Benzylisoquinoline alkaloid biosynthesis in opium poppy: an update

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.