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Genome Mining for Fungal Secondary Metabolic Gene Clusters

  • Grayson T. Wawrzyn
  • Mark A. Held
  • Sarah E. Bloch
  • Claudia Schmidt-DannertEmail author
Part of the Fungal Biology book series (FUNGBIO)

Abstract

Fungi are known for their ability to produce a vast array of valuable chemical compounds, which are utilized in biotechnology and the pharmaceutical industry. In this chapter, we outline recent advances in the development of genomic and bioinformatics resources for the discovery of genes involved in natural product biosynthesis, focusing on the major natural product classes: polyketides, nonribosomal peptides, and terpenes. These groups of compounds are all produced from simple, scaffold molecules that are further modified to create a diverse portfolio of bioactive products. Biosynthetic clusters of genes responsible for the production of these compounds are prolific in fungal systems and typically include key scaffold-producing enzymes and a multitude of modification enzymes. This chapter highlights how the recent explosion in bioinformatics tools and genomic resources can be applied to mining fungal genomes for the novel natural product biosynthetic pathways, providing key examples of well-studied fungal biosynthetic gene clusters.

Keywords

Fungal metabolites Genome mining Polyketide Nonribosomal peptide Terpene Bioinformatics Natural products 

Notes

Acknowledgements

Research on terpenoid biosynthesis in C.S-D’s laboratory is supported by the National Institute of Health Grant GM080299 (to C.S-D.). G.T.W. and S.E.B. were supported by the predoctoral National Institute of Health traineeship: GM08700 (G.T.W.) and GM008347 (S.E.B.).

References

  1. 1.
    Stajich JE, Wilke SK, Ahren D, Au CH, Birren BW, Borodovsky M et al (2010 Jun 29) Insights into evolution of multicellular fungi from the assembled chromosomes of the mushroom Coprinopsis cinerea (Coprinus cinereus). Proc Natl Acad Sci USA 107(26):11889–11894PubMedCentralPubMedGoogle Scholar
  2. 2.
    Blackwell M (2011 Mar) The fungi: 1, 2, 3.. 5.1 million species? Am J Bot 98(3):426–438PubMedGoogle Scholar
  3. 3.
    Elisashvili V (2012) Submerged cultivation of medicinal mushrooms: bioprocesses and products (review). Int J Med Mushrooms 14(3):211–239PubMedGoogle Scholar
  4. 4.
    Hu F, Liu J, Du G, Hua Z, Zhou J, Chen J (2012 Aug) Key cytomembrane abc transporters of Saccharomyces cerevisiae fail to improve the tolerance to d-limonene. Biotechnol Lett 34(8):1505–1509PubMedGoogle Scholar
  5. 5.
    Kang J, Park J, Choi H, Burla B, Kretzschmar T, Lee Y et al (2011) Plant ABC transporters. Arabidopsis Book 9:e0153PubMedCentralPubMedGoogle Scholar
  6. 6.
    Brase S, Encinas A, Keck J, Nising CF (2009 Sep) Chemistry and biology of mycotoxins and related fungal metabolites. Chem Rev 109(9):3903–3990PubMedGoogle Scholar
  7. 7.
    Zhong JJ, Xiao JH (2009) Secondary metabolites from higher fungi: discovery, bioactivity, and bioproduction. Adv Biochem Eng Biotechnol 113:79–150PubMedGoogle Scholar
  8. 8.
    Lindequist U, Niedermeyer THJ, Julich WD (2005) The pharmacological potential of mushrooms. Evid Based Complement Alternat Med 2(3):285–299PubMedCentralPubMedGoogle Scholar
  9. 9.
    Alves MJ, Ferreira IC, Dias J, Teixeira V, Martins A, Pintado M (2012 Nov) A review on antimicrobial activity of mushroom (basidiomycetes) extracts and isolated compounds. Planta Med 78(16):1707–1718PubMedGoogle Scholar
  10. 10.
    Zjawiony JK (2004 Feb) Biologically active compounds from Aphyllophorales (polypore) fungi. J Nat Prod 67(2):300–310PubMedGoogle Scholar
  11. 11.
    Wawrzyn GT, Quin MB, Choudhary S, Lopez-Gallego F, Schmidt-Dannert C (2012 Jun 22) Draft genome of omphalotus olearius provides a predictive framework for sesquiterpenoid natural product biosynthesis in basidiomycota. Chem Biol 19(6):772–783PubMedCentralPubMedGoogle Scholar
  12. 12.
    Agger S, Lopez-Gallego F, Schmidt-Dannert C (2009 Jun) Diversity of sesquiterpene synthases in the basidiomycete Coprinus cinereus. Mol Microbiol 72(5):1181–1195PubMedCentralPubMedGoogle Scholar
  13. 13.
    Lopez-Gallego F, Wawrzyn GT, Schmidt-Dannert C (2010 Dec) Selectivity of fungal sesquiterpene synthases: role of the active site’s h-1 a loop in catalysis. Appl Environ Microbiol 76(23):7723–7733PubMedCentralPubMedGoogle Scholar
  14. 14.
    Lopez-Gallego F, Agger SA, Abate-Pella D, Distefano MD, Schmidt-Dannert C (2010 May) Sesquiterpene synthases cop4 and cop6 from Coprinus cinereus: catalytic promiscuity and cyclization of farnesyl pyrophosphate geometric isomers. Chembiochem [Article] 11(8):1093–1106PubMedCentralPubMedGoogle Scholar
  15. 15.
