Structural basis for psilocybin biosynthesis.
Chunyan Meng, Wenting Guo, Chuan Xiao, Yan Wen, Xudong Zhu, Qingrong Zhang, Yuxuan Liang, Hongwei Li, Sha Xu, Yuntan Qiu, Haitao Chen, Wei-Jye Lin, Baixing Wu
Nature Communications March 22, 2025 DOI: 10.1038/s41467-025-58239-x (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study with structural biology and animal model Peer reviewed |
|---|---|
| Population | Female mice with depression-like behaviors induced by sub-chronic variable stress |
| Intervention | biosynthetic intermediates of psilocybin |
| Topics | Psilocybin |
| Keywords | Psychedelics Mental health Biochemistry Pharmaceutical research Mycology |
| Citations | 4 |
| Key findings | Crystal structures of psilocybin biosynthetic enzymes reveal catalytic mechanisms, and the intermediate norbaeocystin shows antidepressant effects in a mouse model. |
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.