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Tremorgenic and neurotoxic paspaline-derived indole-diterpenes: biosynthetic diversity, threats and applications

  • László Kozák
  • Zoltán Szilágyi
  • László Tóth
  • István Pócsi
  • István Molnár
Mini-Review
  • 63 Downloads

Abstract

Indole-diterpenes (IDTs) such as the aflatrems, janthitrems, lolitrems, paspalitrems, penitrems, shearinines, sulpinines, and terpendoles are biogenetically related but structurally varied tremorgenic and neurotoxic mycotoxins produced by fungi. All these metabolites derive from the biosynthetic intermediate paspaline, a frequently occurring IDT on its own right. In this comprehensive review, we highlight the similarities and differences of the IDT biosynthetic pathways that lead to the generation of the main paspaline-derived IDT subgroups. We survey the taxonomic distribution and the regulation of IDT production in various fungi and compare the organization of the known IDT biosynthetic gene clusters. A detailed assessment of the highly diverse biological activities of these mycotoxins leads us to emphasize the significant losses that paspaline-derived IDTs cause in agriculture, and compels us to warn about the various hazards they represent towards human and livestock health. Conversely, we also describe the potential utility of these versatile molecules as lead compounds for pharmaceutical drug discovery, and examine the prospects for their industrial scale manufacture in genetically manipulated IDT producers or domesticated host microorganisms in synthetic biological production systems.

Keywords

Indole-diterpene Fungal secondary metabolite Biosynthesis Mycotoxin Food and feed safety Drug discovery Heterologous production 

Notes

Funding information

This work was supported by the European Union and the European Social Fund through the project EFOP-3.6.1-16-2016-00022 (to I. P.), the Higher Education Institutional Excellence Program of the Ministry of Human Capacities in Hungary (Biotechnology thematic program to I. P. and I. M.) and the U.S. National Institutes of Health (NIGMS 5R01GM114418 to I. M.).

Compliance with ethical standards

Conflict of interest

I. P. declares no conflict of interests. I. M. has disclosed financial interests in Teva Pharmaceuticals Works Ltd., Hungary, and DSM Nutritional Products, LLC, USA, which are unrelated to the subject of the research presented here. L. K., Z. S., and L. T. are employees of Teva Pharmaceutical Works Ltd., Hungary. Responsibility for the conclusions drawn, and the opinions expressed in this article are solely those of the authors and are not shared by Teva Pharmaceutical Works Ltd.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the Authors.

Supplementary material

253_2018_9594_MOESM1_ESM.pdf (518 kb)
ESM 1 (PDF 517 kb)

