-wide gene expression responses of Penicillium chrysogenum to phenylacetic acid consumption and penicillinG production. BMC Genomics 10:75

    PubMed Central  PubMed  Google Scholar 

  76. Heneghan MN, Yakasai AA, Halo LM, Song Z, Bailey AM, Simpson TJ, Cox RJ, Lazarus CM (2010) First heterologous reconstruction of a complete functional fungal biosynthetic multigene cluster. ChemBioChem 11:1508–1512

    CAS  PubMed  Google Scholar 

  77. Henrikson JC, Hoover AR, Joyner PM, Cichewicz RH (2009) A chemical epigenetics approach for engineering the in situ biosynthesis of a cryptic natural product from Aspergillus niger. Org Biomol Chem 7:435–438

    CAS  PubMed  Google Scholar 

  78. Hoff B, Kamerewerd J, Sigl C, Mitterbauer R, Zadra I, Kurnsteiner H, Kuck U (2010) Two components of a velvet-like complex control hyphal morphogenesis, conidiophore development, and penicillin biosynthesis in Penicillium chrysogenum. Eukaryot Cell 9:1236–1250

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Hoffmeister D, Keller NP (2007) Natural products of filamentous fungi: enzymes, genes, and their regulation. Nat Prod Rep 24:393–416

    CAS  PubMed  Google Scholar 

  80. Hohn TM, McCormick SP, Desjardins AE (1993) Evidence for a gene cluster involving trichothecene-pathway biosynthetic genes in Fusarium sporotrichioides. Curr Genet 24:291–295

    CAS  PubMed  Google Scholar 

  81. Huang X, Li HM (2009) Cloning and bioinformatic analysis of lovastatin biosynthesis regulatory gene lovE. Chin Med J (Engl) 122:1800–1805

    CAS  Google Scholar 

  82. Hutchinson CR, Fujii I (1995) Polyketide synthase gene manipulation: a structure-function approach in engineering novel antibiotics. Annu Rev Microbiol 49:201–238

    CAS  PubMed  Google Scholar 

  83. Ikeda H, Ishikawa J, Hanamoto A, Shinose M, Kikuchi H, Shiba T, Sakaki Y, Hattori M, Omura S (2003) Complete genome sequence and comparative analysis of the industrial microorganism Streptomyces avermitilis. Nat Biotechnol 21:526–531

    PubMed  Google Scholar 

  84. Itoh T, Kushiro T, Fujii I (2012) Reconstitution of a secondary metabolite biosynthetic pathway in a heterologous fungal host. Methods Mol Biol 944:175–182

    CAS  PubMed  Google Scholar 

  85. Jain S, Keller N (2013) Insights to fungal biology through LaeA sleuthing. Fungal Biol Rev 27:51–59

    Google Scholar 

  86. Kao CM, Pieper R, Cane DE, Khosla C (1996) Evidence for two catalytically independent clusters of active sites in a functional modular polyketide synthase. Biochemistry 35:12363–12368

    CAS  PubMed  Google Scholar 

  87. Karimi-Aghcheh R, Bok JW, Phatale PA, Smith KM, Baker SE, Lichius A, Omann M, Zeilinger S, Seiboth B, Rhee C, Keller NP, Freitag M, Kubicek CP (2013) Functional analyses of Trichoderma reesei LAE1 reveal conserved and contrasting roles of this regulator. G3 (Bethesda) 3:369–378

    Google Scholar 

  88. Kawauchi M, Nishiura M, Iwashita K (2013) Fungus-specific sirtuin HstD coordinates secondary metabolism and development through control of LaeA. Eukaryot Cell 12:1087–1096

    CAS  PubMed  Google Scholar 

  89. Kealey JT, Liu L, Santi DV, Betlach MC, Barr PJ (1998) Production of a polyketide natural product in nonpolyketide-producing prokaryotic and eukaryotic hosts. Proc Natl Acad Sci U S A 95:505–509

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Keller NP, Hohn TM (1997) Metabolic pathway gene clusters in filamentous fungi. Fungal Genet Biol 21:17–29

    CAS  Google Scholar 

  91. Kennedy J, Auclair K, Kendrew SG, Park C, Vederas JC, Hutchinson CR (1999) Modulation of polyketide synthase activity by accessory proteins during lovastatin biosynthesis. Science 284:1368–1372

    CAS  PubMed  Google Scholar 

  92. Khaldi N, Seifuddin FT, Turner G, Haft D, Nierman WC, Wolfe KH, Fedorova ND (2010) SMURF: genomic mapping of fungal secondary metabolite clusters. Fungal Genet Biol 47:736–741

    CAS  PubMed Central  PubMed  Google Scholar 

  93. Kim JE, Jin J, Kim H, Kim JC, Yun SH, Lee YW (2006) GIP2, a putative transcription factor that regulates the aurofusarin biosynthetic gene cluster in Gibberella zeae. Appl Environ Microbiol 72:1645–1652