    Wackler B, Lackner G, Chooi YH, Hoffmeister D (2012 Aug 13) Characterization of the Suillus grevillei quinone synthetase grea supports a nonribosomal code for aromatic alpha-keto acids. Chembiochem 13(12):1798–1804PubMedGoogle Scholar
  16. 16.
    Schneider P, Bouhired S, Hoffmeister D (2008 Nov) Characterization of the atromentin biosynthesis genes and enzymes in the homobasidiomycete Tapinella panuoides. Fungal Genet Biol 45(11):1487–1496PubMedGoogle Scholar
  17. 17.
    Winterberg B, Uhlmann S, Linne U, Lessing F, Marahiel MA, Eichhorn H et al (2010 Mar) Elucidation of the complete ferrichrome a biosynthetic pathway in Ustilago maydis. Mol Microbiol 75(5):1260–1271PubMedGoogle Scholar
  18. 18.
    Welzel K, Eisfeld K, Antelo L, Anke T, Anke H (2005 Aug 1) Characterization of the ferrichrome a biosynthetic gene cluster in the homobasidiomycete Omphalotus olearius. FEMS Microbiol Lett 249(1):157–163PubMedGoogle Scholar
  19. 19.
    Quin MB, Wawrzyn G, Schmidt-Dannert C (2013 May) Purification, crystallization and preliminary x-ray diffraction analysis of omp6, a protoilludene synthase from Omphalotus olearius. Acta Crystallogr Sect F Struct Biol Cryst Commun 69(5):574–577PubMedCentralPubMedGoogle Scholar
  20. 20.
    Bushley KE, Ripoll DR, Turgeon BG (2008 Dec 3) Module evolution and substrate specificity of fungal nonribosomal peptide synthetases involved in siderophore biosynthesis. BMC Evol Biol 8(328). doi:10.1186/1471-2148-8-328PubMedCentralPubMedGoogle Scholar
  21. 21.
    Bushley KE, Turgeon BG (2010 Jan 26) Phylogenomics reveals subfamilies of fungal nonribosomal peptide synthetases and their evolutionary relationships. BMC Evol Biol 10(26). doi:10.1186/1471-2148-10-26Google Scholar
  22. 22.
    Condon BJ, Leng YQ, Wu DL, Bushley KE, Ohm RA, Otillar R et al (2013 Jan) Comparative genome structure, secondary metabolite, and effector coding capacity across Cochliobolus pathogens. Plos Genet 9(1):e1003233PubMedCentralPubMedGoogle Scholar
  23. 23.
    Turgeon BG, Oide S, Bushley K (2008 Feb) Creating and screening Cochliobolus heterostrophus non-ribosomal peptide synthetase mutants. Mycol Res 112(Pt 2):200–206PubMedGoogle Scholar
  24. 24.
    Bushley KE, Raja R, Jaiswal P, Cumbie JS, Nonogaki M, Boyd AE et al (2013) The genome of Tolypocladium inflatum: evolution, organization and expression of the cyclosporin biosynthetic gene cluster. PLoS Genet 9(6):e1003496PubMedCentralPubMedGoogle Scholar
  25. 25.
    Martin F, Cullen D, Hibbett D, Pisabarro A, Spatafora JW, Baker SE et al (2011 Jun) Sequencing the fungal tree of life. New Phytol 190(4):818–821PubMedGoogle Scholar
  26. 26.
    Gibson DM, King BC, Hayes ML, Bergstrom GC (2011 Jun) Plant pathogens as a source of diverse enzymes for lignocellulose digestion. Curr Opin Microbiol 14(3):264–270PubMedGoogle Scholar
  27. 27.
    Shendure J, Lieberman Aiden E (2012 Nov) The expanding scope of DNA sequencing. Nat Biotechnol 30(11):1084–1094PubMedCentralPubMedGoogle Scholar
  28. 28.
    Morin E, Kohler A, Baker AR, Foulongne-Oriol M, Lombard V, Nagy LG et al (2012 Oct 23) Genome sequence of the button mushroom Agaricus bisporus reveals mechanisms governing adaptation to a humic-rich ecological niche. Proc Natl Acad Sci USA 109(43):17501–17506PubMedCentralPubMedGoogle Scholar
  29. 29.
    Chen S, Xu J, Liu C, Zhu Y, Nelson DR, Zhou S et al (2012) Genome sequence of the model medicinal mushroom Ganoderma lucidum. Nat Commun 3:913PubMedCentralPubMedGoogle Scholar
  30. 30.
    Nishida H, Nagatsuka Y, Sugiyama J (2011) Draft genome sequencing of the enigmatic basidiomycete Mixia osmundae. J Gen Appl Microbiol 57(1):63–67PubMedGoogle Scholar
  31. 31.
    Ohm RA, de Jong JF, Lugones LG, Aerts A, Kothe E, Stajich JE et al (2010 Sep) Genome sequence of the model mushroom schizophyllum commune. Nat Biotechnol 28(9):957–963PubMedGoogle Scholar
  32. 32.
    Martinez D, Challacombe J, Morgenstern I, Hibbett D, Schmoll M, Kubicek CP et al (2009 Feb 10) Genome, transcriptome, and secretome analysis of wood decay fungus Postia placenta supports unique mechanisms of lignocellulose conversion. Proc Natl Acad Sci USA 106(6):1954–1959PubMedCentralPubMedGoogle Scholar
  33. 33.
