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De Novo Biosynthesis of Antidepressant Psilocybin in Escherichia coli

Zhangrao Huang, Yongpeng Yao, Rong Di, Jianchao Zhang, Yuanyuan Pan, Gang Liu

Microbial Biotechnology April 1, 2025 DOI: 10.1111/1751-7915.70135 (opens in new tab)

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Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Population Escherichia coli bacteria
Intervention engineering the P450 electron transfer chain
Topics Psilocybin
Keywords Escherichia coli Tryptamine Biochemistry Biosynthesis Enzyme
Citations 12
Key findings De novo synthesis of psilocybin in E. coli was achieved by engineering the fungal P450 enzyme PsiH and optimizing the biosynthetic pathway, yielding 79.4 mg/L of psilocybin, a 100-fold improvement over the starting strain.

Abstract

ABSTRACT Psilocybin, a tryptamine‐derived alkaloid, has been granted Breakthrough Therapy designation by the U.S. FDA for treatment‐resistant depression, underscoring its clinical importance. Therefore, sustainable and economic production is urgently needed. Manufacturing of psilocybin in Escherichia coli has drawn great attention. However, due to the low expression and activity of the eukaryotic cytochrome P450 enzyme PsiH in the psilocybin biosynthetic pathway, de novo synthesis of psilocybin in prokaryotic cells has been hampered. To overcome this dilemma, we herein demonstrated de novo synthesis of psilocybin in E. coli by constructing PsiH variants with N‐terminal domain modifications and expressing the entire biosynthetic pathway at a concordantly low temperature. Improving the supply of precursor and engineering the P450 electron transfer chain resulted in a 33‐fold increase in the titre of norbaeocystin (105.3 mg/L), a key intermediate of psilocybin biosynthesis, and a 17‐fold increase in the titre of psilocybin (14 mg/L). Further enhancement of psilocybin production was achieved by converting norbaeocystin to psilocybin by overexpressing an extra copy of the methyltransferase gene psiM . Finally, 79.4 mg/L of psilocybin was produced by optimising flask fermentation conditions, a 100‐fold improvement over the starting strain. Our work demonstrates the successful fungal P450 engineering to improve the catalytic activity in E. coli and will advance the sustainable production of the important antidepressant psilocybin in prokaryotic microbial cells.

Comparable studies

Other experimental studies on psilocybin, most cited first.

Study Year Design Participants
Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers 1998 Experimental study
Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin Participants in controlled laboratory experiments receiving a moderate to high oral... 2015 Validation study using pooled data from five laboratory experiments n = 184
Broadband Cortical Desynchronization Underlies the Human Psychedelic State Healthy human participants 2013 Experimental study
Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer Participants with cancer-related psychiatric distress who completed a parent randomized... 2020 Long-term within-subjects follow-up analysis n = 15
Enzymatic Synthesis of Psilocybin 2017 Laboratory study

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Psilocybin Depression