Granted Patent
B2
US 12,480,131 · App. 17/436,546 · Granted Nov 25, 2025
Tropane alkaloid (TA) producing non-plant host cells, and methods of making and using the same
C12N15/52C12N9/0006C12N9/0022C12N9/0032C12N9/0071C12N9/1007C12N9/78C12N9/88C12P17/12C12P17/188C12Y101/01027C12Y101/01206C12Y101/01236C12Y101/01237C12Y102/01003C12Y104/0301C12Y104/03021C12Y104/03022C12Y105/03017C12Y106/02004C12Y114/11011C12Y201/01053C12Y203/01001C12Y203/01035C12Y204/02028C12Y205/01022C12Y206/01057C12Y207/07009C12Y207/11001C12Y305/01053C12Y305/03001C12Y305/03011C12Y305/03012C12Y401/01001C12Y401/01017C12Y401/01019C12Y402/01051C12Y403/01024C12Y403/01025
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Abstract
Provided herein, among other things, is an engineered non-plant cell that produces a tropane alkaloid product, a precursor of a tropane alkaloid product, or a derivative of a tropane alkaloid product. A method for producing a tropane alkaloid, a precursor of a tropane alkaloid product, or a derivative of a tropane alkaloid product that makes use of the cell is also described.
Claims (19)
1 . An engineered non-plant cell that produces a precursor of a tropane alkaloid product, a tropane alkaloid product, or a derivative of a tropane alkaloid product, wherein the engineered non-plant cell comprises a heterologous coding sequences encoding hyoscyamine dehydrogenase (HDH) within a pathway for producing the precursor of a tropane alkaloid product, the tropane alkaloid product, or the derivative of a tropane alkaloid product.
2 . The engineered cell of claim 1 , wherein the cell further comprises one or more alterations to one or more endogenous metabolic pathways or regulatory mechanisms selected from the group of endogenous arginine metabolism, endogenous phenylalanine and phenylpropanoid metabolism, endogenous polyamine regulatory mechanisms and metabolism, and endogenous acetate metabolism.
3 . The engineered cell of claim 2 , wherein endogenous arginine metabolism is altered in the cell by modifications to one or more coding sequences of one or more endogenous enzymes, wherein at least one of the enzymes is selected from the group consisting of glutamate N-acetyltransferase, acetylglutamate kinase, N-acetyl-y-glutamyl-phosphate reductase, acetylornithine aminotransferase, ornithine acetyltransferase, ornithine carbamoyltransferase, argininosuccinate synthase, argininosuccinate lyase, and arginase.
4 . The engineered cell of claim 2 , wherein endogenous phenylalanine and phenylpropanoid metabolism is altered in the engineered cell by modifications to one or more coding sequences of one or more endogenous enzymes, wherein at least one of the enzymes is selected from the group consisting of pentafunctional AROM polypeptide, chorismate synthase, chorismate mutase, prephenate dehydratase, aromatic aminotransferase, and phenylacrylic acid decarboxylase.
5 . The engineered cell of claim 2 , wherein endogenous polyamine regulatory mechanisms are altered in the engineered cell by modifications to one or more coding sequences of one or more endogenous proteins, wherein at least one of the proteins is selected from the group consisting of methylthioadenosine phosphorylase, ornithine decarboxylase, ornithine decarboxylase antizyme, polyamine oxidase, spermidine synthase, spermine synthase, polyamine transporter, and polyamine permease.
6 . The engineered cell of claim 2 , wherein endogenous acetate metabolism is altered in the engineered cell by modifications to one or more coding sequences of one or more endogenous enzymes, wherein at least one of the enzymes is selected from the group consisting of alcohol dehydrogenase and aldehyde dehydrogenase.
7 . The engineered cell of claim 1 , wherein the engineered cell further comprises one or more alterations to endogenous glycoside metabolism.
8 . The engineered cell of claim 7 , wherein endogenous glycoside metabolism is altered in the engineered cell by modifications to one or more coding sequences of one or more endogenous enzymes, wherein at least one of the enzymes is selected from the group consisting of glucan 1,3-f3-glucosidase and steryl-P-glucosidase.
9 . The engineered cell of claim 8 , wherein the modifications to one or more coding sequences is selected from the group consisting of a feedback inhibition alleviating mutation in a biosynthetic enzyme or regulatory protein gene native to the cell, a transcriptional modulation modification of a biosynthetic enzyme gene native to the cell, and an inactivating mutation in an enzyme or protein native to the cell.
10 . The engineered cell of claim 1 , wherein the engineered cell is selected from the group consisting of a microbial cell, a fungal cell, a yeast cell, and a bacterial cell.
11 . The engineered cell of claim 10 , wherein the engineered cell is a fungal cell.
12 . The engineered cell of claim 1 , wherein the engineered cell further comprises one or more heterologous coding sequences for one or more enzymes, wherein at least one of the enzymes is selected from the group consisting of arginine decarboxylase, agmatine ureohydrolase, agmatinase, putrescine N-methyltransferase, N-methylputrescine oxidase, pyrrolidine ketide synthase, tropinone synthase, cytochrome P450 reductase, tropinone reductase, phenylalanine ammonia-lyase, tyrosine ammonia-lyase, phenylpyruvate reductase, 4-coumarate-CoA ligase, 3-phenyllactic acid UDP-glucosyltransferase 84A27, littorine synthase, littorine mutase, hyoscyamine 6β-hydroxylase/dioxygenase, and cocaine synthase.
13 . The engineered cell of claim 1 , wherein the engineered cell further comprises one or more heterologous coding sequences encoding one or more enzymes which comprise one or more soluble protein domains fused to the N-terminus of a serine carboxypeptidase-like acyltransferase domain for the purpose of enabling functional expression of the acyltransferase domain in a sub-cellular compartment of the engineered cell.
14 . The engineered cell of claim 1 , wherein the engineered cell produces a precursor of a tropane alkaloid product selected from the group consisting of an agmatine, N-carbamoylputrescine, N-methylputrescine, 4-methylaminobutanal, N-methylpyrrolinium, 4-(1-methyl-2-pyrrodiny 1)-3-oxobutanoic acid, tropinone, tropine, pseudotropine, ecgonine, methylecgonine, coenzyme A covalently bonded to phenyllactic acid by means of a thioester linkage, a sugar covalently bonded to cinnamic acid, ferulic acid, coumaric acid, and phenyllactic acid by means of a glycosidic linkage.
15 . The engineered cell of claim 1 , wherein the engineered cell produces a tropane alkaloid product selected from the group consisting of a hyoscyamine, atropine, anisodamine, scopolamine, calystegine, cocaine, and a non-natural tropane alkaloid.
16 . The engineered cell of claim 15 , wherein the engineered cell produces a tropane alkaloid product selected from the group consisting of a hyoscyamine, atropine, and a scopolamine.