References

  1. Aaronson S (1988) Paspalum spp. and Claviceps paspali in ancient and modern India. J Ethnopharmacol 24:345–348CrossRefPubMedGoogle Scholar
  2. Andersen AJC, Hansen PJ, Joergensen K, Nielsen KF (2016) Dynamic cluster analysis: an unbiased method for identifying A + 2 element containing compounds in liquid chromatographic high-resolution time-of-flight mass spectrometric data. Anal Chem 88:12461–12469.  https://doi.org/10.1021/acs.analchem.6b03902 CrossRefPubMedGoogle Scholar
  3. Andersen B, Frisvad JC (2004) Natural occurrence of fungi and fungal metabolites in moldy tomatoes. J Agric Food Chem 52:7507–7513.  https://doi.org/10.1021/jf048727k CrossRefPubMedGoogle Scholar
  4. Anderson RA, Joyce C, Davis M, Reagan JW, Clark M, Shelness GS, Rudel LL (1998) Identification of a form of acyl-CoA:cholesterol acyltransferase specific to liver and intestine in nonhuman primates. J Biol Chem 273:26747–26754.  https://doi.org/10.1074/jbc.273.41.26747 CrossRefPubMedGoogle Scholar
  5. Arcamone F, Bonino C, Chain EB, Ferretti A, Pennella P, Tonolo A, Vero L (1960) Production of lysergic acid derivatives by a strain of Claviceps paspali Stevens and Hall in submerged culture. Nature 187:238–239.  https://doi.org/10.1038/187238a0 CrossRefPubMedGoogle Scholar
  6. Asano S, Bratz IN, Berwick ZC, Fancher IS, Tune JD, Dick GM (2012) Penitrem A as a tool for understanding the role of large conductance Ca2+/voltage-sensitive K+ channels in vascular function. J Pharmacol Exp Ther 342:453–460.  https://doi.org/10.1124/jpet.111.191072 CrossRefPubMedPubMedCentralGoogle Scholar
  7. Aue WP, Bartholdi E, Ernst RR (1976) Two-dimensional spectroscopy. Application to nuclear magnetic resonance. J Chem Phys 64:2229–2246.  https://doi.org/10.1063/1.432450 CrossRefGoogle Scholar
  8. Barbesgaard P, Heldt-Hansen H, Diderichsen B (1992) On the safety of Aspergillus oryzae: a review. Appl Microbiol Biotechnol 36:569–572.  https://doi.org/10.1007/BF00183230 CrossRefPubMedGoogle Scholar
  9. Bauer JI, Gross M, Cramer B, Wegner S, Hausmann H, Hamscher G, Usleber E (2017) Detection of the tremorgenic mycotoxin paxilline and its desoxy analog in ergot of rye and barley: a new class of mycotoxins added to an old problem. Anal Bioanal Chem 409:5101–5112.  https://doi.org/10.1007/s00216-017-0455-y CrossRefPubMedGoogle Scholar
  10. Belofsky GN, Gloer JB, Wicklow DT, Dowd PF (1995) Antiinsectan alkaloids: shearinines A-C and a new paxilline derivative from the ascostromata of Eupenicillium shearii. Tetrahedron 51:3959–3968.  https://doi.org/10.1016/0040-4020(95)00138-X CrossRefGoogle Scholar
  11. Berntsen HF, Bogen IL, Wigestrand MB, Fonnum F, Walaas SI, Moldes-Anaya A (2017) The fungal neurotoxin penitrem A induces the production of reactive oxygen species in human neutrophils at submicromolar concentrations. Toxicology 392:64–70.  https://doi.org/10.1016/j.tox.2017.10.008 CrossRefPubMedGoogle Scholar
  12. Botha CJ, Kellerman TS, Fourie N (1996) A tremorgenic mycotoxicosis in cattle caused by Paspalum distichum (l.) infected by Claviceps paspali. J S Afr Vet Assoc 67:36–37PubMedGoogle Scholar
  13. Bunger J (2004) Cytotoxicity of occupationally and environmentally relevant mycotoxins. Toxicology 202:199–211.  https://doi.org/10.1016/j.tox.2004.05.007 CrossRefPubMedGoogle Scholar
  14. Byrne KM, Smith SK, Ondeyka JG (2002) Biosynthesis of nodulisporic acid A: precursor studies. J Am Chem Soc 124:7055–7060.  https://doi.org/10.1021/ja017183p CrossRefPubMedGoogle Scholar
  15. Camardo Leggieri M, Decontardi S, Bertuzzi T, Pietri A, Battilani P (2016) Modeling growth and toxin production of toxigenic fungi signaled in cheese under different temperature and water activity regimes. Toxins 9:e4.  https://doi.org/10.3390/toxins9010004 CrossRefPubMedGoogle Scholar
  16. Carvalho de Lucena KF, Rodrigues JMN, Campos EM, Dantas AFM, Pfister JA, Cook D, Medeiros RMT, Riet-Correa F (2014) Poisoning by Ipomoea asarifolia in lambs by the ingestion of milk from ewes that ingest the plant. Toxicon Off J Int Soc Toxinology 92:129–132.  https://doi.org/10.1016/j.toxicon.2014.10.019 CrossRefGoogle Scholar
  17. Cases S, Novak S, Zheng YW, Myers HM, Lear SR, Sande E, Welch CB, Lusis AJ, Spencer TA, Krause BR, Erickson SK, Farese RVJ (1998) ACAT-2, a second mammalian acyl-CoA:cholesterol acyltransferase. Its cloning, expression, and characterization. J Biol Chem 273:26755–26764.  https://doi.org/10.1074/jbc.273.41.26755 CrossRefPubMedGoogle Scholar
  18. Cawdell-Smith AJ, Scrivener CJ, Bryden WL (2010) Staggers in horses grazing paspalum infected with Claviceps paspali. Aust Vet J 88:393–395.  https://doi.org/10.1111/j.1751-0813.2010.00624.x CrossRefPubMedGoogle Scholar
  19. Cole RJ, Dorner JW, Cox RH, Raymond LW (1983) Two classes of alkaloid mycotoxins produced by Penicillium crustosum Thom isolated from contaminated beer. J Agric Food Chem 31:655–657.  https://doi.org/10.1021/jf00117a045 CrossRefPubMedGoogle Scholar
  20. Cole RJ, Dorner JW, Lansden JA, Cox RH, Pape C, Cunfer B, Nicholson SS, Bedell DM (1977) Paspalum staggers: isolation and identification of tremorgenic metabolites from sclerotia of Claviceps paspali. J Agric Food Chem 25:1197–1201.  https://doi.org/10.1021/jf60213a061 CrossRefPubMedGoogle Scholar
  21. Cole RJ, Kirksey JW, Wells JM (1974) A new tremorgenic metabolite from Penicillium paxilli. Can J Microbiol 20:1159–1162.  https://doi.org/10.1139/m74-179 CrossRefPubMedGoogle Scholar
  22. Dalziel JE, Finch SC, Dunlop J (2005) The fungal neurotoxin lolitrem B inhibits the function of human large conductance calcium-activated potassium channels. Toxicol Lett 155:421–426.  https://doi.org/10.1016/j.toxlet.2004.11.011 CrossRefPubMedGoogle Scholar
  23. De Jesus AE, Steyn PS, Van Heerden FR, Vleggaar R, Wessels PL, Hull WE (1981) Structure and biosynthesis of the penitrems A-F, six novel tremorgenic mycotoxins from Penicillium crustosum. J Chem Soc Chem Commun 6:289–291.  https://doi.org/10.1039/C39810000289
  24. Dhodary B, Schilg M, Wirth R, Spiteller D (2018) Secondary metabolites from Escovopsis weberi and their role in attacking the garden fungus of leaf-cutting ants. Chem Eur J 24:4445–4452.  https://doi.org/10.1002/chem.201706071 CrossRefPubMedGoogle Scholar
  25. di Menna ME, Finch SC, Popay AJ, Smith BL (2012) A review of the Neotyphodium lolii / Lolium perenne symbiosis and its associated effects on animal and plant health, with particular emphasis on ryegrass staggers. N Z Vet J 60:315–328.  https://doi.org/10.1080/00480169.2012.697429 CrossRefPubMedGoogle Scholar
  26. Dorling PR, Colegate SM, Allen JG, Nickels R, Mitchell AA, Main DC, Madin B (2004) Calystegines isolated from Ipomoea spp. possibly associated with an ataxia syndrome in cattle in North Western Australia. In: Acamovic T, Stewart CS, Pennycott TW (eds) Poisonous plants and related toxins. CABI, Wallingford, pp 140–145CrossRefGoogle Scholar
