Engineering artificial biosynthetic pathways for efficient microbial production of psilocybin and psilocin
Cui Guo, Nguyen N T Luu, Maryem M Adwer, Hamed Hosseinzadeh, Venkatesh Balan, Yajun Yan, Yuheng Lin
Metabolic Engineering November 5, 2025 DOI: 10.1016/j.ymben.2025.11.002 via OpenAlex
Summary
AI-generated from the abstractPsychedelic-assisted therapy is emerging as a promising approach for depression, with psilocybin showing efficacy for post-traumatic stress disorder and treatment-resistant depression, but its low natural abundance makes extraction costly. Engineered microbial production has been limited by dependence on the CYP450 hydroxylase (PsiH) in the natural biosynthetic pathway. Researchers designed, validated, and optimized artificial biosynthetic pathways in Escherichia coli that bypass PsiH, enabling efficient psilocybin and psilocin production. De novo biosynthesis achieved record titers of 557.91 mg/L in shake flasks and 2.00 g/L in a bioreactor, outperforming previous microbial engineering efforts and demonstrating commercial potential via combinatorial metabolic engineering and synthetic biology.
Study at a glance
| Characteristics | Preprint Peer reviewed |
|---|---|
| Population | Escherichia coli bacteria |
| Topics | Psilocybin |
| Keywords | Metabolic engineering Escherichia coli Synthetic biology Biochemistry |
| Citations | 5 |
| Key finding | Artificial biosynthetic pathways in Escherichia coli that bypass the CYP450 hydroxylase (PsiH) enable efficient psilocybin and psilocin production, achieving record titers of 557.91 mg/L in shake flasks and 2.00 g/L in a bioreactor. |
Abstract
Psychedelic-assisted therapy is emerging as a highly promising approach for treating depression, with psilocybin, a psychoactive compound in magic mushrooms, gaining the most recognition for its efficacy in treating post-traumatic stress disorder and treatment-resistant depression. However, its low natural abundance makes extraction costly, necessitating alternative production methods. While engineered microbial production has been explored, dependence on the CYP450 hydroxylase (PsiH) in the natural biosynthetic pathway remains a major bottleneck, limiting production efficiency. Here, we report the design, validation, and optimization of artificial biosynthetic pathways in Escherichia coli that bypass PsiH, enabling efficient psilocybin and psilocin production. De novo biosynthesis of psilocybin achieved record titers of 557.91 mg/L in shake flasks and 2.00 g/L in a bioreactor, outperforming previous microbial engineering efforts. This work demonstrates the great commercial potential of microbial psilocybin production via combinatorial metabolic engineering and synthetic biology approaches.