Dissimilar Reactions and Enzymes for Psilocybin Biosynthesis in Inocybe and Psilocybe Mushrooms
Angewandte Chemie International Edition – September 21, 2025
Source: OpenAlex
Summary
Psilocybin, a key compound in Psychedelics and Drug Studies, evolved through entirely separate biological pathways in different mushroom species. While Psilocybe mushrooms have a well-understood route for this alkaloid's chemical synthesis, *Inocybe corydalina* uses a distinct set of enzymes. Characterizing four enzymes from *I. corydalina* revealed a branched pathway, also producing baeocystin. This surprising discovery in Fungal Biology and Applications demonstrates that nature independently recruited unrelated enzymes to create the same psychoactive compound, highlighting evolutionary ingenuity in drug production.
Abstract
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) species, among them Inocybe corydalina , produce 1 as well. In product formation assays, we characterized four recombinantly produced biosynthesis enzymes of this species in vitro: IpsD, a pyridoxal‐5′‐phosphate‐dependent l ‐tryptophan decarboxylase, the kinase IpsK, and two near‐identical methyltransferases, IpsM1 and IpsM2. The fifth enzyme, the insoluble monooxygenase IpsH, was analyzed in silico. Surprisingly, none of the reactions intrinsic to the 1 pathway in Psilocybe species takes place in I. corydalina . Contrasting the situation in Psilocybe , the Inocybe pathway is branched and leads to baeocystin (4‐phosphoryloxy‐ N ‐methyltryptamine, 3 ) as a second end product. Our results demonstrate that mushrooms recruited distantly or entirely unrelated enzymes to evolve the metabolic capacity for 1 biosynthesis twice independently.