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Kimura M, Tokai T, Takahashi-Ando N, Ohsato S, Fujimura M (2007) Molecular and genetic studies of fusarium trichothecene biosynthesis: pathways, genes, and evolution. Biosci Biotechnol Biochem 71:2105–2123

    CAS  PubMed  Google Scholar 

  95. Kimura N, Tsuge T (1993) Gene cluster involved in melanin biosynthesis of the filamentous fungus Alternaria alternata. J Bacteriol 175:4427–4435

    CAS  PubMed Central  PubMed  Google Scholar 

  96. Konig CC, Scherlach K, Schroeckh V, Horn F, Nietzsche S, Brakhage AA, Hertweck C (2013) Bacterium induces cryptic meroterpenoid pathway in the pathogenic fungus Aspergillus fumigatus. ChemBioChem 14:938–942

    PubMed  Google Scholar 

  97. Konigs M, Lenczyk M, Schwerdt G, Holzinger H, Gekle M, Humpf HU (2007) Cytotoxicity, metabolism and cellular uptake of the mycotoxin deoxynivalenol in human proximal tubule cells and lung fibroblasts in primary culture. Toxicology 240:48–59

    PubMed  Google Scholar 

  98. 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 U S A 100:15670–15675

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Kubicek CP, Herrera-Estrella A, Seidl-Seiboth V, Martinez DA, Druzhinina IS, Thon M, Zeilinger S, Casas-Flores S, Horwitz BA, Mukherjee PK, Mukherjee M, Kredics L, Alcaraz LD, Aerts A, Antal Z, Atanasova L, Cervantes-Badillo MG, Challacombe J, Chertkov O, McCluskey K, Coulpier F, Deshpande N, von Dohren H, Ebbole DJ, Esquivel-Naranjo EU, Fekete E, Flipphi M, Glaser F, Gomez-Rodriguez EY, Gruber S, Han C, Henrissat B, Hermosa R, Hernandez-Onate M, Karaffa L, Kosti I, Le Crom S, Lindquist E, Lucas S, Lubeck M, Lubeck PS, Margeot A, Metz B, Misra M, Nevalainen H, Omann M, Packer N, Perrone G, Uresti-Rivera EE, Salamov A, Schmoll M, Seiboth B, Shapiro H, Sukno S, Tamayo-Ramos JA, Tisch D, Wiest A, Wilkinson HH, Zhang M, Coutinho PM, Kenerley CM, Monte E, Baker SE, Grigoriev IV (2011) Comparative genome sequence analysis underscores mycoparasitism as the ancestral life style of Trichoderma. Genome Biol 12:R40

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Lackner G, Misiek M, Braesel J, Hoffmeister D (2012) Genome mining reveals the evolutionary origin and biosynthetic potential of basidiomycete polyketide synthases. Fungal Genet Biol 49:996–1003

    CAS  PubMed  Google Scholar 

  101. Lee I, Oh JH, Shwab EK, Dagenais TR, Andes D, Keller NP (2009) HdaA, a class 2 histone deacetylase of Aspergillus fumigatus, affects germination and secondary metabolite production. Fungal Genet Biol 46:782–790

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Lee SS, Lee JH, Lee I (2013) Strain improvement by overexpression of the laeA gene in Monascus pilosus for the production of Monascus-fermented rice. J Microbiol Biotechnol 23:959–965

    CAS  PubMed  Google Scholar 

  103. Lim FY, Hou Y, Chen Y, Oh JH, Lee I, Bugni TS, Keller NP (2012) Genome-based cluster deletion reveals an endocrocin biosynthetic pathway in Aspergillus fumigatus. Appl Environ Microbiol 78:4117–4125

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Lin HC, Chooi YH, Dhingra S, Xu W, Calvo AM, Tang Y (2013) The fumagillin biosynthetic gene cluster in Aspergillus fumigatus encodes a cryptic terpene cyclase involved in the formation of beta-trans-bergamotene. J Am Chem Soc 135:4616–4619

    CAS  PubMed  Google Scholar 

  105. Liu H, Jiang H, Haltli B, Kulowski K, Muszynska E, Feng X, Summers M, Young M, Graziani E, Koehn F, Carter GT, He M (2009) Rapid cloning and heterologous expression of the meridamycin biosynthetic gene cluster using a versatile Escherichia coli-streptomyces artificial chromosome vector, pSBAC. J Nat Prod 72:389–395

    CAS  PubMed  Google Scholar 

  106. Liu T, Chiang YM, Somoza AD, Oakley BR, Wang CC (2011) Engineering of an “unnatural” natural product by swapping polyketide synthase domains in Aspergillus nidulans. J Am Chem Soc 133:13314–13316

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Liu Y, Wu F (2010) Global burden of aflatoxin-induced hepatocellular carcinoma: a risk assessment. Environ Health Perspect 118:818–824

