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.
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
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
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.
Nature Communications
March 28, 2024
Jesse Hudspeth, Kai Rogge, Sebastian Dörner et al.
24 citations
Psilocybin, the natural hallucinogen in magic mushrooms, is produced in a final biosynthetic step where the enzyme PsiM adds two methyl groups to norbaeocystin. Atomic-resolution crystal structures (0.9 Å) of PsiM at different reaction stages reveal its detailed methylation mechanism. Structural and phylogenetic evidence indicates PsiM evolved from METTL16-family RNA methyltransferases, and its bound substrates mimic RNA. Limitations inherited from its ancestral scaffold prevent efficient psilocybin assembly and block trimethylation to aeruginascin. These insights will aid bioengineering efforts to create psilocybin variants with improved therapeutic properties.
Chemistry - A European Journal
June 1, 2021
Claudius Lenz, Sebastian Dörner, Alexander Sherwood et al.
19 citations
Psilocin, the psychoactive compound derived from psilocybin, turns blue when mushrooms containing it are bruised. This blue color was previously thought to come from a specific chemical dimer (5,5'-coupled quinone). By synthesizing stable, ring-methylated derivatives of psilocin and analyzing their oxidized forms with spectroscopy and computational modeling, researchers showed that the blue color actually arises from a different dimer (7,7'-coupled quinoid). The original hypothesis was not supported.
Fungal biology and biotechnology
April 25, 2024
Paula Sophie Seibold, Sebastian Dörner, Janis Fricke et al.
8 citations
Psilocybin, a psychedelic alkaloid, can account for up to 2% of the dry mass of Psilocybe mushrooms, creating a high demand for its precursor L-tryptophan during carpophore (fruiting body) formation. Using Psilocybe mexicana, researchers found that genes for L-tryptophan biosynthesis (trpE1, trpD, trpB) were upregulated in carpophores, while genes for L-tryptophan-consuming pathways (idoA, iasA) were massively downregulated. The IasA enzyme was characterized as the first microbial L-tryptophan-preferring acetaldehyde synthase. Comparison with Psilocybe cubensis revealed species-specific differences in regulation. This coordination of primary and secondary metabolism routes L-tryptophan toward psilocybin production, providing initial insight into how Basidiomycota manage metabolic flux.