Abstract
Benzylisoquinoline alkaloids (BIAs) are a group of specialized metabolites found predominantly in the plant order Ranunculales. Approximately 2500 naturally occurring BIAs have been identified, many of which possess a variety of potent biological and pharmacological properties. The initial BIA skeleton is formed via condensation by a unique enzyme, norcoclaurine synthase, of the l-tyrosine derivatives dopamine and 4-hydroxyphenylacetaldehyde, yielding (S)-norcoclaurine as a central intermediate. The vast diversity of BIA structures is subsequently derived from (1) transformation of the basic BIA backbone by oxidative enzymes, particularly cytochromes P450 and FAD-linked oxidases, and (2) further structural and functional group modification by tailoring enzymes, which also include various reductases, dioxygenases, acetyltransferases, and carboxylesterases. Most of the biosynthetic enzymes responsible for the biosynthesis of major BIAs (i.e. morphine, noscapine, papaverine, and sanguinarine) in opium poppy (Papaver somniferum), and other compounds (e.g. berberine) in related plants, have been isolated and partially characterized. Diversity in BIA metabolism is driven by the modular and repetitive recruitment, and subsequent neo-functionalization, of a limited number of ancestral enzymes. In this review, BIA biosynthetic enzymes are discussed in the context of their respective families, facilitating exploration of common phylogeny and biochemical mechanisms.
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Abbreviations
- 2-ODD:
-
2-Oxoglutarate-dependent dioxygenase
- 2-OG:
-
2-Oxoglutarate
- 4′OMT:
-
3′-Hydroxy-N-methylcoclaurine 4′-hydroxylase
- 4-HPAA:
-
4-Hydroxyphenylacetaldehyde
- 6OMT:
-
Norcoclaurine 6-O-methyltransferase
- 7OMT:
-
Reticuline 7-O-methyltransferase
- AKR:
-
Aldo-keto reductase
- AT1:
-
1,13-Dihydroxy-N-methylcanadine 13-O-acetyltransferase
- BBE:
-
Berbrine bridge enzyme
- BIA:
-
Benzylisoquinoline alkaloid
- BS:
-
Berbamunine synthase
- CAS:
-
Canadine synthase
- CFS:
-
Cheilanthifoline synthase
- CNMT:
-
Coclaurine N-methyltransferase
- CoA:
-
Coenzyme A
- CODM:
-
Codeine O-demethylase
- COR:
-
Codeinone reductase
- CPR:
-
Cytochrome P450 reductase
- CTS:
-
Corytuberine synthase
- CXE:
-
Carboxylesterase
- CYP:
-
Cytochrome P450
- DBOX:
-
Dihydrobenzophenanthridine oxidase
- DOPA:
-
3,4-Dihydroxyphenylalanine
- DRS:
-
1,2-Dehydroreticuline synthase
- DRR:
-
1,2-Dehydroreticuline reductase
- FAD:
-
Flavin adenine dinucleotide
- FADOX:
-
FAD-linked oxidoreductase
- MSH:
-
N-Methylstylopine 14-hydroxylase
- MT:
-
Methyltransferase
- NADPH:
-
Nicotinamide adenine dinucleotide phosphate
- N7OMT:
-
Norreticuline 7-O-methyltransferase
- NCS:
-
Norcoclaurine synthase
- NMCH:
-
(S)-N-Methylcoclaurine 3′-hydroxylase
- NMT:
-
N-Methyltransferase
- NOS:
-
Noscapine synthase
- OMT:
-
O-Methyltransferase
- P6H:
-
Protopine 6-hydroxylase
- P7ODM:
-
Papaverine 7-O-demethylase
- PavNMT:
-
Pavine N-methyltransferase
- PR10:
-
Pathogenesis-related protein 10
- PMT:
-
Putrescine N-methyltransferase
- PODA:
-
Protopine O-dealkylase
- REPI:
-
Reticuline epimerase
- RNMT:
-
Reticuline N-methyltransferase
- SalAT:
-
Salutaridinol 7-O-acetyltransferase
- SalR:
-
Salutaridine reductase
- SalSyn:
-
Salutaridine synthase
- SAM:
-
S-Adenosylmethionine
- SanR:
-
Sanguinarine reductase
- SDR:
-
Short-chain dehydrogenase/reductase
- SOMT:
-
Scoulerine 9-O-methyltransferase
- SPDS:
-
Spermidine synthase
- SPS:
-
Stylopine synthase
- STOX:
-
(S)-Tetrahydroprotoberberine oxidase
- T6ODM:
-
Thebaine 6-O-demethylase
- TIM:
-
Triosephosphate isomerase
- TNMT:
-
Tetrahydroprotoberberine N-methyltransferase
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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. MRP is the recipient of a University of Calgary Eyes High Postdoctoral Scholarship. JSM is the recipient of a Natural Sciences and Engineering Reserach Council of Canada Postgraduate Scholarship.
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PJF owns stock in, serves on the Board of Directors of, and is provided compensation by Epimeron Inc. MD, MRP and JSM also receive compensation from Epimeron as contractors.
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Dastmalchi, M., Park, M.R., Morris, J.S. et al. Family portraits: the enzymes behind benzylisoquinoline alkaloid diversity. Phytochem Rev 17, 249–277 (2018). https://doi.org/10.1007/s11101-017-9519-z
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DOI: https://doi.org/10.1007/s11101-017-9519-z