‘Magic Mushroom’ Enzyme Mystery Solved

Researchers unravel the biosynthesis of the psychoactive drug psilocybin, making the large-scale production a possibility…

The euphoria and hallucinations induced from eating Psilocybe “magic mushrooms” have earned the fungi a cult following. Sandoz chemist Albert Hofmann isolated and determined the structure of psilocybin, the main ingredient in mushrooms that leads to the psychedelic effects, nearly 60 years ago. That discovery and subsequent mind-altering experiments by Harvard University psychologist Timothy F. Leary have left scientists longing to develop a large-scale synthesis of the compound for medical uses, which include treating anxiety and depression in terminal cancer patients and treating nicotine addiction. Yet no one has been able to unravel the enzymatic pathway the mushrooms use to make psilocybin, until now.

During their study, Hoffmeister and co-workers sequenced the genomes of two mushroom species to identify the genes that govern the fungal enzymatic production of psilocybin. They further used engineered bacteria and fungi to confirm the gene activity and exact order of synthetic steps. This process includes a newly discovered enzyme that decarboxylates tryptophan, an enzyme that adds a hydroxyl group, an enzyme that catalyzes phosphorylation, and an enzyme that mediates two sequential amine methylation steps. With that knowledge in hand, the team designed a one-pot reaction using three of the enzymes to prepare psilocybin from 4-hydroxy-L-tryptophan.

“The publication by Hoffmeister and colleagues highlights a terrific example of genomics-based biocatalyst-pathway discovery,” adds natural products researcher Jon S. Thorson of the University of Kentucky. “While psilocybin biosynthesis derives from a series of fairly simple chemical transformations, this new study identifies the contributing genes and biocatalysts for the first time and, importantly, provides strong evidence to support a revision of the order of the key steps proposed more than five decades ago. This work clearly sets the stage for bioengineered psilocybin production and/or for analogs that may serve as compelling alternatives to existing synthetic strategies.”

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