17 . The engineered cell of claim 1 , wherein the engineered cell produces a derivative of a tropane alkaloid product selected from the group consisting of p-hydroxyatropine, p-hydroxyhyoscyamine, p-fluorohyoscyamine, p-chlorohyoscyamine, p-bromohyoscyamine, p-fluoroscopolamine, p-chloropscopolamine, p-bromoscopolamine, N-methylhyoscyamine, N-butylhyoscyamine, N-methylscopolamine, N-butylscopolamine, N-acetylhyoscyamine, and N-acetylscopolamine.
18 . The engineered cell of claim 1 , wherein transport of one or more tropane alkaloids, one or more tropane alkaloid precursors, and/or one or more tropane alkaloid derivatives across intracellular membranes or across the plasma membrane is modified in the cell.
19 . The engineered cell of claim 18 , wherein modified transport is enabled by one or more heterologous coding sequences encoding one or more transporters, wherein at least one of the transporters is selected from the group consisting of a multidrug and toxin extrusion transporter, a nitrate/peptide family transporter, an ATP-binding cassette transporter, and a pleiotropic drug resistance transporter.
Assignments (2)
SECURITY INTEREST
Recorded Aug 29, 2025
From: ANTHEIA, INC.
To: HERCULES CAPITAL, INC., AS AGENT
Reel/Frame 072750/0812 →
ASSIGNMENT OF ASSIGNOR'S INTEREST
Recorded Sep 3, 2021
From: SMOLKE, CHRISTINA D.; SRINIVASAN, PRASHANTH
To: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY
Reel/Frame 057387/0275 →
Continuity (4)
Provisional Application
62891771
· Aug 26, 2019
Provisional Application
62848419
· May 15, 2019
Provisional Application
62815709
· Mar 8, 2019
References Cited (338)
US 2778832A
· Gates, Jr. et al.
· 1957
[cited by applicant]
US 3785927A
· Schoenewaldt et al.
· 1974
[cited by applicant]
US 4764615A
· Ayyangar et al.
· 1988
[cited by applicant]
US 6183985B1
· Shuster
· 2001
[cited by applicant]
US 6204337B1
· Corcoran et al.
· 2001
[cited by applicant]
US 6579985B1
· Hill
· 2003
[cited by applicant]
US 6949645B1
· Francis
· 2005
[cited by applicant]
US 7037674B1
· Kutchan et al.
· 2006
[cited by applicant]
US 7045290B2
· Lindquist et al.
· 2006
[cited by applicant]
US 7193127B1
· Kutchan et al.
· 2007
[cited by applicant]
US 7390642B2
· Kutchan et al.
· 2008
[cited by applicant]
US 7514251B2
· Kutchan et al.
· 2009
[cited by applicant]
US 7767428B2
· Kutchan et al.
· 2010
[cited by applicant]
US 8318474B1
· Smolke et al.
· 2012
[cited by applicant]
US 8710226B2
· Patel et al.
· 2014
[cited by applicant]
US 8735111B2
· Vanhercke et al.
· 2014
[cited by applicant]
US 8975063B2
· Smolke et al.
· 2015
[cited by applicant]
US 8993280B2
· Sato et al.
· 2015
[cited by applicant]
US 9200261B2
· Winzer et al.
· 2015
[cited by applicant]
US 9322039B2
· Smolke et al.
· 2016
[cited by applicant]
US 9376696B1
· Smolke et al.
· 2016
[cited by applicant]
US 9447444B2
· Winzer et al.
· 2016
[cited by applicant]
US 9458481B2
· Winzer et al.
· 2016
[cited by applicant]
US 9534241B2
· Smolke et al.
· 2017
[cited by applicant]
US 9725732B2
· Winzer et al.
· 2017
[cited by applicant]
US 9862979B2
· Winzer et al.
· 2018
[cited by applicant]
US 9926329B2
· Huntley et al.
· 2018
[cited by applicant]
US 20040038352A1
· Maier
· 2004
[cited by applicant]
US 20050139490A1
· Chou et al.
· 2005
[cited by applicant]
US 20060185032A1
· Kutchan et al.
· 2006
[cited by applicant]
US 20070199090A1
· Apuya et al.
· 2007
[cited by applicant]
US 20070298481A1
· Sato
· 2007
[cited by applicant]
US 20080102499A1
· Templeton et al.
· 2008
[cited by applicant]
US 20080196123A1
· Kutchan et al.
· 2008
[cited by applicant]
US 20100075385A1
· Kutchan et al.
· 2010
[cited by applicant]
US 20130340119A1
· Plesch et al.
· 2013
[cited by applicant]
US 20140013465A1
· Coombs et al.
· 2014
[cited by applicant]
US 20160340704A1
· Martin et al.
· 2016
[cited by applicant]
US 20170253898A1
· Smolke et al.
· 2017
[cited by applicant]
US 20190100781A1
· Smolke et al.
· 2019
[cited by applicant]
US 20190127770A1
· Siddiqui et al.
· 2019
[cited by applicant]
CA 2728766A1
· 2009
[cited by applicant]
CN 102657652A
· 2012
[cited by applicant]
CS 277517B6
· 1993
[cited by applicant]
EP 1512748A1
· 2005
[cited by applicant]
EP 1837396A1
· 2007
[cited by applicant]
JP H05504252A
· 1993
[cited by applicant]
JP 2000300277A
· 2000
[cited by applicant]
JP 2009225669A
· 2009
[cited by applicant]
JP 2014525255A
· 2014
[cited by applicant]
WO WO2000058333A1
· 2000
[cited by applicant]
WO WO2002101052A2
· 2002
[cited by applicant]
WO WO2005021763A2
· 2005
[cited by applicant]
WO WO2006015887A2
· 2006
[cited by applicant]
WO WO2008067070A2
· 2008
[cited by applicant]
WO WO2008067070A3
· 2008
[cited by applicant]
WO WO2008153094A1
· 2008
[cited by applicant]
WO WO2009122436A2
· 2009
[cited by applicant]
WO WO2011058446A2
· 2011
[cited by applicant]
WO WO2011161431A2
· 2011
[cited by applicant]
WO WO2012039438A1
· 2012
[cited by applicant]
WO WO2012135389A2
· 2012
[cited by applicant]
WO WO2013136057A2
· 2013
[cited by applicant]
WO WO2014143744A2
· 2014
[cited by applicant]
WO WO2015021561A1
· 2015
[cited by applicant]
WO WO2015066642A1
· 2015
[cited by applicant]
WO WO2015081437A1
· 2015
[cited by applicant]
WO WO2015103711A1
· 2015
[cited by applicant]
WO WO2014143744A3
· 2015
[cited by applicant]
WO WO2015164960A1
· 2015
[cited by applicant]
WO WO2015173590A1
· 2015
[cited by applicant]
WO WO2016049364A2
· 2016
[cited by applicant]
WO WO2016081371A1
· 2016
[cited by applicant]
WO WO2016149821A1
· 2016
[cited by applicant]
WO WO2016179296A1
· 2016
[cited by applicant]
WO WO2016207643A1
· 2016
[cited by applicant]
WO WO2017083632A1
· 2017
[cited by applicant]
WO WO2017122011A1
· 2017
[cited by applicant]
WO WO2018000089A1
· 2018
[cited by applicant]
WO WO2018005553A1
· 2018
[cited by applicant]
WO WO2018027324A1
· 2018
[cited by applicant]
WO WO2018029282A1
· 2018
[cited by applicant]
WO WO2018039749A1
· 2018
[cited by applicant]
WO WO2018136654A1
· 2018
[cited by applicant]
WO WO2018203947A9
· 2018
[cited by applicant]
WO WO2019013696A1
· 2019
[cited by applicant]
Mugford et al. “A serine carboxypeptidase-like acyltransferase is required for synthesis of antimicrobial compounds and disease resistance in oats. Plant Cell. Aug. 2009;21” (Year: 2009).
