Mescaline, a substituted phenethylamine protoalkaloid, is the primary hallucinogenic compound in psychedelic cacti such as Lophophora williamsii (commonly known as peyote). The mescaline biosynthetic pathway has been postulated for half a century; it entails hydroxylation and decarboxylation of l-tyrosine to dopamine through tyramine or l-3,4-dihydroxyphenylalanine (l-DOPA), followed by a series of O-methylations and hydroxylations to mescaline. However, the specific enzymes responsible for these transformations remained unknown. Now, Berman et al. have identified the enzymes responsible for the six steps of mescaline biosynthesis.

After de novo whole-genome and transcriptome sequencing and profiling, the team examined where biosynthesis occurs in the plant, finding that mescaline and related phenethylamines are produced in the button skin, the top of the cactus. They identified LwTyDC2 as the decarboxylase responsible for the initial transformation of l-tyrosine into tyramine and l-DOPA into dopamine, while LwCYP76AD131, a cytochrome P450 enzyme, catalyzed the meta-hydroxylations of tyramine to dopamine. Subsequently, N-methyltransferase 2, termed LwNMT1, was found to be responsible for N-methylating and N,N-dimethylating all intermediates of the mescaline pathway, showing a broad substrate tolerance. LwOMT1 and LwOMT5 O-methylated the two meta-hydroxyl groups and produced mescaline in vitro, while LwOMT10 and LwOMT11 targeted the para-hydroxyl groups of other pathway metabolites. Molecular modelling of the different methyltransferase enzymes shed light on their regioselectivity. Reconstitution of the pathway in Saccharomyces cerevisiae and Nicotiana benthamiana stopped short of producing mescaline in vivo.

麦司卡林是一种取代的苯乙胺原生物碱，是迷幻仙人掌（如 Lophophora williamsii）（俗称仙人掌）中的主要致幻化合物。麦斯卡林生物合成途径的假设已经有半个世纪了。它需要 L-酪氨酸通过酪胺或 L-3,4-二羟基苯丙氨酸 (L-DOPA) 羟基化和脱羧为多巴胺，然后进行一系列 O-甲基化和羟基化为麦司卡林。然而，负责这些转化的特定酶仍然未知。现在，伯曼等人。已经确定了负责麦司卡林生物合成六个步骤的酶。

经过从头全基因组和转录组测序和分析后，研究小组检查了植物中生物合成发生的位置，发现麦斯卡林和相关的苯乙胺是在仙人掌顶部的纽扣皮中产生的。他们确定LwTyDC2是脱羧酶，负责将L-酪氨酸初步转化为酪胺，将L-DOPA初步转化为多巴胺，而LwCYP76AD131（一种细胞色素P450酶）则催化酪胺向多巴胺的间羟基化。随后，N-甲基转移酶 2（称为 LwNMT1）被发现负责麦司卡林途径的所有中间体的 N-甲基化和 N,N-二甲基化，显示出广泛的底物耐受性。 LwOMT1和LwOMT5对两个间位羟基进行O-甲基化并在体外产生麦司卡林，而LwOMT10和LwOMT11则针对其他途径代谢物的对位羟基。不同甲基转移酶的分子模型揭示了它们的区域选择性。酿酒酵母和本塞姆氏烟草中途径的重建未能在体内产生麦司卡林。