ChemBioChem
May 18, 2022
Sebastian Dörner, Kai Rogge, Janis Fricke et al.
43 citations
Psilocybe magic mushrooms are best known for producing psilocybin and psilocin, but their broader secondary metabolome is poorly understood. Genomes of five species (P. azurescens, P. cubensis, P. cyanescens, P. mexicana, and P. serbica) revealed much greater and unexplored metabolic diversity than chemical analyses alone. P. cyanescens and P. mexicana were identified as aeruginascin producers. Lumichrome and verpacamide A were also detected as Psilocybe metabolites. These findings support efforts to understand phenomena like paralytic effects attributed to some magic mushrooms.
ChemBioChem
May 31, 2019
Janis Fricke, Alexander M. Sherwood, Robert B. Kargbo et al.
38 citations
Psilocybin and its precursor baeocystin are indole alkaloids from psychotropic Psilocybe mushrooms, currently under clinical investigation for depression and anxiety. A biocatalytic route was developed to synthesize 6-methylated psilocybin and baeocystin from 4-hydroxy-6-methyl-L-tryptophan, using the Psilocybe cubensis enzymes PsiD and PsiK for decarboxylation and phosphorylation, and PsiM for N-methylation. An in silico structural model of PsiM revealed a well-conserved SAM-binding core with peripheral nonconserved elements that likely determine substrate preferences.
ChemBioChem
December 4, 2019
Richard Demmler, Janis Fricke, Sebastian Dörner et al.
31 citations
Psilocybe cubensis mushrooms produce psilocybin through a five-step pathway that consumes ATP and SAM, requiring efficient recycling of these co-substrates. The adenosine kinase and SAH hydrolase enzymes from the fungus help regenerate SAM. Gene expression increases in fungal primordia and fruiting bodies. A one-pot reaction combining the methyltransferase PsiM with SAH hydrolase shows that removing the byproduct SAH enables continued biosynthesis.
ChemBioChem
August 11, 2018
Felix Blei, Janis Fricke, Jonas Wick et al.
31 citations
Psilocybe mushrooms produce the psychoactive alkaloid psilocybin from L-tryptophan. A newly identified enzyme, TrpM, mono- and dimethylates L-tryptophan itself, unlike the previously known PsiM enzyme that methylates norbaeocystin. TrpM does not act on tryptamine, indicating a second L-tryptophan-dependent pathway separate from psilocybin biosynthesis. TrpM originated from an ancient duplication of part of the egtDB gene, which codes for an ergothioneine biosynthesis enzyme. This duplicated gene was mostly lost during mushroom evolution but independently re-evolved in various genera. The findings suggest a mechanism where weakly selected genes are preserved by being retained within a widely distributed, conserved metabolic pathway.
ChemBioChem
April 28, 2022
Claudius Lenz, Sebastian Dörner, Felix Trottmann et al.
26 citations
Psilocybin, the main alkaloid in psychedelic mushrooms, acts as a prodrug to psilocin, a potent psychedelic that alters human consciousness. Its positional isomer bufotenin differs in reported pharmacology. Experiments tested whether psilocin's C-4 hydroxy group influences properties through pseudo-ring formation via an intramolecular hydrogen bond (IMHB). NMR spectroscopy and quantum chemical calculations compared hydrogen bond behavior in 4- and 5-hydroxylated tryptamines. Evidence shows a pseudo-ring in psilocin and that sidechain/hydroxyl interactions affect oxidation kinetics. The propensity to form IMHBs leads to more uncharged species that cross the blood-brain barrier, unlike bufotenin. This helps explain psilocin's pharmacology and supports developing psilocybin as a therapy for major depressive disorder.
ChemBioChem
November 3, 2022
Tim Schäfer, Kristina Kramer, Sebastiaan Werten et al.
20 citations
The enzyme PsiD from the mushroom Psilocybe cubensis initiates the production of psilocybin, the psychedelic compound in magic mushrooms that is being investigated as a treatment for major depressive disorder. Unlike most similar enzymes, PsiD does not require pyridoxal phosphate (PLP) and instead resembles type II phosphatidylserine decarboxylases. Through biochemical experiments and computer modeling, researchers identified and confirmed a non-standard serine protease triad that enables the enzyme to cleave itself into its active form. This finding clarifies the molecular mechanism behind the first step of psilocybin biosynthesis.
ChemBioChem
August 24, 2023
Eike Schäfer, Stefan Bartram, Felix Trottmann et al.
7 citations
Psilocybe 'magic mushrooms' are well known for their psychotropic tryptamines, but the diversity of other specialized metabolites, especially terpenoids, has remained unclear. CubA, the single clade II sesquiterpene synthase from Psilocybe cubensis, was produced in Escherichia coli and characterized in vitro, with additional in vivo assays in Aspergillus niger. GC-MS analyses showed CubA functions as a multi-product synthase, producing cubebol, β-copaene, δ-cadinene, and germacrene D as major products depending on reaction conditions. Analysis of mature P. cubensis mushrooms detected β-copaene and δ-cadinene. Closely related enzymes are encoded in genomes of various Psilocybe species, providing insight into the metabolic capacity of the entire genus.
ChemBioChem
May 3, 2025
Nick Zschoche, Markus Gressler, Stefan Bartram et al.
1 citation
Psilocybe cubensis mushrooms, famous for producing the psychedelic compound psilocybin, also possess enzymes that synthesize a variety of other small, potentially bioactive molecules. Four newly identified sesquiterpene synthases, CubB through CubE, are expressed differently in the mushroom's fruiting bodies versus its vegetative mycelium. CubB produces a single compound, nerolidol, while CubC generates multiple sesquiterpenes including β-caryophyllene and α-humulene. CubD and CubE nearly exclusively produce sterpurene. The presence of nerolidol was confirmed in young fruiting bodies and vegetative mycelium. These findings expand understanding of the secondary metabolome of Psilocybe species.
ChemBioChem
October 16, 2024
Jesse Hudspeth, Kai Rogge, Tobias Wagner et al.
1 citation
The enzyme PsiM from the mushroom Psilocybe cubensis catalyzes the final step in psilocybin biosynthesis, adding two methyl groups to the substrate norbaeocystin. A single amino acid change, M247N, allowed this enzyme to evolve from ancestral monomethylating RNA methyltransferases into a dimethylating enzyme. Mutating this asparagine back to methionine (N247M) or alanine (N247A) eliminated the ability to perform the second methylation. High-resolution crystal structures and kinetic measurements show that Asn247 provides necessary space in the active site for multiple methylations and stabilizes nearby secondary structures through hydrogen bonds, enabling efficient substrate binding and catalysis.
ChemBioChem
April 1, 2026
Sebastian Schober, Lisa Dorfmann, Karl Walther et al.
Psilocybe cubensis magic mushrooms produce not only the psychedelic psilocybin but also a range of sesquiterpenes, natural products that can modulate biological receptors. Five sesquiterpene synthases were characterized: CubF makes α-muurolol, CubG1 and CubG2 produce mainly epi-isozizaene and β-duprezianene, CubH yields dauca-4(11),8-diene, and CubI forms β-barbatene. Gas chromatography revealed that vegetative mycelium and fruiting bodies have different sesquiterpene profiles, with sterpurene prominent in mycelium and dauca-4(11),8-diene in fruiting bodies. This knowledge may help separate the pharmacological effects of whole magic mushrooms from those of pure psilocybin.