  27. Douglas LJ (2003) Candida biofilms and their role in infection. Trends Microbiol 11:30–36.  https://doi.org/10.1016/S0966-842X(02)00002-1 CrossRefPubMedGoogle Scholar
  28. Dowd PF, Cole RJ, Vesonder RF (1988) Toxicity of selected tremorgenic mycotoxins and related compounds to Spodoptera frugiperda and Heliothis zea. J Antibiot 41:1868–1872.  https://doi.org/10.7164/antibiotics.41.1868 CrossRefPubMedGoogle Scholar
  29. EFSA Panel on Contaminants in the Food Chain (CONTAM) (2012) Scientific opinion on the risks for public and animal health related to the presence of citrinin in food and feed: Citrinin in food and feed. EFSA J 10:2605.  https://doi.org/10.2903/j.efsa.2012.2605 CrossRefGoogle Scholar
  30. Ehrlich K, Mack B (2014) Comparison of expression of secondary metabolite biosynthesis cluster genes in Aspergillus flavus, A. parasiticus, and A. oryzae. Toxins 6:1916–1928.  https://doi.org/10.3390/toxins6061916 CrossRefPubMedPubMedCentralGoogle Scholar
  31. El-Banna AA, Leistner L (1988) Production of penitrem A by Penicillium crustosum isolated from foodstuffs. Int J Food Microbiol 7:9–17.  https://doi.org/10.1016/0168-1605(88)90067-0 CrossRefPubMedGoogle Scholar
  32. El-banna AA, Pitt JI, Leistner L (1987) Production of mycotoxins by Penicillium species. Syst Appl Microbiol 10:42–46.  https://doi.org/10.1016/S0723-2020(87)80008-5 CrossRefGoogle Scholar
  33. Eriksen GS, Jaderlund KH, Moldes-Anaya A, Schonheit J, Bernhoft A, Jaeger G, Rundberget T, Skaar I (2010) Poisoning of dogs with tremorgenic Penicillium toxins. Med Mycol 48:188–196.  https://doi.org/10.3109/13693780903225821 CrossRefPubMedGoogle Scholar
  34. Eriksen GS, Moldes-Anaya A, Fæste CK (2013) Penitrem A and analogues: toxicokinetics, toxicodynamics including mechanism of action and clinical significance. World Mycotoxin J 6:263–272.  https://doi.org/10.3920/WMJ2013.1574 CrossRefGoogle Scholar
  35. Fan Y, Wang Y, Liu P, Fu P, Zhu T, Wang W, Zhu W (2013) Indole-diterpenoids with anti-H1N1 activity from the aciduric fungus Penicillium camemberti OUCMDZ-1492. J Nat Prod 76:1328–1336.  https://doi.org/10.1021/np400304q CrossRefPubMedGoogle Scholar
  36. Fehr T, Acklin W (1966) Isolation of 2 new indole derivatives from the mycelia of Claviceps paspali. Helv Chim Acta 49:1907–1910CrossRefGoogle Scholar
  37. Fellows PA, Kyriakidis N, Mantle PG, Waight ES (1981) Electron impact mass spectra of penitrem A, some derivatives and its analogs. Org Mass Spectrom 16:403–404.  https://doi.org/10.1002/oms.1210160909 CrossRefGoogle Scholar
  38. Finch S, Fletcher L, Babu J (2012) The evaluation of endophyte toxin residues in sheep fat. N Z Vet J 60:56–60.  https://doi.org/10.1080/00480169.2011.634746 CrossRefPubMedGoogle Scholar
  39. Finch SC, Thom ER, Babu JV, Hawkes AD, Waugh CD (2013) The evaluation of fungal endophyte toxin residues in milk. N Z Vet J 61:11–17.  https://doi.org/10.1080/00480169.2012.704626 CrossRefPubMedGoogle Scholar
  40. Fletcher LR, Harvey IC (1981) An association of a Lolium endophyte with ryegrass staggers. N Z Vet J 29:185–186.  https://doi.org/10.1080/00480169.1981.34839 CrossRefPubMedGoogle Scholar
  41. Fountain JC, Bajaj P, Pandey M, Nayak SN, Yang L, Kumar V, Jayale AS, Chitikineni A, Zhuang W, Scully BT, Lee RD, Kemerait RC, Varshney RK, Guo B (2016) Oxidative stress and carbon metabolism influence Aspergillus flavus transcriptome composition and secondary metabolite production. Sci Rep 6:38747.  https://doi.org/10.1038/srep38747 CrossRefPubMedPubMedCentralGoogle Scholar
  42. Frisvad JC (1987) High-performance liquid chromatographic determination of profiles of mycotoxines and other secondary metabolites. J Chromatogr A 392:333–347.  https://doi.org/10.1016/S0021-9673(01)94277-3 CrossRefGoogle Scholar
  43. Frisvad JC, Filtenborg O (1983) Classification of terverticillate penicillia based on profiles of mycotoxins and other secondary metabolites. Appl Environ Microbiol 46:1301–1310PubMedPubMedCentralGoogle Scholar
  44. Frisvad JC, Møller LLH, Larsen TO, Kumar R, Arnau J (2018) Safety of the fungal workhorses of industrial biotechnology: update on the mycotoxin and secondary metabolite potential of Aspergillus niger, Aspergillus oryzae, and Trichoderma reesei. Appl Microbiol Biotechnol 102:9481–9515.  https://doi.org/10.1007/s00253-018-9354-1 CrossRefPubMedPubMedCentralGoogle Scholar
  45. Frisvad JC, Thrane U (1987) Standardized high-performance liquid chromatography of 182 mycotoxins and other fungal metabolites based on alkylphenone retention indices and UV-VIS spectra (diode array detection). J Chromatogr 404:195–214.  https://doi.org/10.1016/S0021-9673(01)86850-3 CrossRefPubMedGoogle Scholar
  46. Gallagher RT, Finer J, Clardy J, Leutwiler A, Weibel F, Acklin W, Arigoni D (1980a) Paspalinine, a tremorgenic metabolite from Claviceps paspali Stevens et Hall. Tetrahedron Lett 21:235–238.  https://doi.org/10.1016/S0040-4039(00)71177-4 CrossRefGoogle Scholar
  47. Gallagher RT, Latch CM, Keogh RG (1980b) The janthitrems: fluorescent tremorgenic toxins produced by Penicillium janthinellum isolates from ryegrass pastures. Appl Environ Microbiol 39:272–273PubMedPubMedCentralGoogle Scholar
  48. Gallagher RT, White EP, Mortimer PH (1981) Ryegrass staggers: isolation of potent neurotoxins lolitrem A and lolitrem B from staggers-producing pastures. N Z Vet J 29:189–190.  https://doi.org/10.1080/00480169.1981.34843 CrossRefPubMedGoogle Scholar
  49. Gardiner MR, Royce R, Oldroyd B (1965) Ipomoea muelleri intoxication of sheep in Western Australia. Br Vet J 121:272–277.  https://doi.org/10.1016/S0007-1935(17)41154-7 CrossRefGoogle Scholar
  50. Gardner DR, Welch KD, Lee ST, Cook D, Riet-Correa F (2018) Tremorgenic indole diterpenes from Ipomoea asarifolia and Ipomoea muelleri and the identification of 6,7-dehydro-11-hydroxy-12,13-epoxyterpendole A. J Nat Prod 81:1682–1686.  https://doi.org/10.1021/acs.jnatprod.8b00257 CrossRefPubMedGoogle Scholar
  51. Gao S-S, Li X-M, Williams K, Proksch P, Ji N-Y, Wang B-G (2016) Rhizovarins A–F, indole-diterpenes from the mangrove-derived endophytic fungus Mucor irregularis QEN-189. J Nat Prod 79:2066–2074.  https://doi.org/10.1021/acs.jnatprod.6b00403 CrossRefPubMedGoogle Scholar
  52. Gilbert MK, Mack BM, Wei Q, Bland JM, Bhatnagar D, Cary JW (2016) RNA sequencing of an nsdC mutant reveals global regulation of secondary metabolic gene clusters in Aspergillus flavus. Microbiol Res 182:150–161.  https://doi.org/10.1016/j.micres.2015.08.007 CrossRefPubMedGoogle Scholar
  53. Giovannoni M, Piaz V, Vergelli C, Barlocco D (2003) Selective ACAT inhibitors as promising antihyperlipidemic, antiatherosclerotic and anti-Alzheimer drugs. Mini-Rev Med Chem 3:576–584.  https://doi.org/10.2174/1389557033487890 CrossRefPubMedGoogle Scholar