    Martin F, Aerts A, Ahren D, Brun A, Danchin EG, Duchaussoy F et al (2008 Mar 6) The genome of Laccaria bicolor provides insights into mycorrhizal symbiosis. Nature 452(7183):88–92PubMedGoogle Scholar
  34. 34.
    Floudas D, Binder M, Riley R, Barry K, Blanchette RA, Henrissat B et al (2012 Jun 29) The Paleozoic origin of enzymatic lignin decomposition reconstructed from 31 fungal genomes. Science 336(6089):1715–1719PubMedGoogle Scholar
  35. 35.
    Fernandez-Fueyo E, Ruiz-Duenas FJ, Ferreira P, Floudas D, Hibbett DS, Canessa P et al (2012 Apr 3) Comparative genomics of Ceriporiopsis subvermispora and Phanerochaete chrysosporium provide insight into selective ligninolysis. Proc Natl Acad Sci USA 109(14):5458–5463PubMedCentralPubMedGoogle Scholar
  36. 36.
    Bao D, Gong M, Zheng H, Chen M, Zhang L, Wang H et al (2013) Sequencing and comparative analysis of the straw mushroom (Volvariella volvacea) genome. PLoS ONE 8(3):e58294PubMedCentralPubMedGoogle Scholar
  37. 37.
    Osbourn A (2010 Oct) Secondary metabolic gene clusters: evolutionary toolkits for chemical innovation. Trends Genet 26(10):449–457PubMedGoogle Scholar
  38. 38.
    Brakhage AA, Schroeckh V (2011 Jan) Fungal secondary metabolites—strategies to activate silent gene clusters. Fungal Gen Biol 48(1):15–22Google Scholar
  39. 39.
    Brakhage AA (2013 Jan) Regulation of fungal secondary metabolism. Nat Rev Microbiol 11(1):21–32PubMedGoogle Scholar
  40. 40.
    Yazaki K (2005 Jun) Transporters of secondary metabolites. Curr Opin Plant Biol 8(3):301–307PubMedGoogle Scholar
  41. 41.
    Prasad R, Goffeau A (2012) Yeast ATP-binding cassette transporters conferring multidrug resistance. Annu Rev Microbiol 66:39–63PubMedGoogle Scholar
  42. 42.
    Luzhetskyy A, Vente A, Bechthold A (2005 Jul) Glycosyltransferases involved in the biosynthesis of biologically active natural products that contain oligosaccharides. Mol Biosyst 1(2):117–126PubMedGoogle Scholar
  43. 43.
    Singh S, Phillips GN Jr, Thorson JS (2012 Oct) The structural biology of enzymes involved in natural product glycosylation. Nat Prod Rep 29(10):1201–1237PubMedCentralPubMedGoogle Scholar
  44. 44.
    Lim FY, Sanchez JF, Wang CC, Keller NP (2012) Toward awakening cryptic secondary metabolite gene clusters in filamentous fungi. Meth Enzymol 517:303–324PubMedCentralPubMedGoogle Scholar
  45. 45.
    Cresnar B, Petric S (2011 Jan) Cytochrome p450 enzymes in the fungal kingdom. Biochim Biophys Acta 1814(1):29–35PubMedGoogle Scholar
  46. 46.
    Podust LM, Sherman DH (2012 Oct) Diversity of P450 enzymes in the biosynthesis of natural products. Nat Prod Rep [Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov’t Review] 29(10):1251–1266PubMedCentralPubMedGoogle Scholar
  47. 47.
    Kelly DE, Krasevec N, Mullins J, Nelson DR (2009 Mar) The cypome (cytochrome P450 complement) of Aspergillus nidulans. Fungal Gen Biol [Research Support, Non-U.S. Gov’t] 46(Suppl 1):53–61Google Scholar
  48. 48.
    Barriuso J, Nguyen DT, Li JW, Roberts JN, MacNevin G, Chaytor JL et al (2011 Jun 1) Double oxidation of the cyclic nonaketide dihydromonacolin l to monacolin j by a single cytochrome P450 monooxygenase, LovA. J Am Chem Soc [Research Support Non-US Gov’t] 133(21):8078–8081PubMedGoogle Scholar
  49. 49.
    Artigot MP, Loiseau N, Laffitte J, Mas-Reguieg L, Tadrist S, Oswald IP et al (2009 May) Molecular cloning and functional characterization of two cyp619 cytochrome P450s involved in biosynthesis of patulin in Aspergillus clavatus. Microbiology [Research Support NIH Extramural Research Support Non-US Gov’t] 155(5):1738–1747PubMedCentralPubMedGoogle Scholar
  50. 50.
    Haarmann T, Ortel I, Tudzynski P, Keller U (2006 Apr) Identification of the cytochrome p450 monooxygenase that bridges the clavine and ergoline alkaloid pathways. Chembiochem [Research Support Non-US Gov’t] 7(4):645–652PubMedGoogle Scholar
  51. 51.
    Kelly SL, Kelly DE (2013 Feb 19) Microbial cytochromes P450: biodiversity and biotechnology. Where do cytochromes P450 come from, what do they do and what can they do for us? Philos Trans R Soc Lond B Biol Sci [Research Support NIH Extramural Research Support Non-US Govt Review] 368(1612):20120476PubMedCentralPubMedGoogle Scholar
  52. 52.
