Abstract
For nearly eight millennia, opium poppy (Papaver somniferum) has been bred and cultivated for therapeutic purposes. The medicinal properties of the plant are conferred by specialized metabolites known as benzylisoquinoline alkaloids (BIAs), comprising the narcotic analgesics morphine and codeine, the antimicrobial agent sanguinarine, and the potential anticancer drug noscapine. In addition, naturally occurring thebaine is used for the semi-synthesis of widely prescribed pain-relievers (e.g., oxycodone and hydrocodone), valuable drugs used in the treatment of opioid addiction (i.e., naltrexone), or antidotes for opioid overdose (i.e., naloxone). The complex stereochemistry of many opiates hinders their chemical synthesis and opium poppy remains the sole commercial source of these important pharmaceuticals. For decades, opium poppy has served as a model plant for research aimed at a comprehensive understanding of BIA metabolism. Recent progress in functional genomics has enabled the discovery of a nearly complete collection of BIA biosynthetic genes, many of which are clustered in the opium poppy genome. Advances in synthetic biology have facilitated the successful reconstitution of several BIA biosynthetic pathways in heterologous hosts such as Saccharomyces cerevisiae and Escherichia coli, although the initially low production levels suggest that commercial scale-up will present additional challenges. This review provides an update of key molecular and biochemical aspects of BIA metabolism in opium poppy, including recent biosynthetic gene discoveries, genomic organization, novel BIA transporters, metabolic regulation, and major efforts in the engineering of pathways in plants and microbes.
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Abbreviations
- 2-ODD:
-
2-Oxoglutarate-dependent dioxygenase
- 4-HPAA:
-
4-Hydroxyphenylacetaldehyde
- 4′OMT:
-
3′-Hydroxy-N-methylcoclaurine 4′-O-methyltransferase
- 6OMT:
-
Norcoclaurine 6-O-methyltransferase
- 7OMT:
-
Reticuline 7-O-methyltransferase
- AKR:
-
Aldo-keto reductase
- AT:
-
Acetyltransferase
- AT1:
-
1,13-Dihydroxy-N-methylcanadine 13-O-acetyltransferase
- ATR:
-
Arabidopsis thaliana P450 reductase
- BBE:
-
Berberine bridge enzyme
- BIA:
-
Benzylisoquinoline alkaloid
- BUP:
-
BIA uptake permease
- CAS:
-
Canadine synthase
- Cas9:
-
CRISPR-associated protein 9
- CFS:
-
Cheilanthifoline synthase
- CNMT:
-
Coclaurine N-methyltransferase
- CODM:
-
Codeine O-demethylase
- COR:
-
Codeinone reductase
- CPR:
-
Cytochrome P450 reductase
- CRISPR:
-
Clustered regularly interspaced short palindromic repeats
- CTS:
-
Corytuberine synthase
- CXE:
-
Carboxylesterase
- CXE1:
-
3-O-acetylpapaveroxine carboxylesterase
- CYP:
-
Cytochrome P450
- CYP2D6:
-
Human cytochrome P450
- CYP76AD1:
-
Tyrosine hydroxylase double mutant W13L F309L
- CYP82X1:
-
1-Hydroxy-13-O-acetyl-N-methylcanadine 8-hydroxylase
- CYP82X2:
-
1-Hydroxy-N-methylcanadine 13-O-hydroxylase
- CYP82Y1:
-
N-methylcanadine 1-hydroxylase
- DBOX:
-
Dihydrobenzophenanthridine oxidase
- DHFR:
-
Dihydrofolate reductase
- DODC:
-
l-DOPA-specific decarboxylase
- DOPA:
-
l-3,4-Dihydroxyphenylalanine
- ER:
-
Endoplasmic reticulum
- FADOX:
-
Flavin adenine dinucleotide-linked oxidoreductase
- HPLC:
-
High performance liquid chromatography
- MAO:
-
Monoamine oxidase
- morB:
-
Morphinone reductase
- MS:
-
Mass spectrometry
- MSH:
-
N-methylstylopine 14-hydroxylase
- MT:
-
Methyltransferase
- N7OMT:
-
Norreticuline 7-O-methyltransferase
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- NCS:
-
Norcoclaurine synthase
- NISO:
-
Neopinone isomerase
- NLDS:
-
Norlaudanosoline
- NMCH:
-
N-methylcoclaurine 3′-hydroxylase
- NOS:
-
Noscapine synthase
- OMT:
-
O-methyltransferase
- OMT2:OMT3:
-
4′-O-desmethyl-3-O-acetylpapaveroxine 4′-O-methyltransferase
- P6H:
-
Protopine 6-hydroxylase
- P7ODM:
-
Papaverine 7-O-demethylase
- PCD:
-
Pterin-4-alpha-carbinolamine dehydratase
- PR10:
-
Pathogenesis-related 10 protein
- PTPS:
-
6-Pyruvoyltetrahydropterin synthase
- QDHPR:
-
Quinonoid dihydropteridine reductase
- REPI:
-
Reticuline epimerase
- RNAi:
-
RNA interference
- RNMT:
-
Reticuline N-methyltransferase
- SalAT:
-
Salutaridinol 7-O-acetyltransferase
- SalR:
-
Salutaridine reductase
- SalSyn:
-
Salutaridine synthase
- SanR:
-
Sanguinarine reductase
- SDR:
-
Short-chain dehydrogenases/reductase
- SDR-DRR:
-
1,2-Dehydroreticuline synthase-1,2-dehydroreticuline reductase
- SepR:
-
Sepiapterin reductase
- SOMT:
-
Scoulerine 9-O-methyltransferase
- SPS:
-
Stylopine synthase
- STORR:
-
S to R Reticuline
- STOX:
-
Tetrahydroprotoberberine oxidase
- T6ODM:
-
Thebaine 6-O-demethylase
- TF:
-
Transcription factor
- THS:
-
Thebaine synthase
- TNMT:
-
Tetrahydroprotoberberine N-methyltransferase
- TYDC:
-
Tyrosine decarboxylase
- TYR:
-
Tyrosinase
- TyrAT:
-
Tyrosine aminotransferase
- TyrHM :
-
Feedback inhibition-resistant tyrosine hydroxylase triple mutant R37E R38E W166Y
- VIGS:
-
Virus-induced gene silencing
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Acknowledgements
This work was supported by financial contributions from a Natural Sciences and Engineering Research Council of Canada Discovery Grant to PJF (Grant No. 183573). IMMP is the recipient of the Alberta Innovates Technology Futures Scholarship.
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PJF owns stock in, serves on the Board of Directors of, and is provided compensation by Willow Biosciences Inc. IMMP owns stock in Willow Biosciences Inc.
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Singh, A., Menéndez-Perdomo, I.M. & Facchini, P.J. Benzylisoquinoline alkaloid biosynthesis in opium poppy: an update. Phytochem Rev 18, 1457–1482 (2019). https://doi.org/10.1007/s11101-019-09644-w
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DOI: https://doi.org/10.1007/s11101-019-09644-w