Substrate recognition by the 4‐hydroxytryptamine kinase PsiK in psilocybin biosynthesis

Psilocybin, the hallucinogen from magic mushrooms, is being developed as a treatment for depression and other mental health conditions. Its biosynthesis from the amino acid L-tryptophan requires four sequential steps, the third of which is ATP-dependent phosphorylation of the intermediate 4-hydroxytryptamine, catalyzed by the enzyme PsiK. A crystallographic analysis and structure-based mutagenesis study of PsiK reveals how it recognizes its substrate. These findings will aid future bioengineering to create psilocybin variants with improved therapeutic properties.

Study at a glance

Abstract

Psilocybin, the natural hallucinogen from Psilocybe (magic) mushrooms, is a highly promising drug candidate for the treatment of depression and several other mental health conditions. Biosynthesis of psilocybin from the amino acid l‐ tryptophan involves four strictly sequential modifications. The third of these, ATP‐dependent phosphorylation of the intermediate 4‐hydroxytryptamine, is catalysed by PsiK. Here we present a crystallographic analysis and a structure‐based mutagenesis study of this kinase, providing insight into its mode of substrate recognition. The results of our work will support future bioengineering efforts aimed at generating variants of psilocybin with enhanced therapeutic properties.