    Pinedo C, Wang CM, Pradier JM, Dalmais B, Choquer M, Le Pecheur P et al (2008 Dec 19) Sesquiterpene synthase from the botrydial biosynthetic gene cluster of the phytopathogen Botrytis cinerea. ACS Chem Biol 3(12):791–801PubMedCentralPubMedGoogle Scholar
  53. 53.
    Hohn TM, Beremand PD (1989 Jun) Isolation and nucleotide sequence of a sesquiterpene cyclase gene from the trichothecene producing fungus Fusarium sporotrichoides. Gene [Article] 79(1):131–138PubMedGoogle Scholar
  54. 54.
    Toyomasu T, Nakaminami K, Toshima H, Mie T, Watanabe K, Ito H et al (2004 Jan) Cloning of a gene cluster responsible for the biosynthesis of diterpene aphidicolin, a specific inhibitor of DNA polymerase alpha. Biosci Biotechnol Biochem [Article] 68(1):146–152PubMedGoogle Scholar
  55. 55.
    Toyomasu T, Tsukahara M, Kaneko A, Niida R, Mitsuhashi W, Dairi T et al (2007 Feb) Fusicoccins are biosynthesized by an unusual chimera diterpene synthase in fungi. Proc Natl Acad Sci USA [Article] 104(9):3084–3088PubMedCentralPubMedGoogle Scholar
  56. 56.
    Kimura M, Tokai T, O'Donnell K, Ward TJ, Fujimura M, Hamamoto H et al (2003 Mar 27) The trichothecene biosynthesis gene cluster of Fusarium graminearum F15 contains a limited number of essential pathway genes and expressed non-essential genes. FEBS Lett 539(1–3):105–110PubMedGoogle Scholar
  57. 57.
    Toyomasu T, Tsukahara M, Kenmoku H, Anada M, Nitta H, Ohkanda J et al (2009 Jul 16) Transannular proton transfer in the cyclization of geranylgeranyl diphosphate to fusicoccadiene, a biosynthetic intermediate of fusicoccins. Org Lett 11(14):3044–3047PubMedGoogle Scholar
  58. 58.
    Stanke M, Steinkamp R, Waack S, Morgenstern B (2004 Jul) Augustus: a web server for gene finding in eukaryotes. Nucleic Acids Res [Article] 32:W309–W312PubMedCentralPubMedGoogle Scholar
  59. 59.
    Chen B, Ling H, Chang MW (2013) Transporter engineering for improved tolerance against alkane biofuels in Saccharomyces cerevisiae. Biotechnol Biofuels 6(1):21PubMedCentralPubMedGoogle Scholar
  60. 60.
    Medema MH, Blin K, Cimermancic P, de Jager V, Zakrzewski P, Fischbach MA et al (2011 Jul) antiSMASH: rapid identification, annotation and analysis of secondary metabolite biosynthesis gene clusters in bacterial and fungal genome sequences. Nucleic Acids Res 39(Web Server issue):W339–346PubMedCentralPubMedGoogle Scholar
  61. 61.
    Blin K, Medema MH, Kazempour D, Fischbach MA, Breitling R, Takano E et al (2013 June 3) antiSMASH 2.0-a versatile platform for genome mining of secondary metabolite producers. Nucleic Acids Res 41:W204–12PubMedCentralPubMedGoogle Scholar
  62. 62.
    Kimura M, Tokai T, Takahashi-Ando N, Ohsato S, Fujimura M (2007 Sep) Molecular and genetic studies of Fusarium trichothecene biosynthesis: pathways, genes, and evolution. Biosci Biotechnol Biochem 71(9):2105–2123PubMedGoogle Scholar
  63. 63.
    Csuros M, Rogozin IB, Koonin EV (2011 Sep) A detailed history of intron-rich eukaryotic ancestors inferred from a global survey of 100 complete genomes. PLoS Comput Biol 7(9):e1002150PubMedCentralPubMedGoogle Scholar
  64. 64.
    Freitag J, Ast J, Bolker M (2012 May 24) Cryptic peroxisomal targeting via alternative splicing and stop codon read-through in fungi. Nature 485(7399):522–525PubMedGoogle Scholar
  65. 65.
    Larsen PE, Trivedi G, Sreedasyam A, Lu V, Podila GK, Collart FR (2010) Using deep RNA sequencing for the structural annotation of the Laccaria bicolor mycorrhizal transcriptome. PLoS ONE 5(7):e9780PubMedCentralPubMedGoogle Scholar
  66. 66.
    Misiek M, Braesel J, Hoffmeister D (2011 Aug) Characterisation of the ArmA adenylation domain implies a more diverse secondary metabolism in the genus Armillaria. Fungal Biol 115(8):775–781PubMedGoogle Scholar
  67. 67.
    Misiek M, Hoffmeister D (2008 Feb) Processing sites involved in intron splicing of Armillaria natural product genes. Mycol Res [Article] 112:216–224PubMedGoogle Scholar
  68. 68.
    Wawrzyn GT, Bloch SE, Schmidt-Dannert C (2012) Discovery and characterization of terpenoid biosynthetic pathways of fungi. Meth Enzymol 515:83–105PubMedGoogle Scholar
  69. 69.