    CAS  PubMed Central  PubMed  Google Scholar 

  108. Lo HC, Entwistle R, Guo CJ, Ahuja M, Szewczyk E, Hung JH, Chiang YM, Oakley BR, Wang CC (2012) Two separate gene clusters encode the biosynthetic pathway for the meroterpenoids austinol and dehydroaustinol in Aspergillus nidulans. J Am Chem Soc 134:4709–4720

    CAS  PubMed Central  PubMed  Google Scholar 

  109. Ma LJ, van der Does HC, Borkovich KA, Coleman JJ, Daboussi MJ, Di Pietro A, Dufresne M, Freitag M, Grabherr M, Henrissat B, Houterman PM, Kang S, Shim WB, Woloshuk C, Xie X, Xu JR, Antoniw J, Baker SE, Bluhm BH, Breakspear A, Brown DW, Butchko RA, Chapman S, Coulson R, Coutinho PM, Danchin EG, Diener A, Gale LR, Gardiner DM, Goff S, Hammond-Kosack KE, Hilburn K, Hua-Van A, Jonkers W, Kazan K, Kodira CD, Koehrsen M, Kumar L, Lee YH, Li L, Manners JM, Miranda-Saavedra D, Mukherjee M, Park G, Park J, Park SY, Proctor RH, Regev A, Ruiz-Roldan MC, Sain D, Sakthikumar S, Sykes S, Schwartz DC, Turgeon BG, Wapinski I, Yoder O, Young S, Zeng Q, Zhou S, Galagan J, Cuomo CA, Kistler HC, Rep M (2010) Comparative genomics reveals mobile pathogenicity chromosomes in Fusarium. Nature 464:367–373

    CAS  PubMed Central  PubMed  Google Scholar 

  110. Ma SM, Zhan J, Watanabe K, Xie X, Zhang W, Wang CC, Tang Y (2007) Enzymatic synthesis of aromatic polyketides using PKS4 from Gibberella fujikuroi. J Am Chem Soc 129:10642–10643

    CAS  PubMed Central  PubMed  Google Scholar 

  111. MacCabe AP, Riach MB, Unkles SE, Kinghorn JR (1990) The Aspergillus nidulans npeA locus consists of three contiguous genes required for penicillin biosynthesis. EMBO J 9:279–287

    CAS  PubMed  Google Scholar 

  112. Maiya S, Grundmann A, Li SM, Turner G (2006) The fumitremorgin gene cluster of Aspergillus fumigatus: identification of a gene encoding brevianamide F synthetase. ChemBioChem 7:1062–1069

    CAS  PubMed  Google Scholar 

  113. Maiya S, Grundmann A, Li SM, Turner G (2009) Improved tryprostatin B production by heterologous gene expression in Aspergillus nidulans. Fungal Genet Biol 46:436–440

    CAS  PubMed  Google Scholar 

  114. Maiya S, Grundmann A, Li X, Li SM, Turner G (2007) Identification of a hybrid PKS/NRPS required for pseurotin A biosynthesis in the human pathogen Aspergillus fumigatus. ChemBioChem 8:1736–1743

    CAS  PubMed  Google Scholar 

  115. Manzoni M, Rollini M (2002) Biosynthesis and biotechnological production of statins by filamentous fungi and application of these cholesterol-lowering drugs. Appl Microbiol Biotechnol 58:555–564

    CAS  PubMed  Google Scholar 

  116. Martinez DA, Oliver BG, Graser Y, Goldberg JM, Li W, Martinez-Rossi NM, Monod M, Shelest E, Barton RC, Birch E, Brakhage AA, Chen Z, Gurr SJ, Heiman D, Heitman J, Kosti I, Rossi A, Saif S, Samalova M, Saunders CW, Shea T, Summerbell RC, Xu J, Young S, Zeng Q, Birren BW, Cuomo CA, White TC (2012) Comparative genome analysis of Trichophyton rubrum and related dermatophytes reveals candidate genes involved in infection. MBio 3:e00259–12

  117. Marui J, Ohashi-Kunihiro S, Ando T, Nishimura M, Koike H, Machida M (2010) Penicillin biosynthesis in Aspergillus oryzae and its overproduction by genetic engineering. J Biosci Bioeng 110:8–11

    CAS  PubMed  Google Scholar 

  118. Medema MH, Blin K, Cimermancic P, de Jager V, Zakrzewski P, Fischbach MA, Weber T, Takano E, Breitling R (2011) antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res 39:W339–W346

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Nett M, Ikeda H, Moore BS (2009) Genomic basis for natural product biosynthetic diversity in the actinomycetes. Nat Prod Rep 26:1362–1384

