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 () and Baixing Wu ()
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Chunyan Meng: Sun Yat-Sen University
Wenting Guo: Sun Yat-Sen University
Chuan Xiao: Sun Yat-Sen University
Yan Wen: Sun Yat-Sen University
Xudong Zhu: Sun Yat-Sen University
Qingrong Zhang: Sun Yat-Sen University
Yuxuan Liang: Sun Yat-Sen University
Hongwei Li: Sun Yat-Sen University
Sha Xu: Sun Yat-Sen University Cancer Center
Yuntan Qiu: Sun Yat-Sen University
Haitao Chen: Sun Yat-Sen University
Wei-Jye Lin: Sun Yat-Sen University
Baixing Wu: Sun Yat-Sen University

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-58239-x

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