Structural basis for psilocybin biosynthesis.

Psilocybin, a compound from psychedelic mushrooms, shows promise for treating psychiatric conditions when used in therapy. A biosynthetic method could produce psilocybin quickly and efficiently, and understanding the enzymes involved can improve this process. Researchers determined the crystal structures of three key enzymes—PsiD, PsiK, and PsiM—in various forms, revealing how they work together to convert L-tryptophan into psilocybin. The structures show self-cleavage and self-inhibition mechanisms in PsiD and the stepwise catalytic sequence. Tests on female mice with depression-like behaviors demonstrated antidepressant effects from biosynthetic intermediates, particularly norbaeocystin, highlighting its clinical potential.

Study at a glance

Abstract

Psilocybin shows significant therapeutic potential for psilocybin-assisted psychotherapy in addressing various psychiatric conditions. The biosynthetic approach promises rapid and efficient production of psilocybin. Understanding the enzymes that contribute to the biosynthesis of psilocybin can enhance its production process. In this study, we elucidate the crystal structures of L-tryptophan-specific decarboxylase PsiD in both its apo and tryptamine-bound states, the 4-hydroxytryptamine kinase PsiK bound to its substrate, and several forms of the methyltransferase PsiM in either apo or substrate-bound forms derived from the psychedelic mushroom. Structure-based evaluations reveal the mechanisms of self-cleavage and self-inhibition in PsiD, along with the sequential catalytic steps from 4-hydroxytryptamine to the final compound, psilocybin. Additionally, we showcase the antidepressant properties of biosynthetic intermediates of psilocybin on female mice experiencing depression-like behaviors induced by sub-chronic variable stress. Our studies establish a structural basis for the future biosynthetic production of psilocybin using these enzymes and emphasize the clinical potential of norbaeocystin.