Genomic and transcriptomic data of the mescaline-producing cactus Peyote (Lophophora williamsii)

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 have yet to be disclosed. Here, we investigated the cactus Lophophora williamsii (Peyote), the largest known natural producer of mescaline. We employed a multi-faceted approach, combining de novo whole-genome sequencing with comprehensive chemical profiling, enzymatic assays, molecular modeling, and pathway engineering for pathway elucidation. We identified four groups of enzymes governing the six steps towards mescaline and provided essential insights into the biosynthetic challenges hindering the complete reconstruction of this pathway in heterologous systems. Through chemical profiling and orthology analyses we provide insights into the mescaline biosynthetic pathway in taxonomically distant cacti species . Our findings open up avenues for exploring sustainable production methods and responsible utilization, safeguarding this valuable natural resource for future generations.