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Benzylisoquinoline alkaloid biosynthesis in opium poppy: an update

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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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  1. Aparna Singh and Ivette M. Menéndez-Perdomo contributed equally.

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  1. Department of Biological Sciences, University of Calgary, Calgary, AB, T2N 1N4, Canada

    Aparna Singh, Ivette M. Menéndez-Perdomo & Peter J. Facchini

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  1. Aparna Singh
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Correspondence to Peter J. Facchini.

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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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