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Nowrousian M, Stajich JE, Chu M, Engh I, Espagne E, Halliday K, Kamerewerd J, Kempken F, Knab B, Kuo HC, Osiewacz HD, Poggeler S, Read ND, Seiler S, Smith KM, Zickler D, Kuck U, Freitag M (2010) De novo assembly of a 40 Mb eukaryotic genome from short sequence reads: Sordaria macrospora, a model organism for fungal morphogenesis. PLoS Genet 6:e1000891

    PubMed Central  PubMed  Google Scholar 

  121. Nutzmann HW, Fischer J, Scherlach K, Hertweck C, Brakhage AA (2013) Distinct amino acids of histone H3 control secondary metabolism in Aspergillus nidulans. Appl Environ Microbiol 79:6102–6109

    Google Scholar 

  122. Nutzmann HW, Reyes-Dominguez Y, Scherlach K, Schroeckh V, Horn F, Gacek A, Schumann J, Hertweck C, Strauss J, Brakhage AA (2011) Bacteria-induced natural product formation in the fungus Aspergillus nidulans requires Saga/Ada-mediated histone acetylation. Proc Natl Acad Sci U S A 108:14282–14287

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Nutzmann HW, Schroeckh V, Brakhage AA (2012) Regulatory cross talk and microbial induction of fungal secondary metabolite gene clusters. Methods Enzymol 517:325–341

    PubMed  Google Scholar 

  124. O’Connell RJ, Thon MR, Hacquard S, Amyotte SG, Kleemann J, Torres MF, Damm U, Buiate EA, Epstein L, Alkan N, Altmuller J, Alvarado-Balderrama L, Bauser CA, Becker C, Birren BW, Chen Z, Choi J, Crouch JA, Duvick JP, Farman MA, Gan P, Heiman D, Henrissat B, Howard RJ, Kabbage M, Koch C, Kracher B, Kubo Y, Law AD, Lebrun MH, Lee YH, Miyara I, Moore N, Neumann U, Nordstrom K, Panaccione DG, Panstruga R, Place M, Proctor RH, Prusky D, Rech G, Reinhardt R, Rollins JA, Rounsley S, Schardl CL, Schwartz DC, Shenoy N, Shirasu K, Sikhakolli UR, Stuber K, Sukno SA, Sweigard JA, Takano Y, Takahara H, Trail F, van der Does HC, Voll LM, Will I, Young S, Zeng Q, Zhang J, Zhou S, Dickman MB, Schulze-Lefert P, Loren Ver, van Themaat E, Ma LJ, Vaillancourt LJ (2012) Lifestyle transitions in plant pathogenic Colletotrichum fungi deciphered by genome and transcriptome analyses. Nat Genet 44:1060–1065

    PubMed  Google Scholar 

  125. Oakley CE, Edgerton-Morgan H, Oakley BR (2012) Tools for manipulation of secondary metabolism pathways: rapid promoter replacements and gene deletions in Aspergillus nidulans. Methods Mol Biol 944:143–161

    CAS  PubMed  Google Scholar 

  126. Ohnishi Y, Ishikawa J, Hara H, Suzuki H, Ikenoya M, Ikeda H, Yamashita A, Hattori M, Horinouchi S (2008) Genome sequence of the streptomycin-producing microorganism Streptomyces griseus IFO 13350. J Bacteriol 190:4050–4060

    CAS  PubMed Central  PubMed  Google Scholar 

  127. Oldenburg KR, Vo KT, Michaelis S, Paddon C (1997) Recombination-mediated PCR-directed plasmid construction in vivo in yeast. Nucleic Acids Res 25:451–452

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Oliynyk M, Samborskyy M, Lester JB, Mironenko T, Scott N, Dickens S, Haydock SF, Leadlay PF (2007) Complete genome sequence of the erythromycin-producing bacterium Saccharopolyspora erythraea NRRL23338. Nat Biotechnol 25:447–453

    CAS  PubMed  Google Scholar 

  129. Osswald C, Zipf G, Schmidt G, Maier J, Bernauer HS, Muller R, Wenzel SC (2012) Modular construction of a functional artificial epothilone polyketide pathway. ACS Synth Biol. doi:10.1021/sb300080t

    PubMed  Google Scholar 

  130. Palmer JM, Keller NP (2010) Secondary metabolism in fungi: does chromosomal location matter? Curr Opin Microbiol 13:431–436

    CAS  PubMed Central  PubMed  Google Scholar 

  131. Palmer JM, Perrin RM, Dagenais TR, Keller NP (2008) H3K9 methylation regulates growth and development in Aspergillus fumigatus. Eukaryot Cell 7:2052–2060

    CAS  PubMed Central  PubMed  Google Scholar 

  132. Patananan AN, Palmer JM, Garvey GS, Keller NP, Clarke SG (2013) A novel automethylation reaction in the Aspergillus nidulans LaeA protein generates S-methylmethionine. J Biol Chem 288:14032–14045

