The biosynthetic pathway of the hallucinogen mescaline and its heterologous reconstruction  

作　　者：Paula Berman Luis Alejandro de Haro Ana-Rita Cavaco Sayantan Panda Younghui Dong Nikolay Kuzmich Gabriel Lichtenstein Yoav Peleg Hila Harat Adam Jozwiaki Jianghua Cai Uwe Heinig Sagit Meir Ilana Rogachev Asaph Aharoni 

机构地区：[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]Present address:Department of Cell and Metabolic Biology,Leibniz Institute of Plant Biochemistry,Weinberg 3,06120 Halle(Saale),Germany [5]Department of Molecular&Cellular Pharmacology,University of Miami Miler School of Medicine,Miami,FL 33136,USA [6]Department of Botany and Plant Sciences,University of California Riverside,Riverside,CA 92521,USA [7]Laboratory of Plant Hormones and Development Regulation of Chongqing,School of Life Sciences,Chongqing University,Chongqing 401331,China

出　　处：《Molecular Plant》2024年第7期1129-1150,共22页分子植物（英文版）

基　　金：fellowships from the Israel Ministry of Absorption and the Dean of the Plant Science Department in the Weizmann Institute.We thank Prof.David Nelson(University of Tennessee,USA)for the systematic naming of the cytochrome P450 enzymes characterized in this study;Shmuel Regev and The Regev Nursery(Beit Elazari,Israel)for help in differentiating among Lophophora species;Dr.Ziv Spiegelman for providing several N.benthamiana plants;XINTEZA(https://xinteza.com/)for funding this research;and the Adelis Foundation,the Leona M.and Harry B.Helmsley Charitable Trust,the Jeanne and Joseph Nissim Foundation for Life Sciences,Tom and Sondra Rykoff Family Foundation Research,Ron Sklare and the Raymond Burton Plant Genome Research Fund for supporting the A.A.laboratory。

摘　　要：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.

关 键 词：mescaline Lophophora williamsi Peyote biosynthetic pathway de novo genome sequencing mo-lecular modeling 

分 类 号：Q94[生物学—植物学]