In Vitro Psilocybin Synthesis by Co‐Immobilized Enzymes
Chemistry - A European Journal – April 09, 2025
Source: OpenAlex
Summary
A new biochemical approach achieves quantitative turnover of a precursor into psilocybin, a crucial compound for treating major depressive disorder in Psychedelics and Drug Studies. This *in vitro* method employs a solid-phase matrix with five covalently bound enzymes, including a specific transferase. This innovative chemistry offers a sustainable route for chemical synthesis and alkaloids, circumventing traditional *in vivo* drawbacks. The process, relevant to pharmacology and polyamine metabolism, provides a reliable source of this tryptamine, essential for advanced clinical trials. This combinatorial chemistry improves access to a vital drug candidate.
Abstract
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 enzymes. These enzymes include three Psilocybe enzymes: IasA*, an engineered l ‐tryptophan decarboxylase/aromatic aldehyde synthase, the 4‐hydroxytryptamine kinase PsiK and the norbaeocystin methyltransferase PsiM, along with Escherichia coli nucleosidase MtnN and adenine deaminase Ade. In a proof‐of‐principle experiment, this enzyme‐charged resin allowed for quantitative turnover of 4‐hydroxy‐ l ‐tryptophan into psilocybin. This facile process i) represents a sustainable approach with reusable enzymes, ii) circumvents the drawbacks of in vivo processes while harnessing the selectivity of enzymatic catalysis and iii) helps access an urgently needed drug candidate.