Biosynthetic Pathways to Tropane Alkaloids in the Solanaceae. Potential and Limitations

The tropane alkaloids hyoscyamine and scopolamine are commonly present in members of the Solanaceae such as Datura, Hyoscyamus, and Mandragora. Scopolamine derivatives and hyoscyamine (often as its racemic form atropine) are used in modern medicine as pain and motion sickness relievers, eye pupil dilators and antidotes against organo-phosphate poisoning. The chemical synthesis of tropane alkaloids is involved and impractical, therefore most commercially used tropane alkaloids are extracted from specially grown plants. We have undertaken a project aimed at finding new commercial sources for tropane alkaloids and deciphering key genes and enzymatic steps involved in tropane alkaloid biosynthesis. Alkaloid biosynthesis involves many catalytic steps, catalyzed by enzymes belonging to a wide range of protein families. Tropane alkaloids originate in the roots of Solanaceae plants and the bicyclic tropane skeleton is derived from L-ornithine. Condensation with L-phenylalanine derivatives results in the formation of littorine that then rearranges to hyoscyamine, that subsequently is converted to scopolamine by the action of hyoscyamine 6-hydroxylase, a 2-oxoglutarate dependant dioxygenase enzyme. Unlike the European and North African Mandragora spp., Israeli populations of Mandragora officinarum contain high levels of hyoscyamine but lack scopolamine. Preliminary transcriptomic analyses have indicated that the gene encoding for hyoscyamine-6 hydroxylase is highly conserved among scopolamine-producing Solanaceae but is truncated in Mandragora officinalis. Other yet unknown genes encoding key enzymes in the pathway such as phenyllactate-CoA ligase and littorine synthase are being studied to explore the possibility of enhancing alkaloid content in Solanaceae plants or producing tropane alkaloids using genetically engineered microorganisms.

The research leading to these results has received funding from the European Union’s Seventh Framework Programme for research, technological development and demonstration under grant agreement n° 613513.