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UniProt release 2017_12

Published December 20, 2017

Headline

Swiss-Prot in the sky with psilocybin: the biosynthesis pathway of a psychedelic drug unveiled

Psychedelic mushrooms, also called ‘magic mushrooms’, have been used by humans since prehistoric times and can be found depicted in Stone Age rock art in Europe and Africa. Some cultures have used them for religious rites and ceremonies, especially in pre-Columbian Mesoamerica. Aztecs and Mazatecs referred to them as genius mushrooms, divinatory mushrooms, and wondrous mushrooms. A Psilocybe species was known to the Aztecs as ‘teōnanācatl’, literally ‘the divine mushroom’.

The effects of many psychedelic mushrooms come from the pro-drug psilocybin. When psilocybin is ingested, this natural compound is rapidly metabolized to yield psilocin. This latter acts as a serotonergic psychedelic substance. Its effects include euphoria, altered thinking, visual hallucinations, altered sense of time and spiritual experiences. Some consider the drug as an entheogen and a tool to supplement practices for transcendence. Psilocybin is considered to have low toxicity and harm potential, although some very rare cases of lethality have been reported. In most countries, psilocybin and psilocin are listed as schedule I drugs, i.e. compounds that have a high potential for abuse and are not recognized for medical use.

Nevertheless, over the last 30 years, the potential medical and psychological therapeutic benefits of psilocybin have been investigated. Clinical studies revealed a positive trend in the treatment of existential anxiety with advanced-stage cancer patients and for nicotine addiction. Studies on the clinical use of psilocybin against depression are ongoing.

The structures of both psilocybin and psilocin were determined in 1959 by Hofmann et al., but the basis of their biosynthesis has remained obscure for almost 60 years. The locus for the biosynthesis of psilocybin, called psi, has been recently identified in 2 out of over 100 species of psilocybin mushrooms, namely Psilocybe cubensis and Psilocybe cyanescens.

The psi locus encodes 4 psilocybin biosynthesis enzymes, including a new type of fungal L-tryptophan decarboxylase (psiD), a kinase (psiK), a methyltransferase (psiM), and a cytochrome P450 monooxygenase (psiH). All 4 have been characterized and are sufficient to produce psilocybin from the amino acid L-tryptophan. The first step of the psilocybin biosynthetic pathway is the decarboxylation of L-tryptophan to tryptamine by psiD. The cytochrome P450 monooxygenase psiH then converts tryptamine to 4-hydroxytryptamine. The kinase psiK catalyzes the 4-O-phosphorylation step by converting 4-hydroxytryptamine into norbaeocystin. The methyltransferase psiM eventually catalyzes iterative methyl transfer to the amino group of norbaeocystin to yield psilocybin via a monomethylated intermediate, called baeocystin. The psi locus also contains 2 major facilitator-type transporters (psiT1 and psiT2), as well as a cluster-specific transcriptional regulator (psiR).

As of this release, expertly annotated Psilocybe cubensis psi locus proteins psiD, psiH, psiK, psiM, psiR, psiT1, and psiT2 are publicly and legally available in UniProtKB/Swiss-Prot.

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