    CAS  PubMed  Google Scholar 

  133. Pel HJ, de Winde JH, Archer DB, Dyer PS, Hofmann G, Schaap PJ, Turner G, de Vries RP, Albang R, Albermann K, Andersen MR, Bendtsen JD, Benen JA, van den Berg M, Breestraat S, Caddick MX, Contreras R, Cornell M, Coutinho PM, Danchin EG, Debets AJ, Dekker P, van Dijck PW, van Dijk A, Dijkhuizen L, Driessen AJ, d’Enfert C, Geysens S, Goosen C, Groot GS, de Groot PW, Guillemette T, Henrissat B, Herweijer M, van den Hombergh JP, van den Hondel CA, van der Heijden RT, van der Kaaij RM, Klis FM, Kools HJ, Kubicek CP, van Kuyk PA, Lauber J, Lu X, van der Maarel MJ, Meulenberg R, Menke H, Mortimer MA, Nielsen J, Oliver SG, Olsthoorn M, Pal K, van Peij NN, Ram AF, Rinas U, Roubos JA, Sagt CM, Schmoll M, Sun J, Ussery D, Varga J, Vervecken W, van de Vondervoort PJ, Wedler H, Wosten HA, Zeng AP, van Ooyen AJ, Visser J, Stam H (2007) Genome sequencing and analysis of the versatile cell factory Aspergillus niger CBS 513.88. Nat Biotechnol 25:221–231

    PubMed  Google Scholar 

  134. Perrin RM, Fedorova ND, Bok JW, Cramer RA, Wortman JR, Kim HS, Nierman WC, Keller NP (2007) Transcriptional regulation of chemical diversity in Aspergillus fumigatus by LaeA. PLoS Pathog 3:e50

    PubMed Central  PubMed  Google Scholar 

  135. Reyes-Dominguez Y, Boedi S, Sulyok M, Wiesenberger G, Stoppacher N, Krska R, Strauss J (2012) Heterochromatin influences the secondary metabolite profile in the plant pathogen Fusarium graminearum. Fungal Genet Biol 49:39–47

    CAS  PubMed Central  PubMed  Google Scholar 

  136. Reyes-Dominguez Y, Bok JW, Berger H, Shwab EK, Basheer A, Gallmetzer A, Scazzocchio C, Keller N, Strauss J (2010) Heterochromatic marks are associated with the repression of secondary metabolism clusters in Aspergillus nidulans. Mol Microbiol 76:1376–1386

    CAS  PubMed Central  PubMed  Google Scholar 

  137. Robin J, Bruheim P, Nielsen ML, Noorman H, Nielsen J (2003) Continuous cultivations of a Penicillium chrysogenum strain expressing the expandase gene from Streptomyces clavuligerus: kinetics of adipoyl-7-aminodeacetoxycephalosporanic acid and byproduct formations. Biotechnol Bioeng 83:353–360

    CAS  PubMed  Google Scholar 

  138. Rohlfs M, Albert M, Keller NP, Kempken F (2007) Secondary chemicals protect mould from fungivory. Biol Lett 3:523–525

    PubMed Central  PubMed  Google Scholar 

  139. Rohlfs M, Churchill AC (2011) Fungal secondary metabolites as modulators of interactions with insects and other arthropods. Fungal Genet Biol 48:23–34

    CAS  PubMed  Google Scholar 

  140. Ruegger A, Kuhn M, Lichti H, Loosli HR, Huguenin R, Quiquerez C, von Wartburg A (1976) Cyclosporin A, a peptide metabolite from Trichoderma polysporum (Link ex Pers.) Rifai, with a remarkable immunosuppressive activity. Helv Chim Acta 59:1075–1092

    CAS  PubMed  Google Scholar 

  141. Rugbjerg P, Naesby M, Mortensen UH, Frandsen RJ (2013) Reconstruction of the biosynthetic pathway for the core fungal polyketide scaffold rubrofusarin in Saccharomyces cerevisiae. Microb Cell Fact 12:31

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Ryan KL, Moore CT, Panaccione DG (2013) Partial reconstruction of the ergot alkaloid pathway by heterologous gene expression in Aspergillus nidulans. Toxins (Basel) 5:445–455

    CAS  Google Scholar 

  143. Sakai K, Kinoshita H, Shimizu T, Nihira T (2008) Construction of a citrinin gene cluster expression system in heterologous Aspergillus oryzae. J Biosci Bioeng 106:466–472

    CAS  PubMed  Google Scholar 

  144. Sanchez JF, Entwistle R, Hung JH, Yaegashi J, Jain S, Chiang YM, Wang CC, Oakley BR (2011) Genome-based deletion analysis reveals the prenyl xanthone biosynthesis pathway in Aspergillus nidulans. J Am Chem Soc 133:4010–4017

