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

doi:10.1038/s41467-025-58239-x

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)

Read Full Text

Relevant Not relevant

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.

Comparable studies

Other preclinical and animal studies on psilocybin, most cited first.

Study	Year	Design
Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo Mice	2021	Observational cohort
Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice Mice	2021	Experimental study
Psychedelics reopen the social reward learning critical period Mice	2023	Experimental study in mice
Correlation between the potency of hallucinogens in the mouse head-twitch response assay and their behavioral and subjective effects in other species. C57BL/6J mice	2020	Experimental study with dose-response experiments
Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning Mice	2013	Experimental study

Citations in the library

Cited by 3

Cites 40

and 35 more in the library