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：

---

致幻剂麦司卡林的生物合成途径及其异源重建


麦司卡林是最早发现的天然致幻剂之一，在心理治疗中具有巨大的潜力。尽管如此，尽管假定的生物合成途径已经存在了半个多世纪，但参与该过程的特定酶尚未确定。在这项研究中，我们研究了仙人掌（仙人掌），它是已知最大的苯乙胺麦司卡林天然生产者。我们采用多方面的方法，将全基因组和转录组测序与全面的化学分析、酶分析、分子建模和途径工程相结合，以阐明途径。我们确定了四组酶负责麦司卡林生物合成途径中的六个催化步骤，以及一种甲基转移酶，该酶可将所有苯乙胺中间体甲基化，可能调节仙人掌中麦斯卡林的水平。最后，我们重建了植物和酵母细胞中的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。总而言之，我们的研究为探索可持续生产方法和负责任地利用麦司卡林开辟了道路，为子孙后代保护这一宝贵的自然资源。