The biosynthetic origin of psychoactive kavalactones in kava

Summary

Kava, a medicinal plant used for over 3,000 years in Polynesia, produces kavalactones—compounds that reduce anxiety and pain through mechanisms distinct from benzodiazepines and opioids. This work identifies the seven enzymes that build kavalactones, showing that two of them evolved from an ancestral enzyme to create the core kavalactone structure. Further enzymes then modify this scaffold to generate diverse kavalactones. The pathway was successfully transplanted into bacteria, yeast, and plants, enabling production of kavalactones and their derivatives. This opens a route to developing new treatments for anxiety disorders, which affect over 260 million people worldwide.

Study at a glance

Abstract

For millennia, humans have used plants for medicinal purposes. However, our limited understanding of plant biochemistry hinders the translation of such ancient wisdom into modern pharmaceuticals1. Kava (Piper methysticum) is a medicinal plant native to the Polynesian islands with anxiolytic and analgesic properties supported by over 3,000 years of traditional use as well as numerous recent clinical trials2–5. The main psychoactive principles of kava, kavalactones, are a unique class of polyketide natural products known to interact with central nervous system through mechanisms distinct from those of the prescription psychiatric drugs benzodiazepines and opioids6,7. Here we report de novo elucidation of the biosynthetic pathway of kavalactones, consisting of seven specialized metabolic enzymes. Based on phylogenetic and crystallographic analyses, we highlight the emergence of two paralogous styrylpyrone synthases, both of which have neofunctionalized from an ancestral chalcone synthase to catalyze the formation of the kavalactone scaffold. Structurally diverse kavalactones are then biosynthesized by subsequent regio- and stereo-specific tailoring enzymes. We demonstrate the feasibility of engineering heterologous production of kavalactones and their derivatives in bacterial, yeast, and plant hosts, thus opening an avenue towards the development of new psychiatric therapeutics for anxiety disorders, which affect over 260 million people globally8.