The Evolutionary Pattern of Cocaine and Hyoscyamine Biosynthesis Provides Strategies To Produce Tropane Alkaloids

Cocaine and hyoscyamine are two tropane alkaloids (TA) from Erythroxylaceae and Solanaceae, respectively. These famous compounds possess anticholinergic properties that can be used to treat neuromuscular disorders. While the hyoscyamine biosynthetic pathway has been fully elucidated allowing its de novo synthesis in yeast, the cocaine pathway remained only partially elucidated. Recently, the Huang research group has completed the cocaine biosynthetic route by characterizing its two missing enzymes. This allowed the whole pathway to be transferring into Nicotiana benthamiana to achieve cocaine production. Here, besides highlighting the impact of this discovery, we discuss how TA biosynthesis evolved via the recruitment of two distinct and convergent pathways in Erythroxylaceae and Solanaceae. Finally, while enriching our knowledge on TA biosynthesis, this diversification of the molecular actors involved in cocaine and hyoscyamine biosynthesis opens perspectives in metabolic engineering by exploring enzyme biochemical plasticity that can ease and shorten TA pathway reconstitution in heterologous organisms.

Automated summary

The Huang research group has successfully elucidated the complete pathway for cocaine biosynthesis and transferred it to Nicotiana benthamiana, resulting in the production of cocaine. This discovery not only has significant impact but also reveals the evolution of two distinct and convergent pathways for tropane alkaloid biosynthesis in Erythroxylaceae and Solanaceae. By exploring enzyme biochemical plasticity, this study provides new insights for metabolic engineering in reconstructing tropane alkaloid biosynthesis pathways in heterologous organisms.