  54. Goda AA, Siddique A, Mohyeldin M, Ayoub N, El Sayed K (2018) The maxi-K (BK) channel antagonist penitrem A as a novel breast cancer-targeted therapeutic. Mar Drugs 16:e157.  https://doi.org/10.3390/md16050157 CrossRefPubMedGoogle Scholar
  55. Goda AA, Naguib KM, Mohamed MM, Amra HA, Nada SA, Abdel-Ghaffar A-RB, Gissendanner CR, El Sayed KA (2016) Astaxanthin and docosahexaenoic acid reverse the toxicity of the Maxi-K (BK) channel antagonist mycotoxin penitrem A. Mar Drugs 14:e208.  https://doi.org/10.3390/md14110208 CrossRefPubMedGoogle Scholar
  56. Gordon KE (1993) Tremorgenic encephalopathy: a role of mycotoxins in the production of CNS disease in humans? Can J Neurol Sci J Can Sci Neurol 20:237–239.  https://doi.org/10.1017/S0317167100048010 CrossRefGoogle Scholar
  57. Hayes AW, Presley DB, Neville JA (1976) Acute toxicity of penitrem A in dogs. Toxicol Appl Pharmacol 35:311–320.  https://doi.org/10.1016/0041-008X(76)90290-8 CrossRefPubMedGoogle Scholar
  58. Hocking AD, Holds K, Tobin NF (1988) Intoxication by tremorgenic mycotoxin (penitrem A) in a dog. Aust Vet J 65:82–85.  https://doi.org/10.1111/j.1751-0813.1988.tb07366.x CrossRefPubMedGoogle Scholar
  59. Huang XH, Nishida H, Tomoda H, Tabata N, Shiomi K, Yang DJ, Takayanagi H, Omura S (1995) Terpendoles, novel ACAT inhibitors produced by Albophoma yamanashiensis. II. Structure elucidation of terpendoles A, B, C and D. J Antibiot 48:5–11.  https://doi.org/10.1002/chin.199529248 CrossRefPubMedGoogle Scholar
  60. Imlach WL, Finch SC, Dunlop J, Meredith AL, Aldrich RW, Dalziel JE (2008) The molecular mechanism of “ryegrass staggers,” a neurological disorder of K+ channels. J Pharmacol Exp Ther 327:657–664.  https://doi.org/10.1124/jpet.108.143933 CrossRefPubMedGoogle Scholar
  61. Imlach WL, Finch SC, Zhang Y, Dunlop J, Dalziel JE (2011) Mechanism of action of lolitrem B, a fungal endophyte derived toxin that inhibits BK large conductance Ca2+−activated K+ channels. Toxicon 57:686–694.  https://doi.org/10.1016/j.toxicon.2011.01.013 CrossRefPubMedGoogle Scholar
  62. Kacaniova M, Knazovicka V, Felsociova S, Rovna K (2012) Microscopic fungi recovered from honey and their toxinogenity. J Environ Sci Health Part A Tox Hazard Subst Environ Eng 47:1659–1664.  https://doi.org/10.1080/10934529.2012.687242 CrossRefGoogle Scholar
  63. Kalinina SA, Jagels A, Cramer B, Geisen R, Humpf H-U (2017) Influence of environmental factors on the production of penitrems A-F by Penicillium crustosum. Toxins 9:e210.  https://doi.org/10.3390/toxins9070210 CrossRefPubMedGoogle Scholar
  64. Kalinina SA, Jagels A, Hickert S, Mauriz Marques LM, Cramer B, Humpf H-U (2018) Detection of the cytotoxic penitrems A–F in cheese from the European single market by HPLC-MS/MS. J Agric Food Chem 66:1264–1269.  https://doi.org/10.1021/acs.jafc.7b06001 CrossRefPubMedGoogle Scholar
  65. Kathiravan MK, Salake AB, Chothe AS, Dudhe PB, Watode RP, Mukta MS, Gadhwe S (2012) The biology and chemistry of antifungal agents: a review. Bioorg Med Chem 20:5678–5698.  https://doi.org/10.1016/j.bmc.2012.04.045 CrossRefPubMedGoogle Scholar
  66. Kawai K, Nozawa K (1989) Novel biologically active compounds from Emericella species. Bioact Mol 10:205–212Google Scholar
  67. Knaus H-G, McManus OB, Lee SH, Schmalhofer WA, Garcia-Calvo M, Helms LMH, Sanchez M, Giangiacomo K, Reuben JP (1994) Tremorgenic indole alkaloids potently inhibit smooth muscle high-conductance calcium-activated potassium channels. Biochem Mosc 33:5819–5828.  https://doi.org/10.1021/bi00185a021 CrossRefGoogle Scholar
  68. Knight SD, Parrish CA (2008) Recent progress in the identification and clinical evaluation of inhibitors of the mitotic kinesin KSP. Curr Top Med Chem 8:888–904.  https://doi.org/10.2174/156802608784911626 CrossRefPubMedGoogle Scholar
  69. Kozák L, Szilágyi Z, Vágó B, Kakuk A, Tóth L, Molnár I, Pócsi I (2018) Inactivation of the indole-diterpene biosynthetic gene cluster of Claviceps paspali by Agrobacterium-mediated gene replacement. Appl Microbiol Biotechnol 102:3255–3266.  https://doi.org/10.1007/s00253-018-8807-x CrossRefPubMedGoogle Scholar
  70. Kyle BD, Bradley E, Large R, Sergeant GP, McHale NG, Thornbury KD, Hollywood MA (2013) Mechanisms underlying activation of transient BK current in rabbit urethral smooth muscle cells and its modulation by IP3-generating agonists. Am J Physiol-Cell Physiol 305:609–622.  https://doi.org/10.1152/ajpcell.00025.2013 CrossRefGoogle Scholar
  71. Laakso JA, Gloer JB, Wicklow DT, Dowd PF (1992) Sulpinines A-C and secopenitrem B: new antiinsectan metabolites from the sclerotia of Aspergillus sulphureus. J Org Chem 57:2066–2071.  https://doi.org/10.1021/jo00033a030 CrossRefGoogle Scholar
  72. Lauren DR, Gallagher RT (1982) High-performance liquid chromatography of the janthitrems: fluorescent tremorgenic mycotoxins produced by Penicillium janthinellum. J Chromatogr 248:150–154.  https://doi.org/10.1016/S0021-9673(00)83747-4 CrossRefGoogle Scholar
  73. Lauterbur PC (1973) Image formation by induced local interactions. Examples employing nuclear magnetic resonance. Nature 242:190–191.  https://doi.org/10.1038/242190a0 CrossRefGoogle Scholar
  74. Laws I, Mantle PG (1989) Experimental constraints in the study of the biosynthesis of indole alkaloids in fungi. Microbiology 135:2679–2692.  https://doi.org/10.1099/00221287-135-10-2679 CrossRefGoogle Scholar
  75. Lee H, Roark W, Picard J, Sliskovic D, Roth B, Stanfield R, Hamelehle K, Bousley R, Krause B (1998) Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents: synthesis and structure-activity relationships of novel series of sulfonamides, acylphosphonamides and acylphosphoramidates. Bioorg Med Chem Lett 8:289–294.  https://doi.org/10.1016/S0960-894X(98)00011-0 CrossRefPubMedGoogle Scholar
  76. Lee ST, Gardner DR, Cook D (2017) Identification of indole diterpenes in Ipomoea asarifolia and Ipomoea muelleri, plants tremorgenic to livestock. J Agric Food Chem 65:5266–5277.  https://doi.org/10.1021/acs.jafc.7b01834 CrossRefPubMedGoogle Scholar
  77. Lewis PR, Donoghue MB, Hocking AD, Cook L, Granger LV (2005) Tremor syndrome associated with a fungal toxin: sequelae of food contamination. Med J Aust 182:582–584PubMedGoogle Scholar
  78. Liu C, Minami A, Dairi T, Gomi K, Scott B, Oikawa H (2016) Biosynthesis of shearinine: diversification of a tandem prenyl moiety of fungal indole diterpenes. Org Lett 18:5026–5029.  https://doi.org/10.1021/acs.orglett.6b02482 CrossRefPubMedGoogle Scholar
  79. Liu C, Minami A, Noike M, Toshima H, Oikawa H, Dairi T (2013) Regiospecificities and prenylation mode specificities of the fungal indole diterpene prenyltransferases AtmD and PaxD. Appl Environ Microbiol 79:7298–7304.  https://doi.org/10.1128/AEM.02496-13 CrossRefPubMedPubMedCentralGoogle Scholar
