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...
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 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...
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 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 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...
Abstract Psilocybe mushrooms are best known for their l ‐tryptophan‐derived psychotropic alkaloid psilocybin. Dimethylation of norbaeocystin, the precursor of psilocybin, by the enzyme PsiM is a critical step during the biosynthesis of psilocybin. However, the “magic” mushroom Psilocybe serbica also mono‐ and dimethylates l ‐tryptophan, which is incompatible with the specificity of PsiM. Here,...