Characterization of the Gateway Decarboxylase for Psilocybin Biosynthesis

Summary

A unique biochemical mechanism drives psilocybin production: the PsiD enzyme, unlike many natural product catalysts, operates without pyridoxal phosphate. This chemistry insight reveals PsiD, vital for the psychedelic compound's formation, resembles type II phosphatidylserine decarboxylases. In silico modeling and experimental biology verified a non-canonical serine protease triad enabling autocatalytic cleavage. This illuminates the initial step in the metabolic cascade for psilocybin, a promising drug against major depressive disorder, informing polyamine metabolism and potential chemical synthesis of alkaloids.

Abstract

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 phosphatidylserine decarboxylases. Here, we report on the in vitro biochemical characterization of Psilocybe cubensis PsiD along with in silico modeling of the PsiD structure. A non‐canonical serine protease triad for autocatalytic cleavage of the pro‐protein was predicted and experimentally verified by site‐directed mutagenesis.

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