Metabolic Engineering
March 26, 2020
N. Milne, Philip Tinggaard Thomsen, Niels Aage Tvis Knudsen et al.
126 citations
Psilocybin, the psychoactive alkaloid in magic mushrooms, shows promise for treating psychological and neurological disorders. By inserting genes from Psilocybe cubensis into Saccharomyces cerevisiae, researchers engineered yeast to produce psilocybin and related compounds from scratch. Adding a novel cytochrome P450 reductase from P. cubensis improved yields. In controlled fed-batch fermentations, the final strain produced 627 ± 140 mg/L of psilocybin and 580 ± 276 mg/L of psilocin. Intermediates baeocystin, norbaeocystin, and norpsilocin were also detected. The method also produced natural aeruginascin and a new-to-nature derivative, N-acetyl-4-hydroxytryptamine, laying groundwork for controlled biotechnological production for pharmaceuticals.
Metabolic Engineering
May 26, 2018
Sandra Hoefgen, Jun Lin, Janis Fricke et al.
113 citations
Expressing multiple genes from a biosynthetic pathway in eukaryotic hosts is challenging because each gene typically requires its own regulatory elements. A new vector system overcomes this by arranging genes as a single polycistron, using a picornavirus-inspired 'stop-carry on' mechanism so that all genes are controlled by one promoter. A split fluorescent reporter gene enables easy selection of transformed colonies. The method successfully produced high yields of the mushroom alkaloid psilocybin by expressing the entire biosynthetic gene cluster in the mould Aspergillus nidulans.
Metabolic Engineering
September 21, 2019
Alexandra M. Adams, Nicholas A. Kaplan, Zhangyue Wei et al.
83 citations
A modular biosynthetic production platform for psilocybin was developed in the model microbe Escherichia coli. Multiple genetic optimization techniques improved psilocybin titer by 32-fold. Further fermentation optimization in a fed-batch study achieved a production titer of 1.16 g/L of psilocybin, the highest titer reported from a recombinant organism to date. This work demonstrates progress toward the industrial bioproduction of psilocybin for clinical use.
Metabolic Engineering
May 23, 2023
Lucas M. Friedberg, Abhishek K. Sen, Quynh Nguyen et al.
22 citations
Psychedelic tryptamines such as DMT, 5-MeO-DMT, and bufotenine, found naturally in plants and animals, show clinical promise for treating anxiety and depression. Using genetic and metabolic engineering, researchers developed a biosynthetic pathway in Escherichia coli to produce these compounds. With tryptophan supplementation, DMT reached maximum titers of 74.7 ± 10.5 mg/L in fed-batch 2-L bioreactors. De novo DMT production from glucose achieved 14.0 mg/L, and the study reports the first microbial production of 5-MeO-DMT and bufotenine in vivo. This work establishes a foundation for further optimization toward industrial-scale production.
Metabolic Engineering
November 5, 2025
Cui Guo, Nguyen N T Luu, Maryem M Adwer et al.
5 citations
Psychedelic-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.
Metabolic Engineering
June 14, 2026
Zachary N. Abrahms, Mohammad Majdi, Siena M. Madsen et al.
A new genome engineering strategy called ePathIntegrate uses CRISPR-associated transposases to stably insert complex metabolic pathways into the chromosome of E. coli. When plasmid-optimized pathways for the psychedelic compounds psilocybin and DMT were moved directly to the genome, productivity dropped because promoters behaved differently in the new context. A library of mutant T7 promoters was developed to restore proper transcriptional control. With ePathIntegrate, the re-optimized pathways yielded 1.88 g/L psilocybin and 1.62 g/L DMT in fed-batch bioreactors. Whole-genome sequencing showed precise on-target integration but also some off-target integrations and small mutations, indicating both the promise and current limitations of this approach.