    Keller O, Kollmar M, Stanke M, Waack S (2011 Mar 15) A novel hybrid gene prediction method employing protein multiple sequence alignments. Bioinformatics [Research Support Non-US Gov’t] 27(6):757–763PubMedGoogle Scholar
  70. 70.
    Yu GJ, Wang M, Huang J, Yin YL, Chen YJ, Jiang S et al (2012) Deep insight into the Ganoderma lucidum by comprehensive analysis of its transcriptome. PLoS ONE 7(8):e44031PubMedCentralPubMedGoogle Scholar
  71. 71.
    McGettigan PA (2013 Feb) Transcriptomics in the RNA-seq era. Curr Opin Chem Biol [Research Support Non-US Govt Review] 17(1):4–11PubMedGoogle Scholar
  72. 72.
    Noble LM, Andrianopoulos A (2013 May 21) Fungal genes in context: genome architecture reflects regulatory complexity and function. Genome Biol Evol 5(7):1336–52PubMedCentralPubMedGoogle Scholar
  73. 73.
    Yin W, Keller NP (2011 Jun) Transcriptional regulatory elements in fungal secondary metabolism. J Microbiol 49(3):329–339PubMedCentralPubMedGoogle Scholar
  74. 74.
    Bayram O, Braus GH (2012 Jan) Coordination of secondary metabolism and development in fungi: the velvet family of regulatory proteins. FEMS Microbiol Rev 36(1):1–24PubMedGoogle Scholar
  75. 75.
    Ohm RA, de Jong JF, de Bekker C, Wosten HA, Lugones LG (2011 Sep) Transcription factor genes of Schizophyllum commune involved in regulation of mushroom formation. Mol Microbiol 81(6):1433–1445PubMedGoogle Scholar
  76. 76.
    Hur M, Campbell AA, Almeida-de-Macedo M, Li L, Ransom N, Jose A et al (2013) A global approach to analysis and interpretation of metabolic data for plant natural product discovery. Nat Product Rep 30(4):565–583Google Scholar
  77. 77.
    Higashi Y, Saito K (2013 Jan 21) Network analysis for gene discovery in plant-specialized metabolism. Plant Cell Environ 36(9):1597–606PubMedGoogle Scholar
  78. 78.
    Andersen MR, Nielsen JB, Klitgaard A, Petersen LM, Zachariasen M, Hansen TJ et al (2013 Jan 2) Accurate prediction of secondary metabolite gene clusters in filamentous fungi. Proc Natl Acad Sci USA 110(1):E99–E107PubMedCentralPubMedGoogle Scholar
  79. 79.
    Chooi YH, Tang Y (2012 Nov 16) Navigating the fungal polyketide chemical space: from genes to molecules. J Org Chem 77(22):9933–9953PubMedCentralPubMedGoogle Scholar
  80. 80.
    Evans BS, Robinson SJ, Kelleher NL (2011 Jan) Surveys of non-ribosomal peptide and polyketide assembly lines in fungi and prospects for their analysis in vitro and in vivo. Fungal Genet Biol 48(1):49–61PubMedCentralPubMedGoogle Scholar
  81. 81.
    Boettger D, Hertweck C (2013 Jan 2) Molecular diversity sculpted by fungal PKS-NRPS hybrids. Chembiochem 14(1):28–42PubMedGoogle Scholar
  82. 82.
    Donadio S, Monciardini P, Sosio M (2007 Oct) Polyketide synthases and nonribosomal peptide synthetases: the emerging view from bacterial genomics. Nat Prod Rep 24(5):1073–1109PubMedGoogle Scholar
  83. 83.
    Paumi CM, Chuk M, Snider J, Stagljar I, Michaelis S (2009 Dec) ABC transporters in Saccharomyces cerevisiae and their interactors: new technology advances the biology of the ABCC (MRP) subfamily. Microbiol Mol Biol Rev 73(4):577–593PubMedCentralPubMedGoogle Scholar
  84. 84.
    Wang X (2009 Oct 20) Structure, mechanism and engineering of plant natural product glycosyltransferases. FEBS Lett 583(20):3303–3309PubMedGoogle Scholar
  85. 85.
    Crouzet J, Roland J, Peeters E, Trombik T, Ducos E, Nader J et al (2013 May) Ntpdr1, a plasma membrane ABC transporter from Nicotiana tabacum, is involved in diterpene transport. Plant Mol Biol 82(1–2):181–192PubMedGoogle Scholar
  86. 86.
    Gupta RP, Kueppers P, Schmitt L, Ernst R (2011 Jan) The multidrug transporter Pdr5: a molecular diode? Biol Chem 392(1–2):53–60PubMedGoogle Scholar
  87. 87.
    Syed K, Yadav JS (2012 Nov) P450 monooxygenases (P450ome) of the model white rot fungus Phanerochaete chrysosporium. Crit Rev Microbiol 38(4):339–363PubMedCentralPubMedGoogle Scholar
  88. 88.
    Hansen FT, Sorensen JL, Giese H, Sondergaard TE, Frandsen RJ (2012 Apr 16) Quick guide to polyketide synthase and nonribosomal synthetase genes in Fusarium. Int J Food Microbiol 155(3):128–136PubMedGoogle Scholar
  89. 89.
    Sa-Correia I, dos Santos SC, Teixeira MC, Cabrito TR, Mira NP (2009 Jan) Drug:H+ antiporters in chemical stress response in yeast. Trends Microbiol 17(1):22–31PubMedGoogle Scholar
  90. 90.
