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 (Peyote), the largest known natural producer of the phenethylamine mescaline. We employed a multi-faceted approach, combining 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 -methyltransferase enzyme that -methylates all phenethylamine intermediates, likely modulating mescaline levels in Peyote. Finally, we reconstructed the mescaline biosynthetic pathway in both 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.

中文翻译：

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致幻剂麦斯卡林的生物合成途径及其异源重建


麦斯卡林是最早发现的天然致幻剂之一，在心理治疗方面具有巨大潜力。尽管如此，尽管假设的生物合成途径存在了半个多世纪，但参与该过程的特定酶尚未确定。在这项研究中，我们调查了仙人掌 （Peyote），这是已知最大的苯乙胺麦斯卡林天然生产者。我们采用了一种多方面的方法，将全基因组和转录组测序与全面的化学分析、酶测定、分子建模和通路工程相结合，用于通路解析。我们确定了四组负责麦斯卡林生物合成途径中六个催化步骤的酶，以及一种甲基转移酶，该酶甲基化所有苯乙胺中间体，可能调节 Peyote 中的麦斯卡林水平。最后，我们在植物和酵母细胞中重建了麦斯卡林生物合成途径，为阻碍完全异源麦斯卡林生产的几个挑战提供了新的见解。综上所述，我们的研究为探索可持续生产方法和负责任地利用麦斯卡林开辟了道路，为子孙后代保护这一宝贵的自然资源。