Towards a Molecular Understanding of the Biosynthesis of Amaryllidaceae Alkaloids in Support of Their Expanding Medical Use

Abstract

The alkaloids characteristically produced by the subfamily Amaryllidoideae of the Amaryllidaceae, bulbous plant species that include well know genera such as Narcissus (daffodils) and Galanthus (snowdrops), are a source of new pharmaceutical compounds. Presently, only the Amaryllidaceae alkaloid galanthamine, an acetylcholinesterase inhibitor used to treat symptoms of Alzheimer’s disease, is produced commercially as a drug from cultivated plants. However, several Amaryllidaceae alkaloids have shown great promise as anti-cancer drugs, but their further clinical development is restricted by their limited commercial availability. Amaryllidaceae species have a long history of cultivation and breeding as ornamental bulbs, and phytochemical research has focussed on the diversity in alkaloid content and composition. In contrast to the available pharmacological and phytochemical data, ecological, physiological and molecular aspects of the Amaryllidaceae and their alkaloids are much less explored and the identity of the alkaloid biosynthetic genes is presently unknown. An improved molecular understanding of Amaryllidaceae alkaloid biosynthesis would greatly benefit the rational design of breeding programs to produce cultivars optimised for the production of pharmaceutical compounds and enable biotechnology based approaches.

Alkaloid Constituents of the Amaryllidaceae Plant Amaryllis belladonna L

“…Each species produces a mixture of alkaloids, often with a few dominant compounds and a larger number of compounds at lower concentrations, which is likely to result from differences in substrate specificity and expression level of the various biosynthetic enzymes [8]. The evolution of the biosynthetic pathways in the production of Amaryllidaceae alkaloids remains unclear [9].…”

Biosynthesis of the Amaryllidaceae alkaloids

“…These reactions are also part of phenylpropanoid metabolism, so that AA biosynthesis nicely shows the connections between two plant specialized pathways, alkaloid and phenylpropanoid. On the other hand, tyrosine is decarboxylated to tyramine by tyrosine decarboxylase (TYDC) Eichhorn et al, 1998;Grisebach, 1973;Takos & Rook, 2013). TYDC is a unique and key regulatory enzyme in many alkaloid-producing plants.…”

“…1). For example, antitumor AAs of the narciclasine-type are derived by a para-para phenol coupling step Kornienko & Evidente, 2008;Takos & Rook, 2013).…”

“…Narciclasine levels are higher in Narcissus tazetta (65mg/kg) compared with other Amaryllidaceaea species such as L. aestivum (30mg/kg) and Galanthus nivalis (10mg/kg) however this yield is still too low for lucrative applications (Kornienko & Evidente, 2008). Currently, only galanthamine is used clinically and almost entirely produced from Leucojum and Narcissus cultivated plant species (Takos & Rook, 2013). Most AAs available commercially are obtained from their natural sources and only a few are produced synthetically.…”

“…Most AAs available commercially are obtained from their natural sources and only a few are produced synthetically. Although several chemical syntheses for galanthamine, narciclasine and others AAs have been described (Kornienko & Evidente, 2008;Takos & Rook, 2013), chemists are still struggling to 115 devise a reasonably short synthetic pathway that can be used to produce these compounds on an economically viable commercial scale. Since most AAs display promising biological activities [but are produced in small quantities relative to the potential clinical and commercial demand], there are obvious interests in engineering AA production in plants or in heterologous expression systems.…”