    Kretzschmar T, Burla B, Lee Y, Martinoia E, Nagy R (2011 Sep 7) Functions of ABC transporters in plants. Essays Biochem 50(1):145–160PubMedGoogle Scholar
  91. 91.
    Wendlandt S, Lozano C, Kadlec K, Gomez-Sanz E, Zarazaga M, Torres C et al (2013 Feb) The enterococcal ABC transporter gene lsa(E) confers combined resistance to lincosamides, pleuromutilins and streptogramin A antibiotics in methicillin-susceptible and methicillin-resistant Staphylococcus aureus. J Antimicrob Chemother 68(2):473–475PubMedGoogle Scholar
  92. 92.
    Ma SM, Li JW, Choi JW, Zhou H, Lee KK, Moorthie VA et al (2009 Oct 23) Complete reconstitution of a highly reducing iterative polyketide synthase. Science 326(5952):589–592PubMedCentralPubMedGoogle Scholar
  93. 93.
    Rugbjerg P, Naesby M, Mortensen UH, Frandsen RJ (2013 Apr 4) Reconstruction of the biosynthetic pathway for the core fungal polyketide scaffold rubrofusarin in Saccharomyces cerevisiae. Microb Cell Fact 12(1):31PubMedCentralPubMedGoogle Scholar
  94. 94.
    Lackner G, Misiek M, Braesel J, Hoffmeister D (2012 Dec) Genome mining reveals the evolutionary origin and biosynthetic potential of basidiomycete polyketide synthases. Fungal Genet Biol 49(12):996–1003PubMedGoogle Scholar
  95. 95.
    Proctor RH, Brown DW, Plattner RD, Desjardins AE (2003 Mar) Co-expression of 15 contiguous genes delineates a fumonisin biosynthetic gene cluster in Gibberella moniliformis. Fungal Genet Biol 38(2):237–249PubMedGoogle Scholar
  96. 96.
    Ro DK, Ouellet M, Paradise EM, Burd H, Eng D, Paddon CJ et al (2008) Induction of multiple pleiotropic drug resistance genes in yeast engineered to produce an increased level of anti-malarial drug precursor, artemisinic acid. BMC Biotechnol 8:83PubMedCentralPubMedGoogle Scholar
  97. 97.
    Soukup AA, Chiang YM, Bok JW, Reyes-Dominguez Y, Oakley BR, Wang CC et al (2012 Oct) Overexpression of the Aspergillus nidulans histone 4 acetyltransferase EsaA increases activation of secondary metabolite production. Mol Microbiol 86(2):314–330PubMedCentralPubMedGoogle Scholar
  98. 98.
    Christianson DW (2008 Apr) Unearthing the roots of the terpenome. Curr Opin Chem Biol 12(2):141–150PubMedCentralPubMedGoogle Scholar
  99. 99.
    Davis EM, Croteau R (2000) Cyclization enzymes in the biosynthesis of monoterpenes, sesquiterpenes, and diterpenes. Biosynthesis: aromatic polyketides, isoprenoids, alkaloids. Springer, Berlin, p 53–95Google Scholar
  100. 100.
    Mitsuguchi H, Seshime Y, Fujii I, Shibuya M, Ebizuka Y, Kushiro T (2009 May 13) Biosynthesis of steroidal antibiotic fusidanes: functional analysis of oxidosqualene cyclase and subsequent tailoring enzymes from Aspergillus fumigatus. J Am Chem Soc 131(18):6402–6411PubMedGoogle Scholar
  101. 101.
    Kimura M, Kushiro T, Shibuya M, Ebizuka Y, Abe I (2010 Jan 1) Protostadienol synthase from Aspergillus fumigatus: functional conversion into lanosterol synthase. Biochem Biophys Res Commun 391(1):899–902PubMedGoogle Scholar
  102. 102.
    Cane DE, Kang I (2000 Apr 15) Aristolochene synthase: purification, molecular cloning, high-level expression in Escherichia coli, and characterization of the Aspergillus terreus cyclase. Arch Biochem Biophys 376(2):354–364PubMedGoogle Scholar
  103. 103.
    Proctor RH, Hohn TM (1993 Feb) Aristolochene synthase—isolation, characterization, and bacterial expression of a sesquiterpenoid biosynthetic gene (Ari1) from Penicillium roqueforti. J Biol Chem [Article] 268(6):4543–4548PubMedGoogle Scholar
  104. 104.
    Engels B, Heinig U, Grothe T, Stadler M, Jennewein S (2011 Mar 4) Cloning and characterization of an Armillaria gallica cDNA encoding protoilludene synthase, which catalyzes the first committed step in the synthesis of antimicrobial melleolides. J Biol Chem 286(9):6871–6878PubMedCentralPubMedGoogle Scholar
  105. 105.
    McCormick SP, Alexander NJ, Harris LJ (2010 Jan) Clm1 of Fusarium graminearum encodes a longiborneol synthase required for culmorin production. Appl Environ Microbiol 76(1):136–141PubMedCentralPubMedGoogle Scholar
  106. 106.
    Brock NL, Tudzynski B, Dickschat JS (2011 Oct 11) Biosynthesis of sesqui- and diterpenes by the gibberellin producer Fusarium fujikuroi. Chembiochem 12(17):2667–12PubMedGoogle Scholar
  107. 107.