    CAS  PubMed Central  PubMed  Google Scholar 

  145. Sarkar A, Funk AN, Scherlach K, Horn F, Schroeckh V, Chankhamjon P, Westermann M, Roth M, Brakhage AA, Hertweck C, Horn U (2012) Differential expression of silent polyketide biosynthesis gene clusters in chemostat cultures of Aspergillus nidulans. J Biotechnol 160:64–71

    CAS  PubMed  Google Scholar 

  146. Schardl CL, Young CA, Hesse U, Amyotte SG, Andreeva K, Calie PJ, Fleetwood DJ, Haws DC, Moore N, Oeser B, Panaccione DG, Schweri KK, Voisey CR, Farman ML, Jaromczyk JW, Roe BA, O’Sullivan DM, Scott B, Tudzynski P, An Z, Arnaoudova EG, Bullock CT, Charlton ND, Chen L, Cox M, Dinkins RD, Florea S, Glenn AE, Gordon A, Guldener U, Harris DR, Hollin W, Jaromczyk J, Johnson RD, Khan AK, Leistner E, Leuchtmann A, Li C, Liu J, Liu J, Liu M, Mace W, Machado C, Nagabhyru P, Pan J, Schmid J, Sugawara K, Steiner U, Takach JE, Tanaka E, Webb JS, Wilson EV, Wiseman JL, Yoshida R, Zeng Z (2013) Plant-symbiotic fungi as chemical engineers: multi-genome analysis of the clavicipitaceae reveals dynamics of alkaloid loci. PLoS Genet 9:e1003323

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Scharf DH, Remme N, Habel A, Chankhamjon P, Scherlach K, Heinekamp T, Hortschansky P, Brakhage AA, Hertweck C (2011) A dedicated glutathione S-transferase mediates carbon-sulfur bond formation in gliotoxin biosynthesis. J Am Chem Soc 133:12322–12325

    CAS  PubMed  Google Scholar 

  148. Scherlach K, Hertweck C (2006) Discovery of aspoquinolones A-D, prenylated quinoline-2-one alkaloids from Aspergillus nidulans, motivated by genome mining. Org Biomol Chem 4:3517–3520

    CAS  PubMed  Google Scholar 

  149. Scherlach K, Sarkar A, Schroeckh V, Dahse HM, Roth M, Brakhage AA, Horn U, Hertweck C (2011) Two induced fungal polyketide pathways converge into antiproliferative spiroanthrones. ChemBioChem 12:1836–1839

    CAS  PubMed  Google Scholar 

  150. Scherlach K, Schuemann J, Dahse HM, Hertweck C (2010) Aspernidine A and B, prenylated isoindolinone alkaloids from the model fungus Aspergillus nidulans. J Antibiot (Tokyo) 63:375–377

    CAS  Google Scholar 

  151. Schjerling P, Holmberg S (1996) Comparative amino acid sequence analysis of the C6 zinc cluster family of transcriptional regulators. Nucleic Acids Res 24:4599–4607

    CAS  PubMed Central  PubMed  Google Scholar 

  152. Schroeckh V, Scherlach K, Nutzmann HW, Shelest E, Schmidt-Heck W, Schuemann J, Martin K, Hertweck C, Brakhage AA (2009) Intimate bacterial-fungal interaction triggers biosynthesis of archetypal polyketides in Aspergillus nidulans. Proc Natl Acad Sci U S A 106:14558–14563

    CAS  PubMed Central  PubMed  Google Scholar 

  153. Schumann J, Hertweck C (2006) Advances in cloning, functional analysis and heterologous expression of fungal polyketide synthase genes. J Biotechnol 124:690–703

    PubMed  Google Scholar 

  154. Seshime Y, Juvvadi PR, Fujii I, Kitamoto K (2005) Discovery of a novel superfamily of type III polyketide synthases in Aspergillus oryzae. Biochem Biophys Res Commun 331:253–260

    CAS  PubMed  Google Scholar 

  155. Shao Z, Zhao H (2012) DNA assembler: a synthetic biology tool for characterizing and engineering natural product gene clusters. Methods Enzymol 517:203–224

    CAS  PubMed  Google Scholar 

  156. Smith DJ, Burnham MK, Edwards J, Earl AJ, Turner G (1990) Cloning and heterologous expression of the penicillin biosynthetic gene cluster from Penicillum chrysogenum. Biotechnology (N Y) 8:39–41

    CAS  Google Scholar 

  157. Sondergaard TE, Hansen FT, Purup S, Nielsen AK, Bonefeld-Jorgensen EC, Giese H, Sorensen JL (2011) Fusarin C acts like an estrogenic agonist and stimulates breast cancer cells in vitro. Toxicol Lett 205:116–121

    CAS  PubMed  Google Scholar 

  158. Sorensen JL, Hansen FT, Sondergaard TE, Staerk D, Lee TV, Wimmer R, Klitgaard LG, Purup S, Giese H, Frandsen RJ (2012) Production of novel fusarielins by ectopic activation of the polyketide synthase 9 cluster in Fusarium graminearum. Environ Microbiol 14:1159–1170