[cited by examiner]
Methods of Analysis: Tropane Alkaloids from Plant Origin Profile image of Philippe ChristenPhilippe Christen 2013, Natural Products pdf (Year: 2013).
[cited by examiner]
Robins, R.J., Parr, A.J., Bent, E.G et al. Studies on the biosynthesis of tropane alkaloids in
[cited by examiner]
Nguyen (“Unravelling the architecture and dynamics of tropane alkaloid biosynthesis pathways using metabolite correlation networks” Phytochemistry, vol. 116, 2015). (Year: 2015).
[cited by examiner]
Junker (“Evolution of the key alkaloid enzyme putrescine N-methyltransferase from spermidine synthase” Front. Plant Sci., Jul. 28, 2013) (Year: 2013).
[cited by examiner]
Viladomat ((2015) “General Overview of Plant Secondary Metabolism.” Plant Biology and Biotechnology. Springer, New Delhi.) (Year: 2015).
[cited by examiner]
Muthana et al. (“Modifications of glycans: biological significance and therapeutic opportunities.” ACS Chem Biol. Jan. 20, 2012;7(1): 31-43. doi: 10.1021/cb2004466. Epub Jan. 11, 2012. PMID: 22195988; PMCID: PMC3262866.…
[cited by examiner]
Cardillo et al., Expression of Brugmansia candida Hyoscyamine 6beta-Hydroxylase gene in
[cited by applicant]
Kohnen-Johannsen et al., Tropane Alkaloids: Chemistry, Pharmacology, Biosynthesis and Production, Molecules, 24(4), 796 (Feb. 22, 2019).
[cited by applicant]
Ping et al., Building Microbial Hosts for Heterologous Production of N-Methylpyrrolinium, ACS Synth. Biol., 8, 2, 257-263 (Jan. 29, 2019).
[cited by applicant]
Srinivasan et al., Engineering a microbial biosynthesis platform for de novo production of tropane alkaloids, Nat Commun 10, 3634 (Aug. 12, 2019 ).
[cited by applicant]
Srinivasan et al., Biosynthesis of medicinal tropane alkaloids in yeast, Nature 585, 614-619 (Sep. 2, 2020).
[cited by applicant]
Srinivasan et al., Engineering cellular metabolite transport for biosynthesis of computationally predicted tropane alkaloid derivatives in yeast, PNAS, vol. 118, No. 25 (Jun. 17, 2021).
[cited by applicant]
Pasternak et al., Preclinical Pharmacology and Opioid Combinations, Pain Med. Mar. 1, 2012; 13(s1): S4-S11.
[cited by applicant]
Facchini et al., Synthetic biosystems for the production of high-value plant metabolites, Trends in Biotechnology, 30 (3):127-31, Dec. 29, 2011.
[cited by applicant]
Singh et al., Protein Engineering Approaches in the Post-Genomic Era, Curr Protein Pept Sci, 18:1-11, 2017.
[cited by applicant]
Zhang et al., Propagated Perturbations from a Peripheral Mutation Show Interactions Supporting WW Domain Thermostability, Structure, 26(11):1474-85, Nov. 6, 2018.
[cited by applicant]
Sadowski et al., The sequence-structure relationship and protein function prediction, Curr Opin Struct Biol, Jun. 2009;19(3):357-62.
[cited by applicant]
Tang et al., Identification of Dehalobacter reductive dehalogenases that catalyse dechlorination of chloroform, 1,1,1-trichloroethane and 1,1-dichloroethane, Phil Trans R Soc B 368: Mar. 18, 2012.
[cited by applicant]
Alcantara et al., Sanguinarine Biosynthesis Is Associated with the Endoplasmic Reticulum in Cultured Opium Poppy Cells after Elicitor Treatment, Plant Physiology, Apr. 22, 2005, 138:173-183.
[cited by applicant]
Allen et al., RNAi-Mediated Replacement of Morphine with the Nonnarcotic Alkaloid Reticuline in Opium Poppy, Nat. Biotechnol. (Nov. 2004), 22:1559-1566.
[cited by applicant]
Altschul et al., Basic Local Alignment Search Tool, J. Molec. Biol. 215:403-410 (May 1990).
[cited by applicant]
Avalos et al., Compartmentalization of Metabolic Pathways in Yeast Mitochondria Improves the Production of Branched-Chain Alcohols, Nat. Biotechnol. (Apr. 2013), 31:335-341.
[cited by applicant]
Axelsson et al., Cell separation, centrifugation. Enc. Indust. Biotechnol: Bioprocess, Bioseparation and Cell Technol., 2010, pp. 1-20; Ed., Flickinger M.C., John Wiley & Sons, Inc.
[cited by applicant]
Ba et al., Semi-Rational Engineering of Cytochrome P450sca-2 in a Hybrid System for Enhanced Catalytic Activity: Insights Into the Important Role of Electron Transfer, Biotechnology and Bioengineering, Nov. 2013, 110(11…
[cited by applicant]
Babiskin et al., A synthetic library of RNA control modules for predictable tuning of gene expression in yeast, Mol. Syst Biol., Jan. 2011;7:471.
[cited by applicant]
Backes et al., Organization of Multiple Cytochrome P450s with NADPH-Cytochrome P450 Reductase in Membranes, Pharmacol. Ther. (May 2003), 98:221-233.
[cited by applicant]
Bairoch, The ENZYME database in 2000, Nucleic Acids Research, Jan. 2000, 28(1):304-305.
[cited by applicant]
Banerjee et al., Improving Enzymes for Biomass Conversion: A Basic Research Perspective, Bioenerg. Res., Jan. 2010, 3:82-92.
[cited by applicant]
Bayer et al., Synthesis of Methyl Halides from Biomass Using Engineered Microbes, J. Am. Chem. Soc. (Apr. 2009), 131:6508-6515.
[cited by applicant]
Beaudoin, Characterization of Oxidative Enzymes Involved in the Biosynthesis of Benzylisoquinoline Alkaloids in Opium Poppy, Mar. 2015, University of Calgary, 409 pages.
