Complete biosynthesis of psychedelic tryptamines from three kingdoms in plants

A biosynthetic pathway for dimethyltryptamine (DMT) was reconstructed in a plant assay, along with the full pathways of five natural psychedelics: psilocin, psilocybin, DMT, bufotenin, and 5-methoxy-DMT. Halogenated analogs of these molecules, which do not occur naturally and may have therapeutic potential for psychiatric conditions, were also engineered. By blending catalytic functions from different organisms and using rational protein design to create mutant enzymes, the production of indolethylamine components in plants became substantially more efficient. This platform enables concurrent biosynthesis and diversification of psychoactive indolethylamines.

Study at a glance

Abstract

-dimethyltryptamine (DMT) biosynthetic pathway in hallucinogenic plant species traditionally used in shamanic rituals for spiritual healing. Leveraging the similarities in their chemical structures, we reconstructed in one plant assay the full biosynthetic pathways of five renowned natural psychedelics; psilocin and psilocybin found in mushrooms, DMT from plants, and bufotenin and 5-methoxy-DMT secreted by the Sonoran Desert toad. We further engineered halogenated analogs of these molecules, which do not naturally occur in plants and exhibit prospective therapeutic potential for psychiatric conditions. Blending catalytic functions across the tree of life, coupled with metabolic engineering guided by rational protein design of mutant enzymes, enabled substantially more efficient in planta production of the indolethylamine components. This work establishes a versatile platform for concurrent biosynthesis and diversification of psychoactive indolethylamines, paving the way for their production in plants.