The Plant journal : for cell and molecular biology
November 1, 2023
Jacinta L Watkins, Qiushi Li, Sam Yeaman et al.
23 citations
Peyote, a cactus native to the Chihuahuan desert, produces the psychoactive compound mescaline, but how the plant makes it has been unknown for over 120 years. Using gene discovery guided by transcriptomics and homology, researchers identified a near-complete biosynthetic pathway from the amino acid l-tyrosine to mescaline. They found a cytochrome P450 enzyme that converts l-tyrosine to l-DOPA, a decarboxylase that produces dopamine, and four specific O-methyltransferases that modify phenethylamines. Biochemical assays with recombinant enzymes and engineered yeast confirmed substrate specificity. An N-methyltransferase was also identified that may contribute to the early steps of tetrahydroisoquinoline alkaloid biosynthesis in peyote.
The Journal of biological chemistry
October 1, 2023
Xue Chen, Jing Li, Lisa Yu et al.
13 citations
A novel indolethylamine N-methyltransferase (RmNMT) from the cane toad (Rhinella marina) was identified and characterized. This enzyme catalyzes the biosynthesis of psychedelic alkaloids such as DMT, 5-methoxy-DMT, and bufotenin, which accumulate in toad skin and parotid glands and have been used ceremonially by Mesoamerican peoples. RmNMT is an effective catalyst not subject to product inhibition and exhibits substrate promiscuity, enabling production of various substituted indolethylamines for purification, pharmacological screening, and metabolic stability assays. Binding evaluations at serotonin receptors showed that primary amines have enhanced affinity at the 5-HT1A receptor compared with tertiary amines. Except for 6-substituted derivatives, N,N-dimethylation protected against catabolism by liver microsomes.
Biodesign research
June 1, 2025
Natali Ozber, Jing Li, Peter J Facchini
2 citations
A new method combining yeast fermentation and enzymes produces the recreational drug MDMA (Ecstasy) and related compounds, offering an alternative to chemical synthesis. The process starts with a yeast-based system that converts ring-substituted benzaldehyde precursors into phenylacetylcarbinol derivatives using variants of pyruvate decarboxylase. Among seven wildtype enzymes tested, Candida tropicalis PDC gave the highest yield from piperonal, and a mutant further improved production. Five of sixteen tested benzaldehyde analogs yielded corresponding derivatives with 20–70% efficiency, allowing purification of milligram quantities. A stereoselective transaminase then converted all five derivatives, followed by N-methylation and chemical reduction to produce MDMA and its analog 6-chloro-MDMA. This is the first reported bioproduction method for MDMA and other methamphetamine derivatives.