Substrate recognition by the 4‐hydroxytryptamine kinase PsiK in psilocybin biosynthesis
FEBS Letters – October 24, 2024
Source: OpenAlex
Summary
Psilocybin, a natural hallucinogen, shows immense promise in Psychedelics and Drug Studies for mental health. Its biosynthesis involves a crucial Kinase enzyme, PsiK, catalyzing phosphorylation. Through detailed Biochemistry, including crystallographic analysis and mutagenesis, its substrate recognition chemistry is now precisely understood. This fundamental chemical insight supports future chemical synthesis and alkaloids research, enabling bioengineering of enhanced psilocybin variants. Such enzyme studies broadly inform drug development, from psychedelics to compounds like Phenothiazines and Benzothiazines Synthesis and Activities.
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.