Angewandte Chemie International Edition
August 1, 2017
Janis Fricke, Felix Blei, Dirk Hoffmeister
210 citations
Psilocybin, the psychoactive compound in magic mushrooms, is synthesized from tryptophan by four fungal enzymes: PsiD (a decarboxylase), PsiK (a kinase), PsiM (a methyltransferase), and PsiH (a monooxygenase). Using a combined reaction of PsiD, PsiK, and PsiM, the authors produced psilocybin enzymatically from 4-hydroxy-L-tryptophan in fewer steps than previously possible. This work identifies the complete biosynthetic pathway, which had been unknown for 60 years, and may enable biotechnological production of psilocybin for pharmaceutical use.
Chemistry - A European Journal
November 14, 2019
Felix Blei, Sebastian Dörner, Janis Fricke et al.
80 citations
The psychotropic effects of Psilocybe 'magic' mushrooms are caused by the alkaloid psilocybin, but their broader secondary metabolome is poorly understood. Analysis of four Psilocybe species identified harmane, harmine, and other tryptophan-derived β-carbolines as natural products, confirmed by NMR spectroscopy and stable-isotope labeling. MALDI-MS imaging showed β-carbolines accumulate toward hyphal apices. As potent monoamine oxidase inhibitors, these β-carbolines are neuroactive and interfere with psilocybin degradation, representing an unprecedented scenario where different natural product pathways from the same building block contribute directly or indirectly to the same pharmacological effects.
Chemistry - A European Journal
July 16, 2018
Janis Fricke, Claudius Lenz, Jonas Wick et al.
52 citations
Psilocybin, the prodrug to the psychotropic compound psilocin, is biosynthesized by numerous mushroom species in the fungal genus Psilocybe and other genera, colloquially known as 'magic mushrooms' for their hallucinogenic effects and recreational use. Clinical trials have recognized psilocybin as a valuable candidate for development into a medication against depression and anxiety. This review highlights the recently elucidated biosynthesis of psilocybin, the concurrently developed concept of enzymatic in vitro and heterologous in vivo production, along with previous synthetic routes. The prospect of psilocybin as a promising therapeutic may entail increased demand, which can be met by biotechnological production. The review also briefly touches on psilocybin's therapeutic relevance and pharmacology.
Chemistry - A European Journal
May 11, 2018
Felix Blei, Florian Baldeweg, Janis Fricke et al.
51 citations
Psilocybin, the main psychoactive alkaloid in 'magic mushrooms,' is being investigated as a potential treatment for depression and anxiety. This work describes an improved method for producing psilocybin enzymatically by adding the mushroom enzyme tryptophan synthase (TrpB) to the reaction. The new route uses cheaper starting materials—4-hydroxyindole and L-serine—to form psilocybin. The same approach also produced two other compounds: a non-natural alkaloid called isonorbaeocystin and the neurotransmitter serotonin. This enzymatic method offers a more cost-effective way to synthesize psilocybin and related molecules for research and potential pharmaceutical use.
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
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.
Angewandte Chemie
August 1, 2017
Janis Fricke, Felix Blei, Dirk Hoffmeister
26 citations
Psilocybin, the psychoactive tryptamine-derived natural product from Psilocybe mushrooms, has had its biosynthetic enzymes characterized. Four enzymes were identified: PsiD, a new class of fungal L-tryptophan decarboxylase; PsiK, catalyzing the phosphotransfer step; PsiM, a methyltransferase performing repeated N-methylation as the final step; and PsiH, a monooxygenase. A step-economical route synthesized psilocybin from 4-hydroxy-L-tryptophan using PsiD, PsiK, and PsiM in a combined reaction. These findings may enable biotechnological production, given renewed pharmaceutical interest.
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.
Thüringer Universitäts- und Landesbibliothek
January 1, 2020
Felix Blei
This doctoral thesis characterizes the biosynthesis of indole alkaloids in Psilocybe fungi, including the first description of psilocybin production and the simultaneous discovery of β-carbolines. The genome of Psilocybe cyanescens was sequenced, revealing a psilocybin biosynthesis cluster that was expressed heterologously in E. coli and A. niger. A continuous in vitro synthesis was developed by linking tryptophan synthase from P. cubensis with the psilocybin pathway, enabling biocatalytic production of psilocybin analogues, including 6-methylpsilocybin. The methyltransferase TrpM was used to characterize l-Hypaphorin biosynthesis without interfering with psilocybin methylation. β-carbolines were identified in Psilocybe fruiting bodies and mycelia, suggesting possible synergistic effects on psilocybin's psychoactivity via monoamine oxidase inhibition.