首页|The biosynthetic pathway of the hallucinogen mescaline and its heterologous reconstruction

The biosynthetic pathway of the hallucinogen mescaline and its heterologous reconstruction

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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 utiliza-tion of mescaline,safeguarding this valuable natural resource for future generations.

mescalineLophophora williamsiiPeyotebiosynthetic pathwayde novo genome sequencingmo-lecular modeling

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

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Department of Plant and Environmental Sciences,Weizmann Institute of Science,Rehovot 7610001,Israel

Department of Cell and Metabolic Biology,Leibniz Institute of Plant Biochemistry,Weinberg 3,06120 Halle(Saale),Germany

Life Sciences Core Facilities,Weizmann Institute of Science,Rehovot 7610001,Israel

The Maurice and Vivienne Wohl Institute for Drug Discovery,Weizmann Institute of Science,Rehovot 7610001,Israel

Department of Molecular & Cellular Pharmacology,University of Miami Miller School of Medicine,Miami,FL 33136,USA

Department of Botany and Plant Sciences,University of California Riverside,Riverside,CA 92521,USA

Laboratory of Plant Hormones and Development Regulation of Chongqing,School of Life Sciences,Chongqing University,Chongqing 401331,China

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2024

10.1016/j.molp.2024.05.012

分子植物(英文版)
中科院上海生命科学研究院植物生理生态所　中国植物生理学会

分子植物(英文版)

CSTPCD
影响因子：0.659
ISSN：1674-2052
年,卷(期)：2024.17(7)