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Family portraits: the enzymes behind benzylisoquinoline alkaloid diversity

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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Correspondence to Peter Facchini.

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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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Keywords

  • Benzylisoquinoline alkaloid
  • Enzyme family
  • Specialized metabolism
  • Cytochrome P450
  • FAD-linked oxidoreductase
  • NADPH-dependent reductase
  • Acetyl-CoA-dependent acetyltransferase
  • Carboxylesterase
  • Pathogenesis-related protein 10