[cited by applicant]
Beaudoin et al., Isolation and Characterization of a cDNA Encoding (S)-cis-N-Methylstylopine 14-Hydroxylase from Opium Poppy, a Key Enzyme in Sanguinarine Biosynthesis, Biochem. Biophys. Res. Commun. (Jan. 2013), 431:59…
[cited by applicant]
Bitter, Heterologous Gene Expression in Yeast, Methods in Enzymology, 152:673-684 (1987).
[cited by applicant]
Branden et al., Introduction to Protein Structure, Garland Publishing Inc., New York, p. 247 (1991).
[cited by applicant]
Braus, Aromatic amino acid biosynthesis in the yeast
[cited by applicant]
Broun et al., Catalytic plasticity of fatty acid modification enzymes underlying chemical diversity of plant lipids, Science. Nov. 13, 1998, 282(5392):1315-7.
[cited by applicant]
Bruce et al., Microbial Degradation of the Morphine Alkaloids. Purification and Characterization of Morphine Dehydrogenase from Pseudomonas putida M10, Biochem. J. (Mar. 1991), 274(3):875-880.
[cited by applicant]
Carillo et. al., The Multiple Sequence Alignment Problem in Biology, SIAM J. Applied Math., 48(5)1078-1083 (Oct. 1988).
[cited by applicant]
CAS Registry No. 466-99-9 (Hydromorphone) Nov. 16, 1984, (Modify Date: Jun. 10, 2019), 3 pages.
[cited by applicant]
CAS Registry No. 57-27-2 (Morphine) Nov. 16, 1984, (Modify Date: Jun. 10, 2019), 19 pages.
[cited by applicant]
CAS Registry No. 86709-01-5 (Neomorphine) Nov. 16, 1984, (Modify Date: Apr. 9, 2021), 3 pages.
[cited by applicant]
Cautha, Model based design of a
[cited by applicant]
Chavez-Bejar et al., Metabolic Engineering of
[cited by applicant]
Chica et al., Semi-rational approaches to engineering enzyme activity: combining the benefits of directed evolution and rational design, Current Opinion in Biotechnology, Jul. 2005, 16:378-384.
[cited by applicant]
Choi et al., Molecular Cloning and Characterization of Coclaurine N-Methyltransferase from Cultured Cells of Coptis japonica, J. Biol. Chem. (Jan. 2002), 277:830-835.
[cited by applicant]
Clark, Plant Molecular Biology: A Laboratory Manual, Chapter 7, Clark, Ed., Springer, Published in 1997.
[cited by applicant]
clinical trials.gov, Fasting Study of Hydromorphone Hydrochloride 8 mg Tablets and Dilaudid 8 mg Tablets, ClinicalTrials.gov, https://web.archive.org/web/20121216193456/https://clinicaltrails.gov/ct2/show/NCT00853554, D…
[cited by applicant]
clinical trials.gov, Morphine vs. Oxycodone for Postoperative Pain Management, ClinicalTrials.gov, https://clinicaltrials.gov/ct2/show/NCT00528177, 2011, 4 pages.
[cited by applicant]
Cooper et al., On the amine oxidases of Klebsiella aerogenes strain W70, FEMS Microbiol. Lett., 146(1):85-89 (Jan. 1997).
[cited by applicant]
Cravens et al., Synthetic biology strategies for microbial biosynthesis of plant natural products, Nature Communications vol. 10, Article No. 2142 (May 2019).
[cited by applicant]
Curran et al., Metabolic engineering of muconic acid production in
[cited by applicant]
Dang et al., CYP82Y1 Is N-Methylcanadine 1-Hydroxylase, a Key Noscapine Biosynthetic Enzyme in Opium Poppy, The Journal of Biological Chemistry, 289(4):2013-2026, Jan. 2014.
[cited by applicant]
Dang et al., Cloning and characterization of canadine synthase involved in noscapine biosynthesis in opium poppy, FEBS Lett. Jan. 3, 2014;588(1):198-204.
[cited by applicant]
Dang et al., Elucidation of the noscapine biosynthetic pathway in opium poppy, Doctoral Thesis, University of Calgary, 2014, 207 pages.
[cited by applicant]
Dastmalchi et al., Neopinone isomerase is involved in codeine and morphine biosynthesis in opium poppy, Nat Chem Biol. Apr. 2019;15(4):384-390.
[cited by applicant]
Daubner et al., Tyrosine Hydroxylase and Regulation of Dopamine Synthesis, Arch Biochem Biophys, Apr. 1, 2011, 508(1):1-12.
[cited by applicant]
De-Eknamkul et al., Purification and properties of 1,2-dehydroreticuline reductase from Papaver somniferum seedlings, Mar. 1992, 31(3):813-821.
[cited by applicant]
De-Eknannkul et al., Enzymic Formation of ( R)-Reticuline from 1,2-Dehydroreticuline in the Opium Poppy Plant, Tetrahedron Letters, 31(34):4855-4858, 1990.
[cited by applicant]
Desgagne-Penix et al., Integration of deep transcriptome and proteome analyses reveals the components of alkaloid metabolism in opium poppy cell cultures, BMC Plant Biology, 10(1):1-17 (2010).
[cited by applicant]
Devereaux et al., A comprehensive set of sequence analysis programs for the VAX, Nucleic Acids Res., 12(1):387-395 (1984).
[cited by applicant]
Devos et al., Practical limits of function prediction, Proteins. Oct. 1, 2000;41(1):98-107.
[cited by applicant]
Diaz Chavez et al., Characterization of two Methylenedioxy Bridge-Forming Cytochrome P450-Dependent Enzymes of Alkaloid Formation in the Mexican Prickly Poppy Argemone mexicana, Arch. Biochem. Biophys. (Mar. 2011), 507:…
[cited by applicant]
Dumas et al., 11 Beta-Hydroxylase Activity in Recombinant Yeast Mitochondria. In vivo Conversion of 11-Deoxycortisol to Hydrocortisone, Eur. J. Biochem. (Mar. 1996), 238:495-504.
[cited by applicant]
Englaender et al., Effect of Genomic Integration Location on Heterologous Protein Expression and Metabolic Engineering in
[cited by applicant]
Enzyme, https://www.enzyme.expasy.org/cgi-bin/enzyme/enzyme-search-de, Nov. 1, 2021, 1 page.
[cited by applicant]
Facchini et al., Differential and Tissue-Specific Expression of a Gene Family for Tyrosine/Dopa Decarboxylase in Opium Poppy, J. Biol. Chem., 269(43):26684-26690 (Oct. 1994).
[cited by applicant]
Farhi et al., Harnessing Yeast Subcellular Compartments for the Production of Plant Terpenoids, Metab. Eng. (May 2011), 13:474-481.
