Elucidation of the mescaline biosynthetic pathway in peyote

Peyote is an entheogenic and medicinal cactus native to the Chihuahuan
desert. The psychoactive and hallucinogenic properties of peyote are
principally attributed to the phenethylamine derivative mescaline. Despite
the isolation of mescaline from peyote over 120 years ago, the
biosynthetic pathway in the plant has remained undiscovered. Here, we use
a transcriptomics and homology-guided gene discovery strategy to elucidate
a near-complete biosynthetic pathway from L-tyrosine to mescaline. We
identified a cytochrome P450 that catalyzes the 3-hydroxylation of
L-tyrosine to L-DOPA, a tyrosine/DOPA decarboxylase yielding dopamine, and
four substrate-specific and regiospecific substituted phenylethylamine
O-methyltransferases. Biochemical assays with recombinant enzymes or
functional analyses performed by feeding putative precursors to engineered
yeast (Saccharomyces cerevisiae) strains expressing candidate peyote
biosynthetic genes were used to determine substrate specificity, which
served as the basis for pathway elucidation. Additionally, an
N-methyltransferase displaying broad substrate specificity and leading to
the production of N-methylated phenethylamine derivatives was identified,
which could also function as an early step in the biosynthesis of
tetrahydroisoquinoline alkaloids in peyote.