  80. Liu C, Tagami K, Minami A, Matsumoto T, Frisvad JC, Suzuki H, Ishikawa J, Gomi K, Oikawa H (2015) Reconstitution of biosynthetic machinery for the synthesis of the highly elaborated indole diterpene penitrem. Angew Chem Int Ed 54:5748–5752.  https://doi.org/10.1002/anie.201501072 CrossRefGoogle Scholar
  81. Lu W, Lin C, Roberts MJ, Waud WR, Piazza GA, Li Y (2011) Niclosamide suppresses cancer cell growth by inducing Wnt co-receptor LRP6 degradation and inhibiting the Wnt/β-catenin pathway. PLoS One 6:e29290.  https://doi.org/10.1371/journal.pone.0029290 CrossRefPubMedPubMedCentralGoogle Scholar
  82. Maes CM, Steyn PS, Van Heerden FR (1982) High-performance liquid chromatography and thin-layer chromatography of penitrems A–F, tremorgenic mycotoxins from Penicillium crustosum. J Chromatogr A 234:489–493.  https://doi.org/10.1016/S0021-9673(00)81893-2 CrossRefGoogle Scholar
  83. Malachova A, Sulyok M, Beltran E, Berthiller F, Krska R (2014) Optimization and validation of a quantitative liquid chromatography-tandem mass spectrometric method covering 295 bacterial and fungal metabolites including all regulated mycotoxins in four model food matrices. J Chromatogr A 1362:145–156.  https://doi.org/10.1016/j.chroma.2014.08.037 CrossRefPubMedGoogle Scholar
  84. Mantle PG, Laws I, Tan MJ, Tizard M (1984) A novel process for the production of penitrem mycotoxins by submerged fermentation of Penicillium nigricans. J Gen Microbiol 130:1293–1298.  https://doi.org/10.1099/00221287-130-5-1293 CrossRefPubMedGoogle Scholar
  85. Mantle PG, Mortimer PH, White EP (1978) Mycotoxic tremorgens of Claviceps paspali and Penicillium cyclopium: a comparative study of effects on sheep and cattle in relation to natural staggers syndromes. Res Vet Sci 24:49–56CrossRefPubMedGoogle Scholar
  86. McMillan LK, Carr RL, Young CA, Astin JW, Lowe RGT, Parker EJ, Jameson GB, Finch SC, Miles CO, McManus OB, Schmalhofer WA, Garcia ML, Kaczorowski GJ, Goetz M, Tkacz JS, Scott B (2003) Molecular analysis of two cytochrome P450 monooxygenase genes required for paxilline biosynthesis in Penicillium paxilli , and effects of paxilline intermediates on mammalian maxi-K ion channels. Mol Gen Genomics 270:9–23.  https://doi.org/10.1007/s00438-003-0887-2 CrossRefGoogle Scholar
  87. de Medeiros FHV, Martins SJ, Zucchi TD, de Melo IS, Batista LR, da Machado JC (2012) Biological control of mycotoxin-producing molds. Ciênc E Agrotecnologia 36:483–497.  https://doi.org/10.1590/S1413-70542012000500001 CrossRefGoogle Scholar
  88. Medeiros RMT, Barbosa RC, Riet-Correa F, Lima EF, Tabosa IM, de Barros SS, Gardner DR, Molyneux RJ (2003) Tremorgenic syndrome in goats caused by Ipomoea asarifolia in Northeastern Brazil. Toxicon Off J Int Soc Toxinology 41:933–935.  https://doi.org/10.1016/S0041-0101(03)00044-8 CrossRefGoogle Scholar
  89. Miyazaki S, Ishizaki I, Ishizaka M, Kanbara T, Ishiguro-Takeda Y (2004) Lolitrem B residue in fat tissues of cattle consuming endophyte-infected perennial ryegrass straw. J Vet Diagn Investig 16:340–342.  https://doi.org/10.1177/104063870401600416 CrossRefGoogle Scholar
  90. Moldes-Anaya A, Rundberget T, Faeste CK, Eriksen GS, Bernhoft A (2012) Neurotoxicity of Penicillium crustosum secondary metabolites: tremorgenic activity of orally administered penitrem A and thomitrem A and E in mice. Toxicon Off J Int Soc Toxinology 60:1428–1435.  https://doi.org/10.1016/j.toxicon.2012.10.007 CrossRefGoogle Scholar
  91. Moldes-Anaya A, Wilkins AL, Rundberget T, Fæste CK (2009) In vitro and in vivo hepatic metabolism of the fungal neurotoxin penitrem A. Drug Chem Toxicol 32:26–37.  https://doi.org/10.1080/01480540802416232 CrossRefPubMedGoogle Scholar
  92. Moldes-Anaya AS, Fonnum F, Eriksen GS, Rundberget T, Walaas SI, Wigestrand MB (2011) In vitro neuropharmacological evaluation of penitrem-induced tremorgenic syndromes: importance of the GABAergic system. Neurochem Int 59:1074–1081.  https://doi.org/10.1016/j.neuint.2011.08.014 CrossRefPubMedGoogle Scholar
  93. Motoyama T, Hayashi T, Hirota H, Ueki M, Osada H (2012) Terpendole E, a kinesin Eg5 inhibitor, is a key biosynthetic intermediate of indole-diterpenes in the producing fungus Chaunopycnis alba. Chem Biol 19:1611–1619.  https://doi.org/10.1016/j.chembiol.2012.10.010 CrossRefPubMedGoogle Scholar
  94. Moyano M, Molina A, Lora A, Mendez J, Rueda A (2010) Tremorgenic mycotoxicosis caused by Paspalum paspaloides (Michx.) Scribner infected by Claviceps paspali: a case report. Vet Med 55:336–338.  https://doi.org/10.17221/2964-VETMED CrossRefGoogle Scholar
  95. Munday-Finch SC, Miles CO, Wilkins AL, Hawkes AD (1995) Isolation and structure elucidation of lolitrem A, a tremorgenic mycotoxin from perennial ryegrass infected with Acremonium lolii. J Agric Food Chem 43:1283–1288.  https://doi.org/10.1021/jf00053a029 CrossRefGoogle Scholar
  96. Munday-Finch SC, Wilkins AL, Miles CO (1996) Isolation of paspaline B, an indole-diterpenoid from Penicillium paxilli. Phytochemistry 41:327–332.  https://doi.org/10.1016/0031-9422(95)00515-3 CrossRefGoogle Scholar
  97. Munday-Finch SC, Wilkins AL, Miles CO (1998) Isolation of lolicine A, lolicine B, lolitriol, and lolitrem N from Lolium perenne infected with Neotyphodium lolii and evidence for the natural occurrence of 31-epilolitrem N and 31-epilolitrem F. J Agric Food Chem 46:590–598.  https://doi.org/10.1021/jf9706787 CrossRefPubMedGoogle Scholar
  98. Naik JT, Mantle PG, Sheppard RN, Waight ES (1995) Penitremones A-C, Penicillium metabolites containing an oxidized penitrem carbon skeleton giving insight into structure-tremorgenic relationships. J Chem Soc Perkin Trans 1 Org Bio-Org Chem 1:1121–1125.  https://doi.org/10.1039/P19950001121 CrossRefGoogle Scholar
  99. Nakazawa J, Yajima J, Usui T, Ueki M, Takatsuki A, Imoto M, Toyoshima YY, Osada H (2003) A novel action of terpendole E on the motor activity of mitotic kinesin Eg5. Chem Biol 10:131–137.  https://doi.org/10.1016/S1074-5521(03)00020-6 CrossRefPubMedGoogle Scholar
  100. Needham M, McGahon MK, Bankhead P, Gardiner TA, Scholfield CN, Curtis TM, McGeown JG (2014) The role of K + and Cl channels in the regulation of retinal arteriolar tone and blood flow. Investig Opthalmology Vis Sci 55:2157–2165.  https://doi.org/10.1167/iovs.13-12948 CrossRefGoogle Scholar
  101. Nett JE, Sanchez H, Cain MT, Andes DR (2010) Genetic basis of Candida biofilm resistance due to drug-sequestering matrix glucan. J Infect Dis 202:171–175.  https://doi.org/10.1086/651200 CrossRefPubMedPubMedCentralGoogle Scholar
  102. Nett JE, Sanchez H, Cain MT, Ross KM, Andes DR (2011) Interface of Candida albicans biofilm matrix-associated drug resistance and cell wall integrity regulation. Eukaryot Cell 10:1660–1669.  https://doi.org/10.1128/EC.05126-11 CrossRefPubMedPubMedCentralGoogle Scholar