[cited by applicant]
Farrow et al., Dioxygenases Catalyze O-Demethylation and O,Odemethylenation with Widespread Roles in Benzylisoquinoline Alkaloid Metabolism in Opium Poppy, J. Biol. Chem. (Aug. 2013), 288:28997-29012.
[cited by applicant]
Farrow et al., Stereochemical inversion of (S)-reticuline by a cytochrome P450 fusion in opium poppy, Nat Chem Biol. Sep. 2015;11(9):728-32.
[cited by applicant]
Fisinger et al., Thebaine Synthase: a New Enzyme in the Morphine Pathway in Papaver somniferum, Natural Product Communications (2007), 2(3):249-253.
[cited by applicant]
Fossati et al., Reconstitution of a 10-gene pathway for synthesis of the plant alkaloid dihydrosanguinarine in
[cited by applicant]
French et al., Biological Production of Semisynthetic Opiates Using Genetically Engineered Bacteria, Biotechnology (N Y) (1995), 13:674-676.
[cited by applicant]
French et al., Purification and Characterization of Morphinone Reductase from Pseudomonas putida M10, Biochem. J. (1994), 301(1):97-103.
[cited by applicant]
French et al., Bacterial morphinone reductase is related to Old Yellow Enzyme, Biochem J. Dec. 15, 1995;312 ( Pt 3):671-8.
[cited by applicant]
Fukuda et al., Breeding of Brewing Yeast Producing a Large Amount of Beta-Phenylethyl Alcohol and Beta-Phenylethyl Acetate, Agricultural and Biological Chemistry, Tokyo, Japan, 54(1):269-271 (1990).
[cited by applicant]
Fukuda et al., Feedback-Insensitive Mutation of 3-Deoxy-D-Arabino-Hepturosonate-7-Phosphate Synthase Caused by a Single Nucleotide Substitution of AR04 Structural Gene in
[cited by applicant]
Fukuda et al., Molecular Breeding of a Sake Yeast with a Mutated AR04 Gene VWhich Causes Both Resistance to o-Fluoro-DL-Phenylalanine and Increased Production of Beta-Phenethyl Alcohol, Journal of Fermentation and Bioen…
[cited by applicant]
Fukuda et al., A mutated ARO4 gene for feedback-resistant DAHP synthase which causes both o-fluoro-DL-phenylalanine resistance and beta-phenethyl-alcohol overproduction in
[cited by applicant]
Galanie et al., Complete biosynthesis of opioids in yeast, Science, Sep. 2015, 349(6252):1095-1100.
[cited by applicant]
Geissler et al., Molecular Modeling and Site-Directed Mutagenesis Reveal the Benzylisoquinoline Binding Site of the Short-Chain Dehydrogenase/Reductase Salutaridine Reductase, Plant Physiol. (2007), 143(4):1493-503.
[cited by applicant]
Gesell et al., CVP719B1 Is Salutaridine Synthase. the C-C Phenol-coupling Enzyme of Morphine Biosynthesis in Opium Poppy, Journal of Biological Chemistry, Sep. 4, 2009, 284(36):24432-24442.
[cited by applicant]
Gesell et al., Heterologous Expression of Two FAD-Dependent Oxidases with (S) Tetrahydroprotoberberine Oxidase Activity from Argemone mexicana and Berberis wilsoniae in Insect Cells, Planta. (2011), 233:1185-1197.
[cited by applicant]
Gold et al., Metabolic engineering of a tyrosine-overproducing yeast platform using targeted metabolomics, Microbial Cell Factories, vol. 14, Article No. 73 (2015).
[cited by applicant]
Grothe et al., Molecular Characterization of the Salutaridinol 7-O-Acetyltransferase Involved in Morphine Biosynthesis in Opium Poppy Papaver somniferum, J. Biol. Chem. (2001), 276:30717-30723.
[cited by applicant]
Guo et al., Mini-review: In vitro Metabolic Engineering for Biomanufacturing of High-value Products, Comput Struct Biotechnol J. Jan. 19, 2017;15:161-167.
[cited by applicant]
Guo et al., Protein tolerance to random amino acid change, PNAS, Jun. 2004, 101(25):9205-9210.
[cited by applicant]
Gustafsson et al., Codon bias and heterologous protein expression, Trends in Biotechnology, 22(7):346-353 (Jul. 2004).
[cited by applicant]
Hagel et al., Benzylisoquinoline Alkaloid Metabolism: a Century of Discovery and a Brave New World, Plant Cell Physiol. (2013), 54:647-672.
[cited by applicant]
Hagel et al., Characterization of a Flavoprotein Oxidase from Opium Poppy Catalyzing the Final Steps in Sanguinarine and Papaverine Biosynthesis, J. Biol. Chem. (2012), 287:42972-42983.
[cited by applicant]
Hagel et al., Dioxygenases Catalyze the O-Demethylation Steps of Morphine Biosynthesis in Opium Poppy, Nat. Chem. Biol. (2010), 6:273-275.
[cited by applicant]
Hartmann et al., Evolution of feedback-inhibited beta/alpha barrel isoenzymes by gene duplication and a single mutation, PNAS, 100(3):862-867 (Feb. 4, 2003).
[cited by applicant]
Hawkins et al., Production of benzylisoquinoline alkaloids in
[cited by applicant]
Hawkins et al., Supplementary Text and Figures. Production of benzylisoquinoline alkaloids in
[cited by applicant]
Hawkins, Metabolic Engineering of
[cited by applicant]
Henikoff et al., Amino acid substitution matrices from protein blocks, Proc. Natl. Acad. Sci. USA, 89:10915-10919 (1992).
[cited by applicant]
Higashi et al., Atomic Structure of Salutaridine Reductase from the Opium Poppy (
[cited by applicant]
Hinnen et al., Chapter 10: Heterologous Gene Expression in Yeast, Yeast Genetic Engineering, Barr et al. eds., Buttervvorths, pp. 193-213 (1989).
[cited by applicant]
Hirata et al., 1,2-Dehydroreticuline synthase, the branch point enzyme opening the morphinan biosynthetic pathway, Phytochemistry, 2004, 65:1039-1046.
[cited by applicant]
Hiroi et al., Dopamine Formation from Tyramine by CYP2D6, Biochemical & Biophysical Research Communications, 249:838-843 (1998).
[cited by applicant]
Ikezawa et al., Molecular Cloning and Characterization of CYP719, a Methylenedioxy Bridge-Forming Enzyme that Belongs to a Novel P450 Family, from Cultured Coptis japonica Cells, J. Biol. Chem. (2003), 278:38557-38565.
[cited by applicant]
Ikezawa et al., Molecular Cloning and Characterization of Methylenedioxy Bridge-Forming Enzymes Involved in Stylopine Biosynthesis in Eschscholzia californica, FEBS J. (2007), 274:1019-1035.
[cited by applicant]
Imai, Substrate recognition: diversity Structural Basis of Chemistry: An Organism, 36(8): 530-533 (1998).
