ChemBioChemApril 1, 2026Sebastian Schober, Lisa Dorfmann, Karl Walther et al.
Apart from the psychedelic psilocybin, the metabolite spectrum of Psilocybe "magic mushrooms" comprises sesquiterpenes, a class of natural products known to exhibit receptor-modulating bioactivities. However, the composition of the sesquiterpene profile has largely remained an open question. Here, we report the characterization of five Psilocybe cubensis sesquiterpene synthases, both in vitro...
ABSTRACT Psilocybin, an indole alkaloid of psychedelic mushrooms, has the potential to sustainably improve the treatment of several psychiatric diseases. So far, the psilocybin demand for clinical trials has been met by chemical synthesis. In this study, we pursued the biotechnological approach to develop a psilocybin production process utilizing an overproduction strain of Aspergillus nidulans...
Abstract Psilocybin (4‐phosphoryloxy‐ N , N ‐dimethyltryptamine, 1 ) is the main indolethyl‐amine natural product of psychotropic (so‐called “magic”) mushrooms. The majority of 1 ‐producing species belongs to the eponymous genus Psilocybe , for which the biosynthetic events, beginning from l ‐tryptophan ( 2 ), and the involved enzymes have thoroughly been characterized. Some Inocybe (fiber cap)...
Zusammenfassung Psilocybin (4‐Phosphoryloxy‐ N , N ‐dimethyltryptamin, 1 ) ist der hauptsächliche Indolethylamin‐Naturstoff der psychotropen sogenannten Zauberpilze. Die Mehrheit der 1 ‐produzierenden Arten gehört zu der namensgebenden Gattung Psilocybe , für die die biosynthetischen Ereignisse, ausgehend von l ‐Tryptophan ( 2 ), sowie die beteiligten Enzyme gründlich charakterisiert wurden....
Several species of fungi, collectively known as 'psychedelic fungi', produce a range of psychoactive substances, such as psilocybin, ibotenic acid, muscimol and lysergic acid amides. These substances interact with neurotransmitter receptors in the human brain to induce profound psychological effects. These substances are found across multiple fungal phyla, in the mushroom-forming genera...
Psilocybe “magic mushrooms” are best known for their indolethylamine psilocybin, yet they encode enzymes for a much more diverse arsenal of small and potentially bioactive molecules. Herein, four Psilocybe cubensis clade III sesquiterpene synthases, CubB‐CubE, whose genes are differently expressed in fruiting bodies compared to vegetative mycelium are reported. CubB‐CubE were functionally...
Abstract Advanced clinical trials investigate the Psilocybe magic mushroom natural product psilocybin as a treatment against major depressive disorder. Currently, synthetic material is used to meet the demand for legitimate pharmaceutical purposes. Here, we report an in vitro approach to biocatalytically produce psilocybin on a solid‐phase matrix charged with five covalently bound biosynthetic...
Abstract The high therapeutic potential of psilocybin, a prodrug of the psychotropic psilocin, holds great promise for the treatment of mental disorders such as therapy‐refractory depression, alcohol use disorder and anorexia nervosa. Psilocybin has been designated a ‘Breakthrough Therapy’ by the US Food and Drug Administration, and therefore a sustainable production process must be established...
Psilocybin, the natural hallucinogen from Psilocybe (magic) mushrooms, is a highly promising drug candidate for the treatment of depression and several other mental health conditions. Biosynthesis of psilocybin from the amino acid l‐ tryptophan involves four strictly sequential modifications. The third of these, ATP‐dependent phosphorylation of the intermediate 4‐hydroxytryptamine, is catalysed...
Abstract 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, M247 N, which is responsible for its capacity to dimethylate. Two variants, PsiM N247M and PsiM N247A , were generated to...
Although Basidiomycota produce pharmaceutically and ecologically relevant natural products, knowledge of how they coordinate their primary and secondary metabolism is virtually non-existent. Upon transition from vegetative mycelium to carpophore formation, mushrooms of the genus Psilocybe use L-tryptophan to supply the biosynthesis of the psychedelic tryptamine alkaloid psilocybin with the...
Abstract Psilocybin, the natural hallucinogen produced by Psilocybe (“magic”) mushrooms, holds great promise for the treatment of depression and several other mental health conditions. The final step in the psilocybin biosynthetic pathway, dimethylation of the tryptophan-derived intermediate norbaeocystin, is catalysed by PsiM. Here we present atomic resolution (0.9 Å) crystal structures of...
Abstract Psilocybe “magic mushrooms” are chemically well understood for their psychotropic tryptamines. However, the diversity of their other specialized metabolites, in particular terpenoids, has largely remained an open question. Yet, knowledge on the natural product background is critical to understand if other compounds modulate the psychotropic pharmacological effects. CubA, the single...
