'Magic mushroom' enzyme mystery solved - C&EN Global Enterprise

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NATURAL PRODUCTS

‘Magic mushroom’ enzyme mystery solved and his coworkers for their painstaking efforts to elucidate the biosynthesis of psilocybin. “Our knowledge of the biosynthesis of fungal natural products has lagged behind our understanding of the corresponding bacterial biosynthetic pathways owing psilocybin. They further used engineered The euphoria and hallucinations induced to a number of unique challenges,” Aldrich bacteria and fungi to confirm the gene from eating Psilocybe “magic mushrooms” says. For instance, the genomes of fungi are activity and exact order of synthetic steps. have earned the fungi a cult following. more complex than those of bacteria, many This process includes a newly discovered Albert Hofmann, a chemist at Sandoz, fungi are still not amenable to genetic maenzyme that decarboxylates tryptophan, isolated and determined the structure nipulation, and cultivating fungi to produce an enzyme that adds a hydroxyl group, of psilocybin, the main ingredient in the sufficient amounts of desired metabolites an enzyme that catalyzes phosphorylamushrooms that leads to the psychedelic is not always straightforward. “The new effects, nearly 60 years ago. That discovery tion, and an enzyme that mediates two work lays the foundation for developing a and subsequent mind-altering experiments sequential amine methylation steps. With fermentation process for production of this that knowledge in hand, the team deby Harvard University psychologist Timpowerful psychedelic fungal drug, which signed a one-pot reaction using three of othy F. Leary have left scientists longing has a fascinating history and pharmacolothe enzymes to prepare psilocybin from to develop a large-scale synthesis of the gy,” Aldrich adds. compound for medical uses, which include 4-hydroxy-l-tryptophan. “The publication by Hoffmeister and Medicinal chemist Courttreating anxiety, depression, and nicotine ney Aldrich of the University colleagues highlights a terrific example addiction. Yet no one has been able to O OH of Minnesota, Twin Cities, of genomics-based biocatalyst-pathway unravel the enzymatic pathway the OH discovery,” adds natural products repraises Hoffmeister mushrooms use to make psilocyNH2 searcher Jon S. Thorson of the University bin until now. Three-enzyme, of Kentucky. “While psilocybin biosynJanis Fricke, Felix Blei, and one-pot synthesis thesis derives from a series of fairly simDirk Hoffmeister of Friedrich N H ple chemical transformations, this new Schiller University Jena have study identifies the contributing genes identified and characterized 4-Hydroxy-L-tryptophan and biocatalysts for the first time and, to the greatest extent so far importantly, provides strong evidence the four enzymes that the OH to support a revision of the order of the mushrooms use to make HO P key steps proposed more than five psilocybin. The team then O decades ago. This work clearly developed the first enzymatic O N(CH3)2 sets the stage for bioengineered synthesis of the compound, psilocybin production and/or setting the stage for its posN for analogs that may serve as compelsible commercial production H ling alternatives to existing synthetic (Angew. Chem. Int. Ed. 2017, Psilocybin strategies.”—STEVE RITTER DOI: 10.1002/anie.201705489). During their study, Hoffmeister and coworkers seResearchers deciphered the biosynthetic route in Psilocybe quenced the genomes of two cyanescens “magic mushrooms” (shown), one of the species that mushroom species to identify make the psychoactive natural product psilocybin, and then used the genes that govern fungal the key enzymes in a one-pot enzymatic synthesis starting from enzymatic production of 4-hydroxy-L-tryptophan.

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C&EN | CEN.ACS.ORG | AUGUST 14/21, 2017

C R E D I T: D I R K H O F F M E I ST E R ( MU S H RO O MS )

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