Characterization of the Gateway Decarboxylase for Psilocybin Biosynthesis

The enzyme PsiD from the mushroom Psilocybe cubensis initiates the production of psilocybin, the psychedelic compound in magic mushrooms that is being investigated as a treatment for major depressive disorder. Unlike most similar enzymes, PsiD does not require pyridoxal phosphate (PLP) and instead resembles type II phosphatidylserine decarboxylases. Through biochemical experiments and computer modeling, researchers identified and confirmed a non-standard serine protease triad that enables the enzyme to cleave itself into its active form. This finding clarifies the molecular mechanism behind the first step of psilocybin biosynthesis.

Study at a glance

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.