    PubMed  Google Scholar 

  159. Soukup AA, Chiang YM, Bok JW, Reyes-Dominguez Y, Oakley BR, Wang CC, Strauss J, Keller NP (2012) Overexpression of the Aspergillus nidulans histone 4 acetyltransferase EsaA increases activation of secondary metabolite production. Mol Microbiol 86:314–330

    CAS  PubMed Central  PubMed  Google Scholar 

  160. Spiering MJ, Moon CD, Wilkinson HH, Schardl CL (2005) Gene clusters for insecticidal loline alkaloids in the grass-endophytic fungus Neotyphodium uncinatum. Genetics 169:1403–1414

    CAS  PubMed  Google Scholar 

  161. Steffan N, Grundmann A, Afiyatullov S, Ruan H, Li SM (2009) FtmOx1, a non-heme Fe(II) and alpha-ketoglutarate-dependent dioxygenase, catalyses the endoperoxide formation of verruculogen in Aspergillus fumigatus. Org Biomol Chem 7:4082–4087

    CAS  PubMed  Google Scholar 

  162. Sterner DE, Nathan D, Reindle A, Johnson ES, Berger SL (2006) Sumoylation of the yeast Gcn5 protein. Biochemistry 45:1035–1042

    CAS  PubMed  Google Scholar 

  163. Strauss J, Reyes-Dominguez Y (2011) Regulation of secondary metabolism by chromatin structure and epigenetic codes. Fungal Genet Biol 48:62–69

    CAS  PubMed  Google Scholar 

  164. Studt L, Wiemann P, Kleigrewe K, Humpf HU, Tudzynski B (2012) Biosynthesis of fusarubins accounts for pigmentation of Fusarium fujikuroi perithecia. Appl Environ Microbiol 78:4468–4480

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Szewczyk E, Chiang YM, Oakley CE, Davidson AD, Wang CC, Oakley BR (2008) Identification and characterization of the asperthecin gene cluster of Aspergillus nidulans. Appl Environ Microbiol 74:7607–7612

    CAS  PubMed Central  PubMed  Google Scholar 

  166. Szewczyk E, Nayak T, Oakley CE, Edgerton H, Xiong Y, Taheri-Talesh N, Osmani SA, Oakley BR (2006) Fusion PCR and gene targeting in Aspergillus nidulans. Nat Protoc 1:3111–3120

    CAS  PubMed  Google Scholar 

  167. Trujillo KM, Tyler RK, Ye C, Berger SL, Osley MA (2011) A genetic and molecular toolbox for analyzing histone ubiquitylation and sumoylation in yeast. Methods 54:296–303

    CAS  PubMed Central  PubMed  Google Scholar 

  168. Tudzynski B, Holter K (1998) Gibberellin biosynthetic pathway in Gibberella fujikuroi: evidence for a gene cluster. Fungal Genet Biol 25:157–170

    CAS  PubMed  Google Scholar 

  169. van den Berg MA, Albang R, Albermann K, Badger JH, Daran JM, Driessen AJ, Garcia-Estrada C, Fedorova ND, Harris DM, Heijne WH, Joardar V, Kiel JA, Kovalchuk A, Martin JF, Nierman WC, Nijland JG, Pronk JT, Roubos JA, van der Klei IJ, van Peij NN, Veenhuis M, von Dohren H, Wagner C, Wortman J, Bovenberg RA (2008) Genome sequencing and analysis of the filamentous fungus Penicillium chrysogenum. Nat Biotechnol 26:1161–1168

    CAS  PubMed  Google Scholar 

  170. van der Westhuizen L, Shephard GS, Rheeder JP, Somdyala NI, Marasas WF (2008) Sphingoid base levels in humans consuming fumonisin-contaminated maize in rural areas of the former Transkei, South Africa: a cross-sectional study. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 25:1385–1391

    PubMed  Google Scholar 

  171. Wang X, Sena Filho JG, Hoover AR, King JB, Ellis TK, Powell DR, Cichewicz RH (2010) Chemical epigenetics alters the secondary metabolite composition of guttate excreted by an atlantic-forest-soil-derived Penicillium citreonigrum. J Nat Prod 73:942–948

    CAS  PubMed Central  PubMed  Google Scholar 

  172. Waring P, Beaver J (1996) Gliotoxin and related epipolythiodioxopiperazines. Gen Pharmacol 27:1311–1316

    CAS  PubMed  Google Scholar 

  173. Watanabe A, Ebizuka Y (2004) Unprecedented mechanism of chain length determination in fungal aromatic polyketide synthases. Chem Biol 11:1101–1106

    CAS  PubMed  Google Scholar 

  174. Weber SS, Polli F, Boer R, Bovenberg RA, Driessen AJ (2012) Increased penicillin production in Penicillium chrysogenum production strains via balanced overexpression of isopenicillin N acyltransferase. Appl Environ Microbiol 78:7107–7113

