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Mm Widdo a Literatura Atariato Telut MM WIDDO A LITERATURAUS009790528B2 ATARIATO TELUT (12 ) United States Patent ( 10 ) Patent No. : US 9 , 790 ,528 B2 Panaccione et al. (45 ) Date of Patent : Oct . 17 , 2017 (54 ) PRODUCTION OF LYSERGIC ACID BY FOREIGN PATENT DOCUMENTS GENETIC MODIFICATION OF A FUNGUS WO 2014 / 030096 A2 2 /2014 (71 ) Applicant : West Virginia University , Morgantown , WV (US ) OTHER PUBLICATIONS ( 72 ) Inventors: Daniel G . Panaccione , Morgantown , Notification of Transmittal of the International Search Report WV (US ) ; Sarah L . Robinson , ( Forms PCT/ ISA / 220 and PCT/ ISA / 210 ) and the Written Opinion Independence , WV (US ) of the International Searching Authority ( Form PCT/ ISA / 237 ) issued on Dec . 1 , 2015 , in the International Application No . PCT / (73 ) Assignee : West Virginia University , US15 / 35784 . ( 19 pages ) . Morgantown , WV (US ) Š?igelová et al ., “ Biotransformation of Ergot Alkaloids by Plant Cell Cultures with High Peroxidase Activity, ” Biotechnology Let ( * ) Notice : Subject to any disclaimer , the term of this ters , (Nov . 1995 ) , vol. 17 , No . 11, pp . 1213 - 1218 . patent is extended or adjusted under 35 Singer et al. , “ High - Throughput TAIL -PCR as a Tool to Identify U . S . C . 154 ( b ) by 0 days . DNA Flanking Insertions, ” Methods in Molecular Biology, ( 2003 ) , vol. 236 , pp . 241 - 272 . ( 21 ) Appl. No. : 14 /739 , 382 ( Continued ) Î( 22 ) Filed : Jun . 15 , 2015 Primary Examiner - Robert Mondesi (65 ) Prior Publication Data Assistant Examiner — Richard Ekstrom US 2015 /0361471 A1 Dec . 17 , 2015 (74 ) Attorney , Agent, or Firm — Buchanan Ingersoll & Related U .S . Application Data Rooney PC ( 60 ) Provisional application No . 62/ 012 ,658 , filed on Jun . 16 , 2014 . ( 57 ) ABSTRACT (51 ) Int. Ci. C12P 17 / 18 ( 2006 .01 ) The present invention provides a method of producing C12N 15 /52 ( 2006 . 01 ) lysergic acid and other ergot alkaloids by genetic modifica (52 ) U . S . CI. tion of a fungus . A strain of fungus comprising Aspergillus CPC . .. .. C12P 17/ 182 ( 2013 .01 ); C12N 15 / 52 fumigatus ( A . fumigatus ) and expressing one or more genes ( 2013 .01 ) of the ergot alkaloid biosynthesis pathway from one or more ( 58 ) Field of Classification Search fungus selected from the group consisting of Epichloë None festucae var . loliixEpichloë typhina isolate Lpl ( E . sp . Lpl ) ; See application file for complete search history . Claviceps species ; Claviceps africana ( C . africana ); Clavi (56 ) References Cited ceps gigantea ( C . gigantea ); Epichloë coenophiala and Periglandula species, wherein gene easA or gene easM is U . S . PATENT DOCUMENTS inactivated in said A . fumigatus , is provided . 3 ,314 , 961 A 4 / 1967 Rutschmann et al. 2015 /0211036 A1 * 7 / 2015 Naesby .. .. C12N 9 / 001 435 / 122 18 Claims, 14 Drawing Sheets " ! NON W 5959 U IL TRAIN waste 1 - 2 , W ixxis 14: 29 - 12. 2 . 22 sigrics ? 233 tari ASK tunnelse: HIMSIAIN sok cic fumigadbazir: Nyergic rets Amer . 4492 EISA Muscypodium : US 9 ,790 , 528 B2 Page 2 ( 56 ) References Cited Ge et al. , “ Bioactive Alkaloids from Endophytic Aspergillus Fumigatus, ” Journal of Natural Products , ( 2009 ) , vol. 72 , No . 4 , pp . 753 -755 . OTHER PUBLICATIONS Goetz et al. , “ Ergot Cluster -Encoded Catalase is Required for Synthesis of Chanoclavine - I in Aspergillus Fumigatus, ” Current Tooley et al. , " Analysis of Claviceps Africana and C . Sorghi from Genetics , ( Jun . 2011 ) , vol. 57 , No . 3 , pp . 201 - 2011 . India using AFLPs, EF - la gene intron 4 , and B - tubulin gene intron Gröger et al . , " Chapter 5 Biochemistry of Ergot Alkaloids -Achieve 3 ,” Mycological Research, (Apr . 2006 ), vol . 110 , No. 4 , pp. 441 ments and Challenges , ” The Alkaloids: Chemistry and Biology , 451. ( 1998 ), vol. 50 , pp . 171 - 218 . Tsai et al . , “ The Developmentally Regulated albl Gene of Aspergil Haarmann et al. , “ The Ergot Alkaloid Gene Cluster in Claviceps lus fumigatus: Its Role in Modulation of Conidial Morphology and Purpurea : Extension of the Cluster Sequence and Intra Species Virulence , ” Journal of Bacteriology, ( Jun . 1998 ) , vol. 180 , No. 12 , Evolution , ” Phytochemistry , ( Jun . 2005 ) , vol. 66 , No . 11 , pp . pp . 3031 - 3038 . 1312 - 1320 . Unsöld et al. , “ Overproduction , Purification and Characterization of Haarmann et al. , “ Identification of the Cytochrome P450 FgaPT2 , a Dimethylallyltryptophan Synthase from Aspergillus Monooxygenase that Bridges the Clavine and Ergoline Alkaloid Fumigatus, ” Microbiology , (May 2005 ) , vol . 151, pp . 1499 - 1505 . Pathways, ” ChemBioChem , ( Apr. 2006 ) , vol. 7 , No . 4 , pp . 645 -652 . Unsöld et al. , “ Reverse Prenyltransferase in the Biosynthesis of Havemann et al . , “ Cyclolization of D - Lysergic Acid Alkaloid Fumigaclavine C in Aspergillus fumigatus: Gene Expression , Puri Peptides , ” Chemistry & Biology , ( Jan . 16 , 2014 ) , vol. 21 , No . 1 , pp . fication , and Characterization of Fumigaclavine C Synthase 146 - 155 . FGAPT1, " ChemBioChem , ( Jan . 2006 ) , vol. 7 , No . 1 , pp . 158 - 164 . Hofmann , “ LSDMy Problem Child ,” McGraw - Hill Book Com Wallwey et al ., “ Ergot Alkaloid Biosynthesis in Aspergillus pany, ( 1980 ) , ISBN 0 -07 -029325 - 2 , 102 pages . Fumigatus: Conversion of Chanoclavine - I to Chanoclavine - I Alde Hynes et al ., “ Isolation of Genomic Clones Containing the amds hyde Catalyzed by a short - chain Alcohol Dehydrogenase FgaDH , " Gene of Aspergillus Nidulans and Their Use in the Analysis of Arch Microbiol , ( Feb . 2010 ), vol . 192 , No . 2 , pp . 127 - 134 . Structural and Regulatory Mutations, ” Molecular and Cellular Biol Wallwey et al. , “ Ergot Alkaloid Biosynthesis in Aspergillus ogy , (Aug . 1983 ) , vol . 3 , No. 8 , pp . 1430 - 1439 . Fumigatus : Conversion of Chanoclavine - I Aldehyde to Festuclavine by the Festuclavine Synthase FgaFS in the presence of the old Kren et al. , " Ergot : The Genus Claviceps, " ( 2003 ) , https: / /books . yellow enzyme FgaOx3 ,” Organic & Biomolecular Chemistry , google . com /books ? isbn = 0203304195 . ( Aug. 2010 ) , vol. 8 , No . 15 , pp . 3500 - 3508 . Langfelder et al ., “ Identification of a Polyketide Synthase Gene Wallwey et al ., “ Ergot Alkaloids: Structure Diversity , Biosynthetic (pksP ) of Aspergillus Fumigatus Involved in Conidial Pigment Gene Clusters and Functional Proof of Biosynthetic Genes ,” Natu Biosynthesis and Virulence, ” Medical Microbiology and Immunol ral Product Reports , (Mar . 