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

Summary

A breakthrough in biochemistry could make Psilocybin-based therapies more accessible. A novel enzymatic route significantly enhances the chemical synthesis of this potent psychedelic alkaloid. Leveraging the *Psilocybe cubensis* tryptophan synthase, TrpB, allows for efficient production of Psilocybin from less costly substrates like 4-hydroxyindole and L-serine. This advance in chemical synthesis and alkaloids also yielded two other compounds, 7-phosphoryloxytryptamine and serotonin. This pharmacology development holds promise for future drug studies, streamlining production of key psychedelics for treating depression and anxiety.

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.

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