    CAS  PubMed Central  PubMed  Google Scholar 

  175. Wei N, Serino G, Deng XW (2008) The COP9 signalosome: more than a protease. Trends Biochem Sci 33:592–600

    CAS  PubMed  Google Scholar 

  176. Wiemann P, Brown DW, Kleigrewe K, Bok JW, Keller NP, Humpf HU, Tudzynski B (2010) FfVel1 and FfLae1, components of a velvet-like complex in Fusarium fujikuroi, affect differentiation, secondary metabolism and virulence. Mol Microbiol 77:972–994

    Google Scholar 

  177. Wiemann P, Guo CJ, Palmer JM, Sekonyela R, Wang CCC, Keller NP (2013) Prototype of an intertwined secondary metabolite supercluster. Proc Natl Acad Sci U S A. doi:10.1073/pnas.1313258110

  178. Wiemann P, Sieber CM, von Bargen KW, Studt L, Niehaus EM, Espino JJ, Huss K, Michielse CB, Albermann S, Wagner D, Bergner SV, Connolly LR, Fischer A, Reuter G, Kleigrewe K, Bald T, Wingfield BD, Ophir R, Freeman S, Hippler M, Smith KM, Brown DW, Proctor RH, Munsterkotter M, Freitag M, Humpf HU, Guldener U, Tudzynski B (2013) Deciphering the cryptic genome: genome-wide analyses of the rice pathogen Fusarium fujikuroi reveal complex regulation of secondary metabolism and novel metabolites. PLoS Pathog 9:e1003475

    CAS  PubMed Central  PubMed  Google Scholar 

  179. Wiemann P, Willmann A, Straeten M, Kleigrewe K, Beyer M, Humpf HU, Tudzynski B (2009) Biosynthesis of the red pigment bikaverin in Fusarium fujikuroi: genes, their function and regulation. Mol Microbiol 72:931–946

    CAS  PubMed  Google Scholar 

  180. Williams RB, Henrikson JC, Hoover AR, Lee AE, Cichewicz RH (2008) Epigenetic remodeling of the fungal secondary metabolome. Org Biomol Chem 6:1895–1897

    CAS  PubMed  Google Scholar 

  181. Wohlleben W, Mast Y, Muth G, Rottgen M, Stegmann E, Weber T (2012) Synthetic biology of secondary metabolite biosynthesis in actinomycetes: engineering precursor supply as a way to optimize antibiotic production. FEBS Lett 586:2171–2176

    CAS  PubMed  Google Scholar 

  182. Woloshuk CP, Foutz KR, Brewer JF, Bhatnagar D, Cleveland TE, Payne GA (1994) Molecular characterization of aflR, a regulatory locus for aflatoxin biosynthesis. Appl Environ Microbiol 60:2408–2414

    CAS  PubMed Central  PubMed  Google Scholar 

  183. Wu D, Oide S, Zhang N, Choi MY, Turgeon BG (2012) ChLae1 and ChVel1 regulate T-toxin production, virulence, oxidative stress response, and development of the maize pathogen Cochliobolus heterostrophus. PLoS Pathog 8:e1002542

    PubMed Central  PubMed  Google Scholar 

  184. Yin W, Keller NP (2011) Transcriptional regulatory elements in fungal secondary metabolism. J Microbiol 49:329–339

    CAS  PubMed Central  PubMed  Google Scholar 

  185. Yin WB, Baccile JA, Bok JW, Chen Y, Keller NP, Schroeder FC (2013) A nonribosomal peptide synthetase-derived iron(III) complex from the pathogenic fungus Aspergillus fumigatus. J Am Chem Soc 135:2064–2067

    CAS  PubMed  Google Scholar 

  186. Yin WB, Chooi YH, Smith AR, Cacho RA, Hu Y, White TC, Tang Y (2013) Discovery of cryptic polyketide metabolites from dermatophytes using heterologous expression in Aspergillus nidulans. ACS Synth Biol. doi:10.1021/sb400048b

  187. Zabala AO, Xu W, Chooi YH, Tang Y (2012) Characterization of a silent azaphilone gene cluster from Aspergillus niger ATCC 1015 reveals a hydroxylation-mediated pyran-ring formation. Chem Biol 19:1049–1059

    CAS  PubMed Central  PubMed  Google Scholar 

  188. Zhou H, Gao Z, Qiao K, Wang J, Vederas JC, Tang Y (2012) A fungal ketoreductase domain that displays substrate-dependent stereospecificity. Nat Chem Biol 8:331–333

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Nancy P. Keller.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wiemann, P., Keller, N.P. Strategies for mining fungal natural products. J Ind Microbiol Biotechnol 41, 301–313 (2014). https://doi.org/10.1007/s10295-013-1366-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10295-013-1366-3

Keywords

Navigation