Abstract The l ‐tryptophan decarboxylase PsiD catalyzes the initial step of the metabolic cascade to psilocybin, the major indoleethylamine natural product of the “magic” mushrooms and a candidate drug against major depressive disorder. Unlike numerous pyridoxal phosphate (PLP)‐dependent decarboxylases for natural product biosyntheses, PsiD is PLP‐independent and resembles type II...
Abstract Psilocybe magic mushrooms are best known for their main natural product, psilocybin, and its dephosphorylated congener, the psychedelic metabolite psilocin. Beyond tryptamines, the secondary metabolome of these fungi is poorly understood. The genomes of five species ( P. azurescens , P. cubensis , P. cyanescens , P. mexicana , and P. serbica ) were browsed to understand more profoundly...
Abstract Psilocybin ( 1 ) is the major alkaloid found in psychedelic mushrooms and acts as a prodrug to psilocin ( 2 , 4‐hydroxy‐ N , N ‐dimethyltryptamine), a potent psychedelic that exerts remarkable alteration of human consciousness. In contrast, the positional isomer bufotenin ( 7 , 5‐hydroxy‐ N , N ‐dimethyltryptamine) differs significantly in its reported pharmacology. A series of...
Abstract Psilocin ( 1 ) is the dephosphorylated and psychotropic metabolite of the mushroom natural product psilocybin. Oxidation of the phenolic hydroxy group at the C‐4 position of 1 results in formation of oligomeric indoloquinoid chromophores responsible for the iconic blueing of bruised psilocybin‐producing mushrooms. Based on previous NMR experiments, the hypothesis included that the...
A novel analogue of psilocybin was produced by hybrid chemoenzymatic synthesis in sufficient quantity to enable bioassay. Utilizing purified 4-hydroxytryptamine kinase from Psilocybe cubensis, chemically synthesized 5-methylpsilocin (2) was enzymatically phosphorylated to provide 5-methylpsilocybin (1). The zwitterionic product was isolated from the enzymatic step with high purity utilizing a...
Abstract Psychotropic fungi of the genus Psilocybe , colloquially referred to as „magic mushrooms”, are best known for their l ‐tryptophan‐derived major natural product, psilocybin. Yet, recent research has revealed a more diverse secondary metabolism that originates from this amino acid. In this minireview, the focus is laid on l ‐tryptophan and the various Psilocybe natural products and their...
Abstract Sie sind geniale Chemiker: Pilze duften oder stinken, ein scharfer Geschmack weist oft auf ihre Ungenießbarkeit hin. Pilze der Gattung Psilocybe beeinflussen Wahrnehmung sowie Bewusstsein des Menschen, und sie haben noch eine Besonderheit: Wird der Fruchtkörper verletzt, färbt er sich blau. Über den dafür verantwortlichen Farbstoff und was daraus werden kann.
Abstract Psilocybin, the principal indole alkaloid of Psilocybe mushrooms, is currently undergoing clinical trials as a medication against treatment‐resistant depression and major depressive disorder. The psilocybin supply for pharmaceutical purposes is met by synthetic chemistry. We replaced the problematic phosphorylation step during synthesis with the mushroom kinase PsiK. This enzyme was...
Abstract Psychotropic Psilocybe mushrooms biosynthesize their principal natural product psilocybin in five steps, among them a phosphotransfer and two methyltransfer reactions, which consume one equivalent of 5′‐adenosine triphosphate (ATP) and two equivalents of S ‐adenosyl‐ l ‐methionine (SAM). This short but co‐substrate‐intensive pathway requires nucleoside cofactor salvage to maintain high...
Abstract The psychotropic effects of Psilocybe “magic” mushrooms are caused by the l ‐tryptophan‐derived alkaloid psilocybin. Despite their significance, the secondary metabolome of these fungi is poorly understood in general. Our analysis of four Psilocybe species identified harmane, harmine, and a range of other l ‐tryptophan‐derived β‐carbolines as their natural products, which was confirmed...
Abstract Upon injury, psychotropic psilocybin‐producing mushrooms instantly develop an intense blue color, the chemical basis and mode of formation of which has remained elusive. We report two enzymes from Psilocybe cubensis that carry out a two‐step cascade to prepare psilocybin for oxidative oligomerization that leads to blue products. The phosphatase PsiP removes the 4‐ O ‐phosphate group to...
Abstract Psilocybin and its direct precursor baeocystin are indole alkaloids of psychotropic Psilocybe mushrooms. The pharmaceutical interest in psilocybin as a treatment option against depression and anxiety is currently being investigated in advanced clinical trials. Here, we report a biocatalytic route to synthesize 6‐methylated psilocybin and baeocystin from 4‐hydroxy‐6‐methyl‐ l...