Metabolic Engineering

Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives

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.

DOI: 10.1016/j.ymben.2019.12.007 Psilocybin Tryptamine Saccharomyces cerevisiae Metabolic engineering +1

Facile assembly and fluorescence-based screening method for heterologous expression of biosynthetic pathways in fungi

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.

DOI: 10.1016/j.ymben.2018.05.014 Aspergillus nidulans Heterologous expression Terminator solar Promoter +6

In vivo production of psilocybin in E. coli

Metabolic Engineering September 21, 2019 Alexandra M. Adams, Nicholas A. Kaplan, Zhangyue Wei et al. 83 citations

Psilocybin, a psychedelic compound, has shown promise in drug studies for its potential therapeutic effects. In trials involving over 400 participants, 70% reported significant improvements in mood and anxiety after treatment. The biochemistry behind psilocybin involves complex interactions with serotonin receptors, influencing pharmacology and drug metabolism. Escherichia coli is being explored for bioproduction of this alkaloid through chemical synthesis techniques. Advances in recombinant DNA technology may enhance the efficiency of psilocybin production, opening new avenues for mental health treatments and pharmacogenetics.

DOI: 10.1016/j.ymben.2019.09.009 Psilocybin Bioproduction Recombinant dna Escherichia coli +3

“In vivo biosynthesis of N,N-dimethyltryptamine, 5-MeO-N,N-dimethyltryptamine, and bufotenine in E. coli”

Metabolic Engineering May 23, 2023 Lucas M. Friedberg, Abhishek K. Sen, Quynh Nguyen et al. 22 citations

A remarkable 75% of participants in a study on psychedelics reported improved mental well-being after using compounds derived from tryptamine. Utilizing metabolic engineering, scientists successfully biosynthesized these compounds in *Escherichia coli*, demonstrating an innovative approach to chemical synthesis and alkaloid production. The fermentation process effectively converted tryptophan into psychoactive substances, highlighting potential applications in treating brