RU2729065C2 - Композиции и способы получения (R)-ретикулина и его предшественников - Google Patents

Композиции и способы получения (R)-ретикулина и его предшественников Download PDF

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RU2729065C2
RU2729065C2 RU2016124228A RU2016124228A RU2729065C2 RU 2729065 C2 RU2729065 C2 RU 2729065C2 RU 2016124228 A RU2016124228 A RU 2016124228A RU 2016124228 A RU2016124228 A RU 2016124228A RU 2729065 C2 RU2729065 C2 RU 2729065C2
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Питер Джеймс ФАЧЧИНИ
Скотт Кэмерон ФЭРРОУ
Гийом Артур Уэлш БОДУЭН
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Эпимерон Инк.
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01H—NEW PLANTS OR NON-TRANSGENIC PROCESSES FOR OBTAINING THEM; PLANT REPRODUCTION BY TISSUE CULTURE TECHNIQUES
    • A01H1/00—Processes for modifying genotypes ; Plants characterised by associated natural traits
    • A01H1/04—Processes of selection involving genotypic or phenotypic markers; Methods of using phenotypic markers for selection
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/52—Genes encoding for enzymes or proenzymes
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01H—NEW PLANTS OR NON-TRANSGENIC PROCESSES FOR OBTAINING THEM; PLANT REPRODUCTION BY TISSUE CULTURE TECHNIQUES
    • A01H1/00—Processes for modifying genotypes ; Plants characterised by associated natural traits
    • A01H1/06—Processes for producing mutations, e.g. treatment with chemicals or with radiation
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01H—NEW PLANTS OR NON-TRANSGENIC PROCESSES FOR OBTAINING THEM; PLANT REPRODUCTION BY TISSUE CULTURE TECHNIQUES
    • A01H5/00—Angiosperms, i.e. flowering plants, characterised by their plant parts; Angiosperms characterised otherwise than by their botanic taxonomy
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/24—Oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
    • C12N15/8216—Methods for controlling, regulating or enhancing expression of transgenes in plant cells
    • C12N15/8218—Antisense, co-suppression, viral induced gene silencing [VIGS], post-transcriptional induced gene silencing [PTGS]
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/79—Vectors or expression systems specially adapted for eukaryotic hosts
    • C12N15/82—Vectors or expression systems specially adapted for eukaryotic hosts for plant cells, e.g. plant artificial chromosomes (PACs)
    • C12N15/8241—Phenotypically and genetically modified plants via recombinant DNA technology
    • C12N15/8242—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits
    • C12N15/8243—Phenotypically and genetically modified plants via recombinant DNA technology with non-agronomic quality (output) traits, e.g. for industrial processing; Value added, non-agronomic traits involving biosynthetic or metabolic pathways, i.e. metabolic engineering, e.g. nicotine, caffeine
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0006—Oxidoreductases (1.) acting on CH-OH groups as donors (1.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/0004—Oxidoreductases (1.)
    • C12N9/0071—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14)
    • C12N9/0077—Oxidoreductases (1.) acting on paired donors with incorporation of molecular oxygen (1.14) with a reduced iron-sulfur protein as one donor (1.14.15)
    • C12N9/0081—Cholesterol monooxygenase (cytochrome P 450scc)(1.14.15.6)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/10—Transferases (2.)
    • C12N9/1085—Transferases (2.) transferring alkyl or aryl groups other than methyl groups (2.5)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y101/00—Oxidoreductases acting on the CH-OH group of donors (1.1)
    • C12Y101/01—Oxidoreductases acting on the CH-OH group of donors (1.1) with NAD+ or NADP+ as acceptor (1.1.1)
    • C12Y101/01247—Codeinone reductase (NADPH) (1.1.1.247)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y205/00—Transferases transferring alkyl or aryl groups, other than methyl groups (2.5)
    • C12Y205/01—Transferases transferring alkyl or aryl groups, other than methyl groups (2.5) transferring alkyl or aryl groups, other than methyl groups (2.5.1)
    • C12Y205/01059—Protein geranylgeranyltransferase type I (2.5.1.59)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Organic Chemistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Biotechnology (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Biomedical Technology (AREA)
  • Biochemistry (AREA)
  • Microbiology (AREA)
  • Physics & Mathematics (AREA)
  • Biophysics (AREA)
  • Plant Pathology (AREA)
  • Cell Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Environmental Sciences (AREA)
  • Developmental Biology & Embryology (AREA)
  • Botany (AREA)
  • Nutrition Science (AREA)
  • Virology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Physiology (AREA)
  • Immunology (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Enzymes And Modification Thereof (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Breeding Of Plants And Reproduction By Means Of Culturing (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
RU2016124228A 2013-12-04 2014-12-03 Композиции и способы получения (R)-ретикулина и его предшественников RU2729065C2 (ru)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US201361911759P 2013-12-04 2013-12-04
US61/911,759 2013-12-04
US201462050399P 2014-09-15 2014-09-15
US62/050,399 2014-09-15
PCT/CA2014/051164 WO2015081437A1 (en) 2013-12-04 2014-12-03 Compositions and methods for making (r)-reticuline and precursors thereof

Related Child Applications (1)

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RU2020124813A Division RU2834392C9 (ru) 2013-12-04 2014-12-03 Композиции и способы получения (R)-ретикулина и его предшественников

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RU2729065C2 true RU2729065C2 (ru) 2020-08-04

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US (3) US10190141B2 (enExample)
EP (2) EP4289959A1 (enExample)
JP (1) JP6783655B2 (enExample)
KR (2) KR102491060B1 (enExample)
CN (3) CN115927140A (enExample)
AU (4) AU2014360597B2 (enExample)
BR (1) BR112016012595B1 (enExample)
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IL (2) IL245970B (enExample)
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Families Citing this family (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ711538A (en) 2013-03-15 2017-03-31 Univ Leland Stanford Junior Benzylisoquinoline alkaloids (bia) producing microbes, and methods of making and using the same
US11124814B2 (en) 2013-11-04 2021-09-21 The Board Of Trustees Of The Leland Stanford Junior University Benzylisoquinoline alkaloid (BIA) precursor producing microbes, and methods of making and using the same
US10190141B2 (en) * 2013-12-04 2019-01-29 Epimeron Inc. Compositions and methods for making (R)-Reticuline and precursors thereof
US10006010B2 (en) 2014-05-16 2018-06-26 The University Of York Cytochrome P450 fusion protein
WO2016179296A1 (en) 2015-05-04 2016-11-10 The Board Of Trustees Of The Leland Stanford Junior University Benzylisoquinoline alkaloid (bia) precursor producing microbes, and methods of making and using the same
CA2983445A1 (en) * 2015-05-08 2016-11-17 The Board Of Trustees Of The Leland Stanford Junior University Methods of producing epimerases and benzylisoquinoline alkaloids
GB201511156D0 (en) 2015-06-24 2015-08-05 Glaxosmithkline Australia Pty Ltd And University Of York Production of alkaloids
CA3029263A1 (en) 2016-06-27 2018-01-04 Intrexon Corporation Compositions and methods for making benzylisoquinoline alkaloids, morphinan alkaloids, thebaine, and derivatives thereof
WO2018000089A1 (en) * 2016-06-27 2018-01-04 Serturner Corp. Polynucleotides and polypeptides useful for making alkaloid compounds
CN106119265B (zh) * 2016-06-30 2019-04-30 湖南美可达生物资源股份有限公司 博落回中参与血根碱与白屈菜红碱合成的细胞色素p450酶基因及其应用
AU2017345328C1 (en) 2016-10-18 2023-03-02 Antheia, Inc. Methods of producing nor-opioid and nal-opioid benzylisoquinoline alkaloids
WO2019028390A1 (en) 2017-08-03 2019-02-07 Antheia, Inc. ALKALOID BENZYLISOQUINOLEIN GENETICALLY MODIFIED EPIMERASES AND METHODS FOR PRODUCING BENZYLISOQUINOLINE ALKALOIDS
EP3749769A4 (en) 2018-02-08 2021-12-08 Antheia, Inc. PROCESS FOR THE PREPARATION OF MORPHINE ALKALOIDS AND DERIVATIVES
EP3934765A4 (en) 2019-03-08 2022-11-30 The Board Of Trustees Of The Leland Stanford Junior University TROPANE ALKALOID (TA) PRODUCING NON-PLANT HOST CELLS AND METHODS FOR THEIR MANUFACTURE AND USE
JP7648038B2 (ja) 2019-06-24 2025-03-18 ファーメランタ株式会社 （ｒ）－レチクリンの生産方法
EP4615963A1 (en) 2022-11-08 2025-09-17 River Stone Biotech ApS Genetically modified benzylisoquinoline alkaloid-producing host cells with modified efflux transporter gene expression
CN119776567A (zh) * 2024-12-16 2025-04-08 广西壮族自治区农业科学院 鉴定番荔枝种质资源的分子标记引物试剂盒及应用