2011) , vol. 28 , No . 3 , pp . 496 -510 . ogy , (Oct . 1998 ) , vol . 187, No. 2 , pp . 79 -89 . Winblad et al ., “ Therapeutic Use of Nicergoline, " Clinical Drug Leuchtmann et al. , “ Nomenclatural Realignment of Neotyphodium Investigation , (Sep . 2008 ) , vol. 28 , No. 9 , pp . 533 -552 . Species with Genus Epichloë, ” Mycologia , ( Mar .- Apr . 2014 ), vol. Agurell et al. , “ A New Ergot Alkaloid from Mexican Maize Ergot, ” 106 , No . 2 , pp . 202 -215 . Acta Pharm . Suecica , ( Jun . 1965 ) , vol . 2 , pp . 231 - 238 . Lin et al. , “ Biosynthesis of Ergot Alkaloids, Synthesis of 6 -Methyl Barrow et al ., “ Biosynthesis of Dihydroergot Alkaloids, " Tetrahe 8 -Acetoxymethylene - 9 - Ergolene and Its Incorporation into dron Letter ; the International Organ for the Rapid Publication of Ergotoxine by Claviceps, " The Journal of Organic Chemistry , (Jun . Preliminary Communications in Organic Chemistry , ( 1974 ) , vol. 15 , 1973 ) , vol. 38 , No . 12 , pp . 2249 - 2251 . No . 16 , pp . 1557 - 1560 . Liu et al. , “ Amplification of Genomic Sequences Flanking T -DNA Baskys et al. , “ Vascular Dementia : Pharmacological Treatment Insertions by Thermal Asymmetric Interlaced Polymerase Chain Approaches and Perspectives , " Clinical Interventions in Aging , Reaction , ” Methods in Molecular Biology , (2005 ) , vol . 286 , pp . (2007 ), vol. 2 , No . 3 , pp . 327 - 335 . 341 - 348 . Beliveau et al. , “ 8 -Hydroxylation of Agroclavine and Elymoclavine Liu et al. , “ High -Efficiency Thermal Asymmetric Interlaced PCR by Fungi, ” Lloydia , (Sep . 1966 ) , vol. 29 , No . 3 , pp . 234 - 238 . for Amplification of Unknown Flanking Sequences, " Cheng et al . , " A Role for Old Yellow Enzyme in Ergot Alkaloid Bio Techniques , (Nov . 2007 ) , vol . 43 , No . 5 , pp . 649 -656 . Biosynthesis , ” Journal of the American Chemical Society , ( Jan . 26 , Lorenz et al . , “ Comparison of Ergot Alkaloid Biosynthesis Gene 2010 ) , vol. 132, No. 6 , pp . 1776 - 1777 . Clusters in Claviceps Species Indicates Loss of Late Pathway Steps Cheng et al. , “ Controlling a Structural Branch Point in Ergot in Evolution of C . fusiformis ,” Applied and Environmental Micro Alkaloid Biosynthesis ,” Journal of the American Chemical Society , biology , (Nov . 2007) , vol. 73, No . 22, pp . 7185 -7191 . ( Aug . 25 , 2010 ) , vol. 132 , No. 37 , pp . 12835 - 12837 . Lorenz et al ., “ The Ergot Alkaloid Gene Cluster : Functional Analy Coyle et al. , " An Ergot Alkaloid Biosynthesis Gene and Clustered ses and Evolutionary Aspects ,” Phytochemistry , ( Oct. -Nov . 2009 ), HypotheticalGene form Aspergillus Fumigatus, ” Applied and Envi vol. 70 , No . 15 - 16 , pp . 1822 - 1832 . ronmentalMicrobiology , ( Jun . 2005 ) , vol . 71 , No . 6 , pp . 3112 - 3118 . Maier et al. , “ Microsomal Oxygenases Involved in Ergoline Alka Coyle et al. , “ An Old Yellow Enzyme Gene Controls the Branch loid Biosynthesis of Various Claviceps Strains, ” Journal of Basic Point between Aspergillus Fumigatus and Claviceps Purpurea Ergot Microbiology , ( 1988 ) , vol. 28 , No. 1 - 2 , pp . 83 - 93 . Alkaloid Pathways, " Applied and
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