The evolution and ecology of psilocybin in nature

Meyer, Matthew J.; Slot, Jason C.

doi:10.1016/j.fgb.2023.103812

Cited by 7 publications

(1 citation statement)

References 288 publications

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“…Despite its prominence in the scientific and public imagination, experimental evidence for the ecological role of psilocybin is largely lacking and speculation reigns supreme, as thoroughly investigated and reviewed in Meyer and Slot (2023) ( 53 ). Psilocybin is a prodrug that is rapidly converted to the dephosphorylated psilocin, which mimics serotonin and binds tightly to serotonin receptors, especially 5-HT 2A , a pharmacological action common to psychedelics ( 54 ).…”

Section: Discussionmentioning

confidence: 99%

Phylogenomics of the psychoactive mushroom genus Psilocybe and evolution of the psilocybin biosynthetic gene cluster

Bradshaw,

Ramírez-Cruz,

Awan

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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Psychoactive mushrooms in the genus Psilocybe have immense cultural value and have been used for centuries in Mesoamerica. Despite the recent surge of interest in these mushrooms due to the psychotherapeutic potential of their natural alkaloid psilocybin, their phylogeny and taxonomy remain substantially incomplete. Moreover, the recent elucidation of the psilocybin biosynthetic gene cluster is known for only five of ~165 species of Psilocybe , four of which belong to only one of two major clades. We set out to improve the phylogeny of Psilocybe using shotgun sequencing of fungarium specimens, from which we obtained 71 metagenomes including from 23 types, and conducting phylogenomic analysis of 2,983 single-copy gene families to generate a fully supported phylogeny. Molecular clock analysis suggests the stem lineage of Psilocybe arose ~67 mya and diversified ~56 mya. We also show that psilocybin biosynthesis first arose in Psilocybe , with 4 to 5 possible horizontal transfers to other mushrooms between 40 and 9 mya. Moreover, predicted orthologs of the psilocybin biosynthetic genes revealed two distinct gene orders within the biosynthetic gene cluster that corresponds to a deep split within the genus, possibly a signature of two independent acquisitions of the cluster within Psilocybe .

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Section: Discussionmentioning

confidence: 99%

Phylogenomics of the psychoactive mushroom genus Psilocybe and evolution of the psilocybin biosynthetic gene cluster

Bradshaw,

Ramírez-Cruz,

Awan

et al. 2024

Proc. Natl. Acad. Sci. U.S.A.

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The Second Methylation in Psilocybin Biosynthesis Is Enabled by a Hydrogen Bonding Network Extending into the Secondary Sphere Surrounding the Methyltransferase Active Site

Hudspeth,

Rogge,

Wagner

et al. 2024

ChemBioChem

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The Psilocybe cubensis SAM‐dependent methyltransferase, PsiM, catalyzes the last step in the biosynthesis of psilocybin. Likely evolved from monomethylating RNA methyltransferases, PsiM acquired a key amino acid exchange in the secondary sphere of the active site, M247N, which is responsible for its capacity to dimethylate. Two variants, PsiMN247M and PsiMN247A, were generated to further examine the role of Asn247 for mono‐ and dimethylation in PsiM. Herein, we present the kinetic profiles of both variants and crystal structures at resolutions between 0.9 and 1.0 Å. Each variant was crystallized as a ternary complex with the non‐methylated acceptor substrate, norbaeocystin and S‐adenosyl‐l‐homocysteine, and in a second complex with the cofactor analog, sinefungin, and the monomethylated substrate, baeocystin. Consistent with the inability of the variants to catalyze a second methyl transfer, these structures reveal catalytically non‐productive conformations and a high level of disorder of the methylamine group of baeocystin. Additionally, both variants exhibit destabilization in the β5‐β7 sheets and a conserved β‐turn of the core Rossmann fold, causing 20‐fold reduced substrate binding and 2‐fold lower catalytic efficiency even with norbaeocystin.

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Understanding the chemical language of the natural pharmacopeia: Whose hallucinogen is it anyway?

Borges

2023

J Biosci

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The evolution and ecology of psilocybin in nature

Cited by 7 publications

References 288 publications

Phylogenomics of the psychoactive mushroom genus Psilocybe and evolution of the psilocybin biosynthetic gene cluster

Phylogenomics of the psychoactive mushroom genus Psilocybe and evolution of the psilocybin biosynthetic gene cluster

The Second Methylation in Psilocybin Biosynthesis Is Enabled by a Hydrogen Bonding Network Extending into the Secondary Sphere Surrounding the Methyltransferase Active Site

Understanding the chemical language of the natural pharmacopeia: Whose hallucinogen is it anyway?

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