The biosynthetic pathway of the hallucinogen mescaline and its heterologous reconstruction

Mescaline, one of the earliest identified natural hallucinogens, has potential for psychotherapy, but its biosynthesis in the peyote cactus (Lophophora williamsii) was not fully understood. By combining genome and transcriptome sequencing with chemical profiling, enzymatic assays, and modeling, researchers identified four groups of enzymes responsible for the six catalytic steps in mescaline production, plus an N-methyltransferase that modifies all phenethylamine intermediates and likely modulates mescaline levels. The pathway was successfully reconstructed in tobacco plants and yeast cells, revealing challenges for complete heterologous production. This work enables sustainable production approaches and responsible use of mescaline.

Study at a glance

Abstract

Mescaline, among the earliest identified natural hallucinogens, holds great potential in psychotherapy treatment. Nonetheless, despite the existence of a postulated biosynthetic pathway for more than half a century, the specific enzymes involved in this process are yet to be identified. In this study, we investigated the cactus Lophophora williamsii (Peyote), the largest known natural producer of the phenethylamine mescaline. We employed a multi-faceted approach, combining de novo whole-genome and transcriptome sequencing with comprehensive chemical profiling, enzymatic assays, molecular modeling, and pathway engineering for pathway elucidation. We identified four groups of enzymes responsible for the six catalytic steps in the mescaline biosynthetic pathway, and an N-methyltransferase enzyme that N-methylates all phenethylamine intermediates, likely modulating mescaline levels in Peyote. Finally, we reconstructed the mescaline biosynthetic pathway in both Nicotiana benthamiana plants and yeast cells, providing novel insights into several challenges hindering complete heterologous mescaline production. Taken together, our study opens up avenues for exploration of sustainable production approaches and responsible utilization of mescaline, safeguarding this valuable natural resource for future generations.