  103. Nicholson MJ, Eaton CJ, Starkel C, Tapper BA, Cox MP, Scott B (2015) Molecular cloning and functional analysis of gene clusters for the biosynthesis of indole-diterpenes in Penicillium crustosum and P. janthinellum. Toxins 7:2701–2722.  https://doi.org/10.3390/toxins7082701 CrossRefPubMedPubMedCentralGoogle Scholar
  104. Nicholson MJ, Koulman A, Monahan BJ, Pritchard BL, Payne GA, Scott B (2009) Identification of two aflatrem biosynthesis gene loci in Aspergillus flavus and metabolic engineering of Penicillium paxilli to elucidate their function. Appl Environ Microbiol 75:7469–7481.  https://doi.org/10.1128/AEM.02146-08 CrossRefPubMedPubMedCentralGoogle Scholar
  105. Nozawa K, Nakajima S, Kawai K, Udagawa S, Horie Y, Yamazaki M (1987) Novel indoloditerpenes, emindoles, and their related compounds from Emericella spp. Tennen Yuki Kagobutsu Toronkai Koen Yoshishu 29:637–643Google Scholar
  106. Ohshiro T, Rudel LL, Omura S, Tomoda H (2007) Selectivity of microbial acyl-CoA: cholesterol acyltransferase inhibitors toward isozymes. J Antibiot 60:43–51.  https://doi.org/10.1038/ja.2007.6 CrossRefPubMedGoogle Scholar
  107. Oikawa H, Minami A, Liu C (2016) Total biosynthesis of fungal indole diterpenes using cell factories. Heterocycles 92:397–421.  https://doi.org/10.3987/REV-15-830 CrossRefGoogle Scholar
  108. Oliveira PM, Zannini E, Arendt EK (2014) Cereal fungal infection, mycotoxins, and lactic acid bacteria mediated bioprotection: from crop farming to cereal products. Food Microbiol 37:78–95.  https://doi.org/10.1016/j.fm.2013.06.003 CrossRefPubMedGoogle Scholar
  109. Olsen M, Gidlund A, Sulyok M (2017) Experimental mould growth and mycotoxin diffusion in different food items. World Mycotoxin J 10:153–161.  https://doi.org/10.3920/WMJ2016.2163 CrossRefGoogle Scholar
  110. Overy DP, Seifert KA, Savard ME, Frisvad JC (2003) Spoilage fungi and their mycotoxins in commercially marketed chestnuts. Int J Food Microbiol 88:69–77.  https://doi.org/10.1016/S0168-1605(03)00086-2 CrossRefPubMedGoogle Scholar
  111. Panaccione DG, Beaulieu WT, Cook D (2014) Bioactive alkaloids in vertically transmitted fungal endophytes. Funct Ecol 28:299–314.  https://doi.org/10.1111/1365-2435.12076 CrossRefGoogle Scholar
  112. Panaccione DG, Cipoletti JR, Sedlock AB, Blemings KP, Schardl CL, Machado C, Seidel GE (2006) Effects of ergot alkaloids on food preference and satiety in rabbits, as assessed with gene-knockout endophytes in perennial ryegrass (Lolium perenne). J Agric Food Chem 54:4582–4587.  https://doi.org/10.1021/jf060626u CrossRefPubMedGoogle Scholar
  113. Parker EJ, Scott BD (2005) Indole-diterpene biosynthesis in ascomycetous fungi. In: An Z (ed) Handbook of industrial mycology, vol 22. Marcel Dekker, New York, pp 405–426Google Scholar
  114. Patterson DS, Roberts BA, Shreeve BJ, MacDonald SM, Hayes AW (1979) Tremorgenic toxins produced by soil fungi. Appl Environ Microbiol 37:172–173PubMedPubMedCentralGoogle Scholar
  115. Philippe G (2016) Lolitrem B and indole diterpene alkaloids produced by endophytic fungi of the genus Epichloe and their toxic effects in livestock. Toxins 8:e47.  https://doi.org/10.3390/toxins8020047 CrossRefPubMedGoogle Scholar
  116. Prencipe S, Siciliano I, Gatti C, Garibaldi A, Gullino ML, Botta R, Spadaro D (2018) Several species of Penicillium isolated from chestnut flour processing are pathogenic on fresh chestnuts and produce mycotoxins. Food Microbiol 76:396–404.  https://doi.org/10.1016/j.fm.2018.07.003 CrossRefPubMedGoogle Scholar
  117. Qiao M-F, Ji N-Y, Liu X-H, Li K, Zhu Q-M, Xue Q-Z (2010) Indoloditerpenes from an algicolous isolate of Aspergillus oryzae. Bioorg Med Chem Lett 20:5677–5680.  https://doi.org/10.1016/j.bmcl.2010.08.024 CrossRefPubMedGoogle Scholar
  118. Rank C, Klejnstrup ML, Petersen LM, Kildgaard S, Frisvad JC, Held Gotfredsen C, Ostenfeld Larsen T (2012) Comparative chemistry of Aspergillus oryzae (RIB40) and A. flavus (NRRL 3357). Metabolites 2:39–56.  https://doi.org/10.3390/metabo2010039 CrossRefPubMedPubMedCentralGoogle Scholar
  119. Řeháček Z, Kozová J, Řičicová A, Kašlík J, Sajdl P, Švarc S, Basappa SC (1971) Role of endogenous tryptophan during submerged fermentation of ergot alkaloids. Folia Microbiol (Praha) 16:35–40.  https://doi.org/10.1007/BF02887333 CrossRefGoogle Scholar
  120. Renaud JB, Sumarah MW (2016) Data independent acquisition-digital archiving mass spectrometry: application to single kernel mycotoxin analysis of Fusarium graminearum infected maize. Anal Bioanal Chem 408:3083–3091.  https://doi.org/10.1007/s00216-016-9391-5 CrossRefPubMedGoogle Scholar
  121. Richard JL, Arp LH (1979) Natural occurrence of the mycotoxin penitrem A in moldy cream cheese. Mycopathologia 67:107–109.  https://doi.org/10.1007/BF00440681 CrossRefPubMedGoogle Scholar
  122. Richard JL, Bacchetti P, Arp LH (1981) Moldy walnut toxicosis in a dog, caused by the mycotoxin, penitrem A. Mycopathologia 76:55–58.  https://doi.org/10.1007/BF00761899 CrossRefPubMedGoogle Scholar
  123. Rundberget T, Skaar I, Flåøyen A (2004) The presence of Penicillium and Penicillium mycotoxins in food wastes. Int J Food Microbiol 90:181–188.  https://doi.org/10.1016/S0168-1605(03)00291-5 CrossRefPubMedGoogle Scholar
  124. Rundberget T, Wilkins AL (2002) Determination of Penicillium mycotoxins in foods and feeds using liquid chromatography–mass spectrometry. J Chromatogr A 964:189–197.  https://doi.org/10.1016/S0021-9673(02)00698-2 CrossRefPubMedGoogle Scholar
  125. Russell R, Paterson M, Kemmelmeier C (1989) Gradient high-performance liquid chromatography using alkylphenone retention indices of insecticidal extracts of Penicillium strains. J Chromatogr A 483:153–168.  https://doi.org/10.1016/S0021-9673(01)93118-8 CrossRefGoogle Scholar
  126. Sabater-Vilar M, Nijmeijer S, Fink-Gremmels J (2003) Genotoxicity assessment of five tremorgenic mycotoxins (fumitremorgen B, paxilline, penitrem A, verruculogen, and verrucosidin) produced by molds isolated from fermented meats. J Food Prot 66:2123–2129.  https://doi.org/10.4315/0362-028X-66.11.2123 CrossRefPubMedGoogle Scholar
  127. Saikia S, Nicholson MJ, Young C, Parker EJ, Scott B (2008) The genetic basis for indole-diterpene chemical diversity in filamentous fungi. Mycol Res 112:184–199.  https://doi.org/10.1016/j.mycres.2007.06.015 CrossRefPubMedGoogle Scholar
  128. Saikia S, Parker EJ, Koulman A, Scott B (2007) Defining paxilline biosynthesis in Penicillium paxilli: functional characterization of two cytochrome P450 monooxygenases. J Biol Chem 282:16829–16837.  https://doi.org/10.1074/jbc.M701626200 CrossRefPubMedGoogle Scholar
  129. Saikia S, Scott B (2009) Functional analysis and subcellular localization of two geranylgeranyl diphosphate synthases from Penicillium paxilli. Mol Gen Genomics 282:257–271.  https://doi.org/10.1007/s00438-009-0463-5 CrossRefGoogle Scholar
