Biocatalytic Production of Psilocybin and Derivatives in Tryptophan Synthase‐Enhanced Reactions

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.

Study at a glance

Abstract

Abstract Psilocybin (4‐phosphoryloxy‐ N , N ‐dimethyltryptamine) is the main alkaloid of the fungal genus Psilocybe , the so‐called “magic mushrooms.” The pharmaceutical interest in this psychotropic natural product as a future medication to treat depression and anxiety is strongly re‐emerging. Here, we present an enhanced enzymatic route of psilocybin production by adding TrpB, the tryptophan synthase of the mushroom Psilocybe cubensis , to the reaction. We capitalized on its substrate flexibility and show psilocybin formation from 4‐hydroxyindole and l ‐serine, which are less cost‐intensive substrates, compared to the previous method. Furthermore, we show enzymatic production of 7‐phosphoryloxytryptamine (isonorbaeocystin), a non‐natural congener of the Psilocybe alkaloid norbaeocystin (4‐phosphoryloxytryptamine), and of serotonin (5‐hydroxytryptamine) by means of the same in vitro approach.