[cited by applicant]
Iraqui et al., Characterisation of
[cited by applicant]
Jensen et al., Plant NADPH-Cytochrome P450 Oxidoreductases, Phytochemistry (2010). 71:132-141.
[cited by applicant]
Jez et al., A new nomenclature for the aldo-keto reductase superfamily, Biochem. Pharmacol., 54:639-647 (1997).
[cited by applicant]
Julien et al., Isolation and Characterization of the epothilone biosynthetic gene cluster from Sorangium cellulosm, Gene, 2000, 249:153-160.
[cited by applicant]
KEGG Compound C06172, Neopinone, https://web.archive.org/web/20130117233034/https://www.genome.jp/dbget-bin/www_bget?C06172, Downloaded on Jul. 8, 2021, 1 page.
[cited by applicant]
Kim et al., Improvement of Reticuline Productivity from Dopamine by Using Engineered
[cited by applicant]
Kimchi-Sarfaty et al., A “Silent” Polymorphism in the MDR1 Gene Changes Substrate Specificity, Science, Jan. 2007, 315(5811):525-528.
[cited by applicant]
Kisselev, Polypeptide Release Factors in Prokaryotes and Eukaryotes:Same Function, Different Structure, Structure, vol. 10, Jan. 2002, 2 pages.
[cited by applicant]
Kocharin, Metabolic Engineering of
[cited by applicant]
Koopman et al., De novo production of the flavonoid naringenin in engineered
[cited by applicant]
Kushnirov, Rapid and Reliable Protein Extraction from Yeast, Yeast (2000), 16:857-860.
[cited by applicant]
Kutchan et al., Molecular Genetics of Plant Alkaloid Biosynthesis, Alkaloids, 50:257-316 (1998).
[cited by applicant]
Kutchan, Heterologous expression of alkaloid biosynthetic genes—a review, Gene, Nov. 7, 1996, 179(1):73-81.
[cited by applicant]
Larkin et al., Increasing Morphinan Alkaloid Production by Over-Expressing Codeinone Reductase in Transgenic Papaver somniferum, Plant Biotechnol. J. (2007), 5:26-37.
[cited by applicant]
Lechner et al., Library of Norcoclaurine Synthases and Their Immobilization for Biocatalytic Transformations, Biotechnol J., Mar. 2018;13(3).
[cited by applicant]
Lee et al., Bacillus licheniformis APase I gene promoter: a strong well-regulated promoter in B. Subtilis, Journal of General Microbiology, 137:1127-1133 (1991).
[cited by applicant]
Lee et al., Metabolic engineering of microorganisms: general strategies and drug production, Drug Discovery Today, 14( 1/2): 78-88 (Jan. 2009).
[cited by applicant]
Lee et al., Norcoclaurine Synthase Is a Member of the Pathogenesis-Related 10/Bet v1 Protein Family[W], Plant Cell. Oct. 2010; 22(10): 3489-3503.
[cited by applicant]
Lenz et al., Acetyl Coenzyme A:Salutaridinol-7-O Acetyltransferase from Papaver somniferum Plant Cell Cultures, J. Biol. Chem. (1995), 270:31091-31096.
[cited by applicant]
Lenz et al., Purification and Properties of Codeinone Reductase (NADPH) from Papaver somniferum Cell Cultures and Differentiated Plants, Eur. J. Biochem. (1995), 233:132-139.
[cited by applicant]
Li et al., Engineering biosynthesis of the anticancer alkaloid noscapine in yeast, Nature Communications, vol. 7, Article No. 12137 (2016).
[cited by applicant]
Li et al., Strategies for microbial synthesis of high-value phytochemicals, Nat Chem, Apr. 2018;10(4):395-404.
[cited by applicant]
Liscombe et al., Molecular cloning and characterization of tetrahydroprotoberberine cis-N-methyltransferase, an enzyme involved in alkaloid biosynthesis in opium poppy, J Biol Chem. May 18, 2007;282(20).
[cited by applicant]
Liscombe et al., Targeted Metabolite and Transcript Profiling for Elucidating Enzyme Function: Isolation of Novel N Methyltransferases from Three Benzylisoquinoline Alkaloid-Producing Species, Plant J. (2009), 60:729-74…
[cited by applicant]
Lister et al., Transformations of codeine to important semisynthetic opiate derivatives by Pseudomonas putida m10,FEMS Microbiol Lett. Dec. 1, 1999;181(1):137-44.
[cited by applicant]
Lütke-Eversloh et al., L-Tyrosine production by deregulated strains of
[cited by applicant]
Lütke-Eversloh et al., Perspectives of biotechnological production of L-tyrosine and its applications, Appl Microbiol Biotechnol. Dec. 2007;77(4):751-62.
[cited by applicant]
Luttik et al., Alleviation of feedback inhibition in
[cited by applicant]
Lv et al., LC-MS-MS Simultaneous Determination of L-Dopa and Its Prod rug L-Dopa n-Pentyl Hydrochloride in Rat Plasma, Chromatographia, 72(3/4):239-243, (2010).
[cited by applicant]
Millgate et al., Morphine-pathway block in top1 poppies, Nature; Sep. 2004, 431:413-414.
[cited by applicant]
Minami et al., Microbial Production of Plant Benzylisoquinoline Alkaloids, Proc. Natl. Acad. Sci. U S A (2008), 105:7393-7398.
[cited by applicant]
Minami, Fermentative Production of Plant Benzylisoquinoline Alkaloids in Microbes, Bioscience, Biotechnology, and Biochemistry, 77(8):1617-1622 (Aug. 7, 2013).
[cited by applicant]
Mishra et al., Wound Induced Tanscriptional Regulation of Benzylisoquinoline Pathway and Characterization of Wound Inducible PsWRKY Transcription Factor from Papaver somniferum, PLoS One, Jan. 30, 2013, 8(1):1-15.
[cited by applicant]
Mitchell et al., Circular permutation of a synthetic eukaryotic chromosome with the telomerator, PNAS, 2014,111,17003-17010.
[cited by applicant]
Mizutani et al., Diversification of P450 Genes During Land Plant Evolution, Annu. Rev. Plant Biol. (2010), 61:291-315.
[cited by applicant]
Moerner et al., Illuminating single molecules in condensed matter, Science, 283(5408):1670-1676 (1999).
[cited by applicant]
Morishige et al., Molecular Characterization of the Sadenosyl-L-Methionine:3′-Hydroxy-N-Methylcoclaurine 4′-O-Methyltransferase Involved in Isoquinoline Alkaloid Biosynthesis in Coptis japonica, J. Biol. Chem. (2000), 2…
[cited by applicant]
Morris et al., Plug-and-Play Benzylisoquinoline Alkaloid Biosynthetic Gene Discovery in Engineered Yeast, in Methods in Enzymology, 144-178 (Elsevier 2016).