  130. Saikia S, Takemoto D, Tapper BA, Lane GA, Fraser K, Scott B (2012) Functional analysis of an indole-diterpene gene cluster for lolitrem B biosynthesis in the grass endosymbiont Epichloë festucae. FEBS Lett 586:2563–2569.  https://doi.org/10.1016/j.febslet.2012.06.035 CrossRefPubMedGoogle Scholar
  131. Saikkonen K, Young CA, Helander M, Schardl CL (2016) Endophytic Epichloë species and their grass hosts: from evolution to applications. Plant Mol Biol 90:665–675.  https://doi.org/10.1007/s11103-015-0399-6 CrossRefPubMedGoogle Scholar
  132. Sallam AA, Ayoub NM, Foudah AI, Gissendanner CR, Meyer SA, El Sayed KA (2013a) Indole diterpene alkaloids as novel inhibitors of the Wnt/β-catenin pathway in breast cancer cells. Eur J Med Chem 70:594–606.  https://doi.org/10.1016/j.ejmech.2013.09.045 CrossRefPubMedGoogle Scholar
  133. Sallam AA, Houssen WE, Gissendanner CR, Orabi KY, Foudah AI, El Sayed KA (2013b) Bioguided discovery and pharmacophore modeling of the mycotoxic indole diterpene alkaloids penitrems as breast cancer proliferation, migration, and invasion inhibitors. MedChemComm 4:1360–1369.  https://doi.org/10.1039/C3MD00198A CrossRefGoogle Scholar
  134. Sanchis V, Scott PM, Farber JM (1988) Mycotoxin-producing potential of fungi isolated from red kidney beans. Mycopathologia 104:157–162.  https://doi.org/10.1007/BF00437431 CrossRefPubMedGoogle Scholar
  135. Santini A, Mikušová P, Sulyok M, Krska R, Labuda R, Šrobárová A (2014) Penicillium strains isolated from Slovak grape berries taxonomy assessment by secondary metabolite profile. Mycotoxin Res 30:213–220.  https://doi.org/10.1007/s12550-014-0205-3 CrossRefPubMedGoogle Scholar
  136. Sarli V, Giannis A (2008) Targeting the kinesin spindle protein: basic principles and clinical implications. Clin Cancer Res Off J Am Assoc Cancer Res 14:7583–7587.  https://doi.org/10.1158/1078-0432.CCR-08-0120 CrossRefGoogle Scholar
  137. 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, Güldener 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.  https://doi.org/10.1371/journal.pgen.1003323.doi:10.1371/journal.pgen.1003323
  138. Scott B, Young CA, Saikia S, McMillan LK, Monahan BJ, Koulman A, Astin J, Eaton CJ, Bryant A, Wrenn RE, Finch SC, Tapper BA, Parker EJ, Jameson GB (2013) Deletion and gene expression analyses define the paxilline biosynthetic gene cluster in Penicillium paxilli. Toxins 5:1422–1446.  https://doi.org/10.3390/toxins5081422 CrossRefPubMedPubMedCentralGoogle Scholar
  139. Scuteri M, Sala de Miguel MA, Viera JB, de Banchero EP (1992) Tremorgenic mycotoxins produced by strains of Penicillium spp. isolated from toxic Poa huecu parodi. Mycopathologia 120:177–182.  https://doi.org/10.1007/BF00436396 CrossRefPubMedGoogle Scholar
  140. Sengun I, Yaman D, Gonul S (2008) Mycotoxins and mould contamination in cheese: a review. World Mycotoxin J 1:291–298.  https://doi.org/10.3920/WMJ2008.x041 CrossRefGoogle Scholar
  141. Sheff JG, Farshidfar F, Bathe OF, Kopciuk K, Gentile F, Tuszynski J, Barakat K, Schriemer DC (2017) Novel allosteric pathway of Eg5 regulation identified through multivariate statistical analysis of hydrogen-exchange mass spectrometry (HX-MS) ligand screening data. Mol Cell Proteomics 16:428–437.  https://doi.org/10.1074/mcp.M116.064246 CrossRefPubMedPubMedCentralGoogle Scholar
  142. Shimada N, Yoshioka M, Mikami O, Tanimura N, Yamanaka N, Hanazumi M, Kojima F, Miyazaki S (2013) Toxicological evaluation and bioaccumulation potential of lolitrem B, endophyte mycotoxin in Japanese black steers. Food Addit Contam Part Chem Anal Control Expo Risk Assess 30:1402–1406.  https://doi.org/10.1080/19440049.2013.790090 CrossRefGoogle Scholar
  143. Shoop WL, Gregory LM, Zakson-Aiken M, Michael BF, Haines HW, Ondeyka JG, Meinke PT, Schmatz DM (2001) Systematic efficacy of nodulisporic acid against fleas on dogs. J Parasitol 87:419–423. https://doi.org/10.1645/0022-3395(2001)087[0419:SEONAA]2.0.CO;2Google Scholar
  144. Sings H, Singh S (2003) Tremorgenic and nontremorgenic 2,3-fused indole diterpenoids. Alkaloids Chem Biol 60:51–163.  https://doi.org/10.1016/S0099-9598(03)60002-7 CrossRefPubMedGoogle Scholar
  145. Sonjak S, Frisvad JC, Gunde-Cimerman N (2005) Comparison of secondary metabolite production by Penicillium crustosum strains, isolated from Arctic and other various ecological niches. FEMS Microbiol Ecol 53:51–60.  https://doi.org/10.1016/j.femsec.2004.10.014 CrossRefPubMedGoogle Scholar
  146. Springer JP, Clardy J (1980) Paspaline and paspalicine, two indole-mevalonate metabolites from Claviceps paspali. Tetrahedron Lett 21:231–234.  https://doi.org/10.1016/S0040-4039(00)71176-2 CrossRefGoogle Scholar
  147. Stewart M, Needham M, Bankhead P, Gardiner TA, Scholfield CN, Curtis TM, McGeown JG (2012) Feedback via Ca 2+ -activated ion channels modulates endothelin 1 signaling in retinal arteriolar smooth muscle. Investig Opthalmology Vis Sci 53:3059–3066.  https://doi.org/10.1167/iovs.11-9192 CrossRefGoogle Scholar
  148. Stoev SD, Dutton MF, Njobeh PB, Mosonik JS, Steenkamp PA (2010) Mycotoxic nephropathy in Bulgarian pigs and chickens: complex aetiology and similarity to Balkan endemic nephropathy. Food Addit Contam 27:72–88.  https://doi.org/10.1080/02652030903207227 CrossRefGoogle Scholar
  149. Sulyok M, Berthiller F, Krska R, Schuhmacher R (2006) Development and validation of a liquid chromatography/tandem mass spectrometric method for the determination of 39 mycotoxins in wheat and maize. Rapid Commun Mass Spectrom 20:2649–2659.  https://doi.org/10.1002/rcm.2640 CrossRefPubMedGoogle Scholar
  150. Sulyok M, Krska R, Schuhmacher R (2007) A liquid chromatography/tandem mass spectrometric multi-mycotoxin method for the quantification of 87 analytes and its application to semi-quantitative screening of moldy food samples. Anal Bioanal Chem 389:1505–1523.  https://doi.org/10.1007/s00216-007-1542-2 CrossRefPubMedGoogle Scholar
  151. Sumarah MW, Miller JD, Blackwell BA (2005) Isolation and metabolite production by Penicillium roqueforti, P. paneum and P. crustosum isolated in Canada. Mycopathologia 159:571–577.  https://doi.org/10.1007/s11046-005-5257-7 CrossRefPubMedGoogle Scholar
  152. Tagami K, Liu C, Minami A, Noike M, Isaka T, Fueki S, Shichijo Y, Toshima H, Gomi K, Dairi T, Oikawa H (2013) Reconstitution of biosynthetic machinery for indole-diterpene paxilline in Aspergillus oryzae. J Am Chem Soc 135:1260–1263.  https://doi.org/10.1021/ja3116636 CrossRefPubMedGoogle Scholar
  153. Tagami K, Minami A, Fujii R, Liu C, Tanaka M, Gomi K, Dairi T, Oikawa H (2014) Rapid reconstitution of biosynthetic machinery for fungal metabolites in Aspergillus oryzae: total biosynthesis of aflatrem. ChemBioChem 15:2076–2080.  https://doi.org/10.1002/cbic.201402195 CrossRefPubMedGoogle Scholar