    Quin MB, Flynn CM, Wawrzyn GT, Choudhary S, Schmidt-Dannert C (2013) Mushroom hunting using bioinformatics: application of a predictive framework facilitates the selective identification of sesquiterpene synthases in basidiomycota. Chembiochem 14(18):2480–91PubMedGoogle Scholar
  108. 108.
    Citron CA, Gleitzmann J, Laurenzano G, Pukall R, Dickschat JS (2012 Jan 23) Terpenoids are widespread in actinomycetes: a correlation of secondary metabolism and genome data. Chembiochem 13(2):202–214PubMedGoogle Scholar
  109. 109.
    Novak R (2011 Dec) Are pleuromutilin antibiotics finally fit for human use? Ann N Y Acad Sci 1241:71–81PubMedGoogle Scholar
  110. 110.
    Shen JW, Ruan Y, Ma BJ (2009 Jun) Diterpenoids of macromycetes. J Basic Microbiol 49(3):242–255PubMedGoogle Scholar
  111. 111.
    Toyomasu T (2008 May) Recent advances regarding diterpene cyclase genes in higher plants and fungi. Biosci Biotechnol Biochem 72(5):1168–1175PubMedGoogle Scholar
  112. 112.
    Troncoso C, Gonzalez X, Bomke C, Tudzynski B, Gong F, Hedden P et al (2010 Aug) Gibberellin biosynthesis and gibberellin oxidase activities in Fusarium sacchari, Fusarium konzum and Fusarium subglutinans strains. Phytochemistry 71(11–12):1322–1331PubMedGoogle Scholar
  113. 113.
    Bomke C, Tudzynski B (2009 Oct-Nov) Diversity, regulation, and evolution of the gibberellin biosynthetic pathway in fungi compared to plants and bacteria. Phytochemistry 70(15–16):1876–1893PubMedGoogle Scholar
  114. 114.
    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(4):e35450PubMedCentralPubMedGoogle Scholar
  115. 115.
    Noike M, Liu C, Ono Y, Hamano Y, Toyomasu T, Sassa T et al (2012 Mar 5) An enzyme catalyzing O-prenylation of the glucose moiety of fusicoccin A, a diterpene glucoside produced by the fungus Phomopsis amygdali. Chembiochem 13(4):566–573PubMedGoogle Scholar
  116. 116.
    Noike M, Ono Y, Araki Y, Tanio R, Higuchi Y, Nitta H et al (2012) Molecular breeding of a fungus producing a precursor diterpene suitable for semi-synthesis by dissection of the biosynthetic machinery. PLoS ONE 7(8):e42090PubMedCentralPubMedGoogle Scholar
  117. 117.
    Ono Y, Minami A, Noike M, Higuchi Y, Toyomasu T, Sassa T et al (2011 Mar 2) Dioxygenases, key enzymes to determine the aglycon structures of fusicoccin and brassicicene, diterpene compounds produced by fungi. J Am Chem Soc 133(8):2548–2555PubMedGoogle Scholar
  118. 118.
    Toyomasu T, Kaneko A, Tokiwano T, Kanno Y, Kanno Y, Niida R et al (2009 Feb 20) Biosynthetic gene-based secondary metabolite screening: a new diterpene, methyl phomopsenonate, from the fungus Phomopsis amygdali. J Org Chem 74(4):1541–1548PubMedGoogle Scholar
  119. 119.
    Toyomasu T, Niida R, Kenmoku H, Kanno Y, Miura S, Nakano C et al (2008 Apr) Identification of diterpene biosynthetic gene clusters and functional analysis of labdane-related diterpene cyclases in Phomopsis amygdali. Biosci Biotechnol Biochem 72(4):1038–1047PubMedGoogle Scholar
  120. 120.
    Fujii R, Minami A, Tsukagoshi T, Sato N, Sahara T, Ohgiya S et al (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(9):1813–1817PubMedGoogle Scholar
  121. 121.
    Chiba R, Minami A, Gomi K, Oikawa H (2013 Feb 1) Identification of ophiobolin F synthase by a genome mining approach: a sesterterpene synthase from Aspergillus clavatus. Org Lett 15(3):594–597PubMedGoogle Scholar
  122. 122.
    Itoh T, Tokunaga K, Matsuda Y, Fujii I, Abe I, Ebizuka Y et al (2010 Oct) Reconstitution of a fungal meroterpenoid biosynthesis reveals the involvement of a novel family of terpene cyclases. Nat Chem 2(10):858–864PubMedGoogle Scholar
  123. 123.
    Guo CJ, Knox BP, Chiang YM, Lo HC, Sanchez JF, Lee KH et al (2012 Nov 16) Molecular genetic characterization of a cluster in A. terreus for biosynthesis of the meroterpenoid terretonin. Org Lett 14(22):5684–5687PubMedCentralPubMedGoogle Scholar
  124. 124.
    Matsuda Y, Awakawa T, Itoh T, Wakimoto T, Kushiro T, Fujii I et al (2012 Aug 13) Terretonin biosynthesis requires methylation as essential step for cyclization. Chembiochem 13(12):1738–1741PubMedGoogle Scholar
  125. 125.
    Itoh T, Tokunaga K, Radhakrishnan EK, Fujii I, Abe I, Ebizuka Y et al (2012 May 29) Identification of a key prenyltransferase involved in biosynthesis of the most abundant fungal meroterpenoids derived from 3,5-dimethylorsellinic acid. Chembiochem 13(8):1132–1135PubMedGoogle Scholar
  126. 126.