[cited by applicant]
Munoz et al., Metabolic engineering of
[cited by applicant]
Nackley et al., Human Catechol-O-Methyltransferase Haplotypes Modulate Protein Expression by Altering mRNA Secondary Structure, Science, Dec. 2006, 314(5807):1930-1933.
[cited by applicant]
Nakagawa et al., A bacterial platform for fermentative production of plant alkaloids, Nature Communications, vol. 2, Article No. 326, 8 pages (May 24, 2011).
[cited by applicant]
Nakagawa et al., Bench-Top Fermentative Production of Plant Benzylisoquinoline Alkaloids Using a Bacterial Platform, Bioeng. Bugs (2012), 3:49-53.
[cited by applicant]
Nakagawa et al., (R,S)-Tetrahydropapaveroline production by stepwise fermentation using engineered
[cited by applicant]
Nakagawa et al., Bioengineering of Isoquinoline Alkaloid Production in Microbial Systems, Advances in Botanical Research 68:183-203, 2013.
[cited by applicant]
Needleman et al., A General Method Applicable to the Search for Similarities in the Amino Acid Sequence of Two Proteins, J. Mol. Biol., 48:443-453 (1970).
[cited by applicant]
Neviogt et al., Engineering promoter regulation, Biotechnol Bioeng, . Feb. 15, 2007;96(3):550-8.
[cited by applicant]
Ng et al., Production of 2,3-butanediol in
[cited by applicant]
Niedz et al., Green fluorescent protein: an in vivo reporter of plant gene expression, Plant Cell Rep., 14:403-406 (1995).
[cited by applicant]
Olson et al., Production of tyrosine from sucrose or glucose achieved by rapid genetic changes to ptlenylalanine-producing
[cited by applicant]
Onoyovwe et al., Morphine Biosynthesis in Opium Poppy Involves Two Cell Types: Sieve Elements and Laticifers, Plant Cell (2013), 25(10): 4110-4122.
[cited by applicant]
Ounaroon et al., (R,S)-Reticuline 7-O-Methyltransferase and (R,S)-Norcoclaurine 6-O-Methyltransferase of Papaver somniferum-cDNA Cloning and Characterization of Methyl Transfer Enzymes of Alkaloid Biosynthesis in Opium …
[cited by applicant]
Paterson, The DNA Revolution, Chapter 2 in: Genome Mapping in Plants; Academic Press/R.G. Landis Company, Austin, TX (1996).
[cited by applicant]
Pauli et al., Molecular cloning and functional heterologous expression of two alleles encoding (S)-N-methylcoclaurine 39-hydroxylase (CYP80B1), a new methyl jasmonateinducible cytochrome P-450-dependent mono-oxygenase o…
[cited by applicant]
Rodrigue, et al., Establishment of a yeast platform strain for production of p-coumaric acid through metabolic engineering of aromatic amino acid biosynthesi, Metab Eng., Sep. 2015;31:181-8.
[cited by applicant]
Rueffer et al., (S)-Norlaudanosoline Synthase—The 181 Enzyme the Benzylisoquinoline Biosynthetic-Pathway, FEBS Letters, 129(1):5-9 (Jun. 1981 ).
[cited by applicant]
Runguphan et al., Redesign of a dioxygenase in morphine biosynthesis, Chem Biol. Jun. 22, 2012;19(6):674-8.
[cited by applicant]
Ruohonen et al., Modifications to the ADHI promoter of
[cited by applicant]
Saez-Vasquez et al., Genome Organization and Function: A View from Yeast and
[cited by applicant]
Salis et al., Automated Design of Synthetic Ribosome Binding Sites to Precisely Control Protein Expression, Nat Biotechnol. Oct. 2009; 27(10):946-950.
[cited by applicant]
Samanani et al., Molecular cloning and characterization of norcoclaurine synthase, an enzyme catalyzing the first committed step in benzylisoquinoline alkaloid biosynthesis, Plant J., 40(2):302-313 (2004).
[cited by applicant]
Sandig et al., Regulation of Endoplasmic Reticulum Biogenesis in Response to Cytochrome P450 Overproduction, Drug Metab. Rev. (1999), 31:393-410.
[cited by applicant]
Sariyar et al., Six Alkaloids from Papaver Species, Phytochemistry, 1986, 25(10):2403-2406.
[cited by applicant]
Sato et al., Purification and Characterization of S-adenosyl-L-methionine: norcoclaurine 6-O-methyltransferase from Cultured Coptis japonica Cells, Eur. J. Biochem. (1994), 225:125-131.
[cited by applicant]
Sato et al., Microbial production of isoquinoline alkaloids as plant secondary metabolites based on metabolic engineering research, Proc Jpn Acad Ser B Phys Biol Sci. May 10, 2013; 89(5): 165-182.
[cited by applicant]
Sauna et al., Silent Polymorphisms Speak: How They Affect Pharmacogenomics and the Treatment of Cancer, Cancer Res., Oct. 2007, 67(20):9609-9612.
[cited by applicant]
Schmidheini et al., A Single Point Mutation Results in a Constitutively Activated and Feedback-Resistant Chorismate Mutase of
[cited by applicant]
Schmidt et al., Poppy alkaloid profiling by electrospray tandem mass spectrometry and electrospray FT-ICR mass spectrometry after [ring-13 C6}-tyramine feeding, Phytochemistry, vol. 68, No. 2, pp. 189-202 (2007).
[cited by applicant]
Seffernick et al., Melamine Deaminase and Atrazine Chlorohydrolase: 98 Percent Identical but Functionally Different, J. Bacteriol. Apr. 2001, 183(8):2405-2410.
[cited by applicant]
Sen et al., Developments in Directed Evolution for Improving Enzyme Functions, Appl Biochem Biotechnol, Aug. 2007, 143:212-223.
[cited by applicant]
Sharafi et al., Metabolic engineering of morphinan alkaloids by over-expression of codeinone reductase in transgenic hairy roots of Papaver bracteatum, the Iranian poppy, Biotechnol Lett. Mar. 2013;35(3):445-53.
[cited by applicant]
Shi et al., Regulation of Tetrahydrobiopterin Synthesis and Bioavailability in Endothelial Cells, Cell Biochemistry and Biophysics, 41, 415-433 (2004).
[cited by applicant]
Siddiqui et al., Advancing Secondary Metabolite Biosynthesis in Yeast with Synthetic Biology Tools, FEMS Yeast Res. (2012), 12:144-170.
[cited by applicant]
Siddiqui et al., A system for multilocus chromosomal integration and transformation-free selection marker rescue, FEMS Yeast Res. Dec. 2014, 14(8):1171-85.
[cited by applicant]
Single Molecule Detection and Manipulation Workshop, Apr. 17-18, 2000, 28 pages. Retrieved from http://www.nigms.nih.gov/news/reports/single_molecules.html.
[cited by applicant]
Smirnova et al., Optical isomerism and biological activity of pharmaceutical preparations. Moscow Univ. Chem. Bull., 2012, 67(3): 95-102.
