1. Academic Validation
  2. The biosynthetic pathway of the hallucinogen mescaline and its heterologous reconstruction

The biosynthetic pathway of the hallucinogen mescaline and its heterologous reconstruction

  • Mol Plant. 2024 Jun 3:S1674-2052(24)00179-5. doi: 10.1016/j.molp.2024.05.012.
Paula Berman 1 Luis Alejandro de Haro 1 Ana-Rita Cavaco 1 Sayantan Panda 1 Younghui Dong 2 Nikolay Kuzmich 3 Gabriel Lichtenstein 1 Yoav Peleg 2 Hila Harat 1 Adam Jozwiak 1 Jianghua Cai 1 Uwe Heinig 2 Sagit Meir 1 Ilana Rogachev 1 Asaph Aharoni 4
Affiliations

Affiliations

  • 1 Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 2 Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 3 The Maurice and Vivienne Wohl Institute for Drug Discovery, Weizmann Institute of Science, Rehovot 7610001, Israel.
  • 4 Department of Plant and Environmental Sciences, Weizmann Institute of Science, Rehovot 7610001, Israel. Electronic address: asaph.aharoni@weizmann.ac.il.
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.

Keywords

Lophophora williamsii; Peyote; biosynthetic pathway; de novo genome sequencing; mescaline; molecular modeling.

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