    Lin HC, Chooi YH, Dhingra S, Xu W, Calvo AM, Tang Y (2013 Mar 27) 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(12):4616–4619PubMedCentralPubMedGoogle Scholar
  127. 127.
    Lo HC, Entwistle R, Guo CJ, Ahuja M, Szewczyk E, Hung JH et al (2012 Mar 14) Two separate gene clusters encode the biosynthetic pathway for the meroterpenoids austinol and dehydroaustinol in Aspergillus nidulans. J Am Chem Soc 134(10):4709–4720PubMedCentralPubMedGoogle Scholar
  128. 128.
    Tagami K, Liu C, Minami A, Noike M, Isaka T, Fueki S et al (2013 Jan 30) Reconstitution of biosynthetic machinery for indole-diterpene paxilline in Aspergillus oryzae. J Am Chem Soc 135(4):1260–1263PubMedGoogle Scholar
  129. 129.
    Saikia S, Nicholson MJ, Young C, Parker EJ, Scott B (2008 Feb) The genetic basis for indole-diterpene chemical diversity in filamentous fungi. Mycol Res 112(Pt 2):184–199PubMedGoogle Scholar
  130. 130.
    Young C, McMillan L, Telfer E, Scott B (2001 Feb) Molecular cloning and genetic analysis of an indole-diterpene gene cluster from Penicillium paxilli. Mol Microbiol 39(3):754–764PubMedGoogle Scholar
  131. 131.
    Young CA, Felitti S, Shields K, Spangenberg G, Johnson RD, Bryan GT et al (2006 Oct) A complex gene cluster for indole-diterpene biosynthesis in the grass endophyte Neotyphodium lolii. Fungal Gen Biol 43(10):679–693Google Scholar
  132. 132.
    Young CA, Tapper BA, May K, Moon CD, Schardl CL, Scott B (2009 Apr) Indole-diterpene biosynthetic capability of Epichloë endophytes as predicted by ltm gene analysis. Appl Environ Microbiol 75(7):2200–2211PubMedCentralPubMedGoogle Scholar
  133. 133.
    Teixeira MC, Godinho CP, Cabrito TR, Mira NP, Sa-Correia I (2012) Increased expression of the yeast multidrug resistance ABC transporter Pdr18 leads to increased ethanol tolerance and ethanol production in high gravity alcoholic fermentation. Microb Cell Fact 11:98PubMedCentralPubMedGoogle Scholar
  134. 134.
    Paddon CJ, Westfall PJ, Pitera DJ, Benjamin K, Fisher K, McPhee D et al (2013 Apr 25) High-level semi-synthetic production of the potent antimalarial artemisinin. Nature 496(7446):528–532PubMedGoogle Scholar
  135. 135.
    Chanda A, Roze LV, Linz JE (2010 Nov) A possible role for exocytosis in aflatoxin export in Aspergillus parasiticus. Eukaryot Cell 9(11):1724–1727PubMedCentralPubMedGoogle Scholar
  136. 136.
    Chanda A, Roze LV, Kang S, Artymovich KA, Hicks GR, Raikhel NV et al (2009 Nov 17) A key role for vesicles in fungal secondary metabolism. Proc Natl Acad Sci USA 106(46):19533–19538PubMedCentralPubMedGoogle Scholar
  137. 137.
    Menke J, Weber J, Broz K, Kistler HC (2013) Cellular development associated with induced mycotoxin synthesis in the filamentous fungus Fusarium graminearum. PLoS ONE 8(5):e63077PubMedCentralPubMedGoogle Scholar
  138. 138.
    Menke J, Dong Y, Kistler HC (2012 Nov) Fusarium graminearum Tri12p influences virulence to wheat and trichothecene accumulation. Mol Plant Microbe Interact 25(11):1408–1418PubMedGoogle Scholar
  139. 139.
    Bai J, Swartz DJ, Protasevich, II, Brouillette CG, Harrell PM, Hildebrandt E et al (2011) A gene optimization strategy that enhances production of fully functional P-glycoprotein in Pichia pastoris. PLoS ONE 6(8):e22577PubMedCentralPubMedGoogle Scholar
  140. 140.
    Bernier SG, Lazarus DD, Clark E, Doyle B, Labenski MT, Thompson CD et al (2004 Jul 20) A methionine aminopeptidase-2 inhibitor, PPI-2458, for the treatment of rheumatoid arthritis. Proc Natl Acad Sci USA 101(29):10768–10773PubMedCentralPubMedGoogle Scholar
  141. 141.
    Schobert R, Knauer S, Seibt S, Biersack B (2011) Anticancer active illudins: recent developments of a potent alkylating compound class. Curr Med Chem 18(6):790–807PubMedGoogle Scholar
  142. 142.
    Seong KY, Pasquali M, Zhou X, Song J, Hilburn K, McCormick S et al (2009 Apr) Global gene regulation by Fusarium transcription factors Tri6 and Tri10 reveals adaptations for toxin biosynthesis. Mol Microbiol 72(2):354–367PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Grayson T. Wawrzyn
    • 1
  • Mark A. Held
    • 1
  • Sarah E. Bloch
    • 1
  • Claudia Schmidt-Dannert
    • 1
    Email author
  1. 1.Department of Biochemistry, Molecular Biology and BiophysicsUniversity of MinnesotaSt. PaulUSA

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