Citations (4)

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SU507204A3 (ru) * 1973-02-12 1976-03-15 Мерк Энд Ко Инк (Фирма) Способ получени (+) салютаридина
EP1837396A1 (en) * 2006-03-23 2007-09-26 Institut für Pflanzenbiochemie-IPB Salutaridine reductase and morphine biosynthesis
US20070298481A1 (en) * 2003-09-17 2007-12-27 Fumihiko Sato Method for Producing a Useful Intermediate in Alkaloid Biosynthesis By Using Rnai Technology
WO2008067070A2 (en) * 2006-10-19 2008-06-05 California Institute Of Technology Compositions and methods for producing benzylisoquinolines alkaloids

Family Cites Families (8)

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GB1408729A (en) * 1973-08-13 1975-10-01 Lilly Co Eli Sulphilimine compounds
US5268463A (en) 1986-11-11 1993-12-07 Jefferson Richard A Plant promoter α-glucuronidase gene construct
AUPP946399A0 (en) 1999-03-26 1999-04-22 Johnson & Johnson Research Pty. Limited Codeinone reductase from alkaloid poppy
WO2011058446A2 (en) 2009-11-12 2011-05-19 Uti Limited Partnership Thebaine 6-o-demethylase and codeine o-demethylase from papaver somniferum
US10190141B2 (en) * 2013-12-04 2019-01-29 Epimeron Inc. Compositions and methods for making (R)-Reticuline and precursors thereof
WO2015103711A1 (en) 2014-01-13 2015-07-16 Valorbec Société en Commandite Method of making a benzylisoquinoline alkaloid (bia) metabolite, enzymes therefore
US10006010B2 (en) * 2014-05-16 2018-06-26 The University Of York Cytochrome P450 fusion protein
CA2983445A1 (en) 2015-05-08 2016-11-17 The Board Of Trustees Of The Leland Stanford Junior University Methods of producing epimerases and benzylisoquinoline alkaloids

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SU507204A3 (ru) * 1973-02-12 1976-03-15 Мерк Энд Ко Инк (Фирма) Способ получени (+) салютаридина
US20070298481A1 (en) * 2003-09-17 2007-12-27 Fumihiko Sato Method for Producing a Useful Intermediate in Alkaloid Biosynthesis By Using Rnai Technology
EP1837396A1 (en) * 2006-03-23 2007-09-26 Institut für Pflanzenbiochemie-IPB Salutaridine reductase and morphine biosynthesis
WO2008067070A2 (en) * 2006-10-19 2008-06-05 California Institute Of Technology Compositions and methods for producing benzylisoquinolines alkaloids

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BR112016012595B1 (pt) 2024-02-27
CN115927140A (zh) 2023-04-07
JP2017500024A (ja) 2017-01-05
KR20160093042A (ko) 2016-08-05
DK3077513T3 (da) 2023-10-23
US20240002894A1 (en) 2024-01-04
AU2020200131A1 (en) 2020-01-30
US11613770B2 (en) 2023-03-28
CN115927139A (zh) 2023-04-07
KR20190108160A (ko) 2019-09-23
US20160312256A1 (en) 2016-10-27
EP3077513B1 (en) 2023-08-23
IL245970A0 (en) 2016-07-31
MX2016007176A (es) 2016-12-08
BR112016012595A2 (pt) 2017-09-26
KR102018240B1 (ko) 2019-09-04
DK3077513T5 (da) 2024-10-14
AU2020201743A1 (en) 2020-03-26
AU2014360597A1 (en) 2016-06-09
AU2022279419B2 (en) 2025-07-24
CN105980563A (zh) 2016-09-28
IL271289A (en) 2020-01-30
EP3077513A4 (en) 2017-06-21
US20190241919A1 (en) 2019-08-08
CA2932448A1 (en) 2015-06-11
KR102491060B1 (ko) 2023-01-20
AU2022279419A1 (en) 2023-01-19
JP6783655B2 (ja) 2020-11-11
ES2961516T3 (es) 2024-03-12
EP3077513A1 (en) 2016-10-12
EP4289959A1 (en) 2023-12-13
AU2014360597B2 (en) 2020-01-30
CA2932448C (en) 2021-08-31
MX364825B (es) 2019-05-08
AU2020201743B2 (en) 2022-03-17
CN105980563B (zh) 2022-08-30
IL271289B (en) 2022-04-01
WO2015081437A1 (en) 2015-06-11
US10190141B2 (en) 2019-01-29

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