  154. Tancinova D, Labuda R (2009) Fungi on wheat bran and their toxinogenity. Ann Agric Environ Med 16:325–331PubMedGoogle Scholar
  155. Tang M-C, Lin H-C, Li D, Zou Y, Li J, Xu W, Cacho RA, Hillenmeyer ME, Garg NK, Tang Y (2015) Discovery of unclustered fungal indole diterpene biosynthetic pathways through combinatorial pathway reassembly in engineered yeast. J Am Chem Soc 137:13724–13727.  https://doi.org/10.1021/jacs.5b06108 CrossRefPubMedPubMedCentralGoogle Scholar
  156. Tao L, Chung SH (2014) Non-aflatoxigenicity of commercial Aspergillus oryzae strains due to genetic defects compared to aflatoxigenic Aspergillus flavus. J Microbiol Biotechnol 24:1081–1087.  https://doi.org/10.4014/jmb.1311.11011 CrossRefPubMedGoogle Scholar
  157. Tarui Y, Chinen T, Nagumo Y, Motoyama T, Hayashi T, Hirota H, Muroi M, Ishii Y, Kondo H, Osada H, Usui T (2014) Terpendole E and its derivative inhibit STLC- and GSK-1-resistant Eg5. ChemBioChem Eur J Chem Biol 15:934–938.  https://doi.org/10.1002/cbic.201300808 CrossRefGoogle Scholar
  158. Thom ER, Popay AJ, Waugh CD, Minneé EMK (2014) Impact of novel endophytes in perennial ryegrass on herbage production and insect pests from pastures under dairy cow grazing in northern New Zealand. Grass Forage Sci 69:191–204.  https://doi.org/10.1111/gfs.12040 CrossRefGoogle Scholar
  159. Thom ER, Waugh CD, Minnee EMK, Waghorn GC (2013) Effects of novel and wild-type endophytes in perennial ryegrass on cow health and production. N Z Vet J 61:87–97.  https://doi.org/10.1080/00480169.2012.715379
  160. Tkacz JS, DiDomenico B (2001) Antifungals: what’s in the pipeline. Curr Opin Microbiol 4:540–545.  https://doi.org/10.1016/S1369-5274(00)00248-4 CrossRefPubMedGoogle Scholar
  161. Tudzynski P, Correia T, Keller U (2001) Biotechnology and genetics of ergot alkaloids. Appl Microbiol Biotechnol 57:593–605.  https://doi.org/10.1007/s002530100801 CrossRefPubMedGoogle Scholar
  162. Uhlig S, Botha CJ, Vralstad T, Rolen E, Miles CO (2009) Indole-diterpenes and ergot alkaloids in Cynodon dactylon (Bermuda grass) infected with Claviceps cynodontis from an outbreak of tremors in cattle. J Agric Food Chem 57:11112–11119.  https://doi.org/10.1021/jf902208w CrossRefPubMedGoogle Scholar
  163. Uhlig S, Egge-Jacobsen W, Vralstad T, Miles CO (2014) Indole-diterpenoid profiles of Claviceps paspali and Claviceps purpurea from high-resolution Fourier transform Orbitrap mass spectrometry. Rapid Commun Mass Spectrom 28:1621–1634.  https://doi.org/10.1002/rcm.6938 CrossRefPubMedGoogle Scholar
  164. Uraguchi K (1969) Mycotoxic origin of cardiac beriberi. J Stored Prod Res 5:227–236.  https://doi.org/10.1016/0022-474X(69)90037-X CrossRefGoogle Scholar
  165. Van de Bittner KC, Nicholson MJ, Bustamante LY, Kessans SA, Ram A, van Dolleweerd CJ, Scott B, Parker EJ (2018) Heterologous biosynthesis of nodulisporic acid F. J Am Chem Soc 140:582–585.  https://doi.org/10.1021/jacs.7b10909 CrossRefPubMedGoogle Scholar
  166. van Dolleweerd CJ, Kessans SA, Van de Bittner KC, Bustamante LY, Bundela R, Scott B, Nicholson MJ, Parker EJ (2018) MIDAS: a modular DNA assembly system for synthetic biology. ACS Synth Biol 7:1018–1029.  https://doi.org/10.1021/acssynbio.7b00363 CrossRefPubMedGoogle Scholar
  167. Vishwanath V, Sulyok M, Labuda R, Bicker W, Krska R (2009) Simultaneous determination of 186 fungal and bacterial metabolites in indoor matrices by liquid chromatography/tandem mass spectrometry. Anal Bioanal Chem 395:1355–1372.  https://doi.org/10.1007/s00216-009-2995-2 CrossRefPubMedGoogle Scholar
  168. Walter SL (2002) Acute penitrem A and roquefortine poisoning in a dog. Can Vet J Rev Veterinaire Can 43:372–374.  https://doi.org/10.1016/0041-008X(76)90290-8 CrossRefGoogle Scholar
  169. Wiewióra B, Żurek G, Pańka D (2015) Is the vertical transmission of Neotyphodium lolii in perennial ryegrass the only possible way to the spread of endophytes? PLoS One 10:e0117231.  https://doi.org/10.1371/journal.pone.0117231 CrossRefPubMedPubMedCentralGoogle Scholar
  170. Wilkins AL, Miles CO, Ede RM, Gallagher RT, Munday SC (1992) Structure elucidation of janthitrem B, a tremorgenic metabolite of Penicillium janthinellum, and relative configuration of the A and B rings of janthitrems B, E, and F. J Agric Food Chem 40:1307–1309.  https://doi.org/10.1021/jf00020a002 CrossRefGoogle Scholar
  171. Yamaguchi T, Nozawa K, Hosoe T, Nakajima S, Kawai K (1993) Indoloditerpenes related to tremorgenic mycotoxins, penitrems, from Penicillium crustosum. Phytochemistry 32:1177–1181.  https://doi.org/10.1016/S0031-9422(00)95087-8 CrossRefGoogle Scholar
  172. You J, Du L, King JB, Hall BE, Cichewicz RH (2013) Small-molecule suppressors of Candida albicans biofilm formation synergistically enhance the antifungal activity of amphotericin B against clinical Candida isolates. ACS Chem Biol 8:840–848.  https://doi.org/10.1021/cb400009f CrossRefPubMedPubMedCentralGoogle Scholar
  173. Young C, McMillan L, Telfer E, Scott B (2001) Molecular cloning and genetic analysis of an indole-diterpene gene cluster from Penicillium paxilli. Mol Microbiol 39:754–764.  https://doi.org/10.1046/j.1365-2958.2001.02265.x CrossRefPubMedGoogle Scholar
  174. Young CA, Bryant MK, Christensen MJ, Tapper BA, Bryan GT, Scott B (2005) Molecular cloning and genetic analysis of a symbiosis-expressed gene cluster for lolitrem biosynthesis from a mutualistic endophyte of perennial ryegrass. Mol Gen Genomics 274:13–29.  https://doi.org/10.1007/s00438-005-1130-0 CrossRefGoogle Scholar
  175. Young CA, Felitti S, Shields K, Spangenberg G, Johnson RD, Bryan GT, Saikia S, Scott B (2006) A complex gene cluster for indole-diterpene biosynthesis in the grass endophyte Neotyphodium lolii. Fungal Genet Biol 43:679–693.  https://doi.org/10.1016/j.fgb.2006.04.004 CrossRefPubMedGoogle Scholar
  176. Zbib N, Repussard C, Tardieu D, Priymenko N, Domange C, Guerre P (2015) Toxicity of endophyte-infected ryegrass hay containing high ergovaline level in lactating ewes. J Anim Sci 93:4098–4109.  https://doi.org/10.2527/jas.2014-8848 CrossRefPubMedGoogle Scholar
  177. Zhang S, Monahan BJ, Tkacz JS, Scott B (2004) Indole-diterpene gene cluster from Aspergillus flavus. Appl Environ Microbiol 70:6875–6883.  https://doi.org/10.1128/AEM.70.11.6875-6883.2004 CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Molecular Biotechnology and Microbiology, Institute of Biotechnology, Faculty of Science and TechnologyUniversity of DebrecenDebrecenHungary
  2. 2.Teva Pharmaceutical Works Ltd.DebrecenHungary
  3. 3.Southwest Center for Natural Products Research, School of Natural Resources and the EnvironmentUniversity of ArizonaTucsonUSA

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