[cited by applicant]
Smith et al., Comparison of Biosequences, Adv. Appl. Math., 2:482-489 (1981).
[cited by applicant]
Soares, Flocculation in
[cited by applicant]
Stewart et al., A Chemist's Perspective on the Use of Genetically Engineered Microbes as Reagents for Organic Synthesis, Biotechnology and Genetic Engineering Reviews, 14:67-143 (1997).
[cited by applicant]
Takemura et al., Molecular Cloning and Characterization of a Cytochrome P450 in Sanguinarine Biosynthesis from Eschscholzia californica Cells, Phytochemistry (2013), 91:100-108.
[cited by applicant]
Teitel et al., An Improved Synthesis of Various Racemic Polyphenolic Tetrahydroisoquinoline alkaloids, Journal of Heterocyclic Chemistry 5:825-829 (1968).
[cited by applicant]
Thompson et al., Clustal W: Improving the Sensitivity of Progressive Multiple Sequence Alignment through sequence weighting, position-specific gap penalties and weight matrix choice, Nucleic Acid Res., 22(22):4673-4680 …
[cited by applicant]
Trenchard et al., De novo production of the key branch point benzylisoquinoline alkaloid reticuline in yeast, Metab. Eng., Jul. 10, 2015, 31:74-83.
[cited by applicant]
Uniprotkb Database, ARO1, ARO1, ARO7, TYR1, https://www.uniprot.org/prg/uniprot/, 2019.
[cited by applicant]
Unterlinner et al., Molecular Cloning and Functional Expression of Codeinone Reductase: the Penultimate Enzyme in Morphine Biosynthesis in the Opium Poppy Papaver somniferum, Plant J. (1999), 18:465-475.
[cited by applicant]
Vuralhan et al., Identification and characterization of phenylpyruvate decarboxylase genes in
[cited by applicant]
Vuralhan, Engineering of aromatic amino acid metabolism in
[cited by applicant]
Walker et al., Mechanistic studies of morphine dehydrogenase and stabilization against covalent inactivation, Biochem J. Feb. 1, 2000;345 Pt 3:687-92.
[cited by applicant]
Whisstock et al., Prediction of protein function from protein sequence and structure, Q Rev Biophys. Aug. 2003, 36(3):307-40.
[cited by applicant]
Wijekoon et al., Systematic Knockdown of Morphine Pathway Enzymes in Opium Poppy Using Virus-Induced Gene Silencing, Plant J. (2012), 69:1052-1063.
[cited by applicant]
Willey et al., Nucleotide sequence and over-expression of morphine dehydrogenase, a plasmid-encoded gene from Pseudomonas putida M10, Biochem J. Mar. 1, 1993; 290(Pt 2): 539-544.
[cited by applicant]
Winzer et al., A Papaver somniferum 10-gene cluster for synthesis of the anticancer alkaloid noscapine, Science. Jun. 29, 2012;336(6089):1704-8.
[cited by applicant]
Witkowski et al., Conversion of a beta-ketoacyl synthase to a malonyl decarboxylase by replacement of the active-site cysteine with glutamine, Biochemistry. Sep. 7, 1999;38(36):11643-50.
[cited by applicant]
Yoshida et al., 2. Diversozyme P450's Evolution and diversity, Chemistry: An Organism, 36(6): 392-398 (1998).
[cited by applicant]
Zeng et al., Integration of Transcriptome, Proteome and Metabolism Data Reveals the Alkaloids Biosynthesis in Macleaya cordata and Macleaya microcarpa, PLOS ONE, 8(1):1-18, 2013.
[cited by applicant]
Zenk et al., Benzylisoquinoline Biosynthesis by Cultivated Plant Cells and Isolated Enzymes, Journal of Natural Products, 48(5):725-738 (1985).
[cited by applicant]
Zhang et al., 14-Hydroxylation of Opiates: Catalytic Direct Autoxidation of Codeinone to 14-Hydroxycodeinone, J. Am. Chem. Soc. (2005), 127:7286-7287.
[cited by applicant]
Ziegler et al., Removal of Substrate Inhibition and Increase in Maximal Velocity in the Short Chain Dehydrogenase/Reductase Salutaridine Reductase Involved in Morphine Biosynthesis, J. Biol. Chem. (2009), 284:26758-2676…
[cited by applicant]
Zimmer et al., Protein Quality—a Determinant of the Intracellular Fate of Membrane-Bound Cytochromes P450 in Yeast, DNA Cell Biol. (1997), 16:501-514.
[cited by applicant]
Zulak et al., GenBank Accession No. FE967184, Mar. 31, 2008 (Mar. 31, 2008), [online] [retrieved on Sep. 19, 2017].
[cited by applicant]
Chattopadhyay et al., Studies on the regulation of ornithine decarboxylase in yeast: Effect of deletion in the MEU1 gene, PNAS, Nov. 8, 2005, 102(45):16158-16163.
[cited by applicant]
Morita et al., Vacuolar transport of nicotine is mediated bya multidrug and toxic compound extrusion(MATE) transporter inNicotiana tabacum, PNAS, Feb. 17, 2009, 106(7):2447-2452.
[cited by applicant]
Beaudoin et al., Benzylisoquinoline alkaloid biosynthesis in opium poppy, Planta (2014) 240:19-32.
[cited by applicant]
Kurtzman et al., Yeast Systematics and Phylogeny—Implications of Molecular Identification Methods for Studies in Ecology, In: Peter, G., Rosa, C. (eds) Biodiversity and Ecophysiology of Yeasts, The Yeast Handbook. Sprin…
[cited by applicant]
Winzer et al., Morphinan biosynthesis in opium poppy requires a P450-oxidoreductase fusion protein, Science, Jun. 25, 2015, vol. 349, Issue 6245, pp. 309-312.
[cited by applicant]
Dang et al., Characterization of Three O-Methyltransferases Involved in Noscapine Biosynthesis in Opium Poppy, Plant Physiology, 159:618-631 (Jun. 2012).
[cited by applicant]
Annett et al., Proceedings of the Society of Public Analysts and other Analytical Chemists, The Analyst, XLV(534): 321-328 (Sep. 1920).
[cited by applicant]
Bhandari et al., Recent updates on codeine, Pharm Methods, 2(1):3-8 (Jan.-Mar. 2011).
[cited by applicant]
Certificate of Analysis, Codeine, Sigma-Aldrich (Jun. 5, 2012).
[cited by applicant]
Dastmalchi et al., Purine Permease-Type Benzylisoquinoline Alkaloid Transporters in Opium Poppy, Plant Physiol, 181(3):916-933 (Nov. 2019).
[cited by applicant]
Larsen et al., Advances in methods for identification and characterization of plant transporter function, J Exp Bot, 68 (15):4045-4056 (Jul. 10, 2017).
[cited by applicant]
Shitan et al., Alkaloid transporters in plants, Plant Biotechnology 31(5):453-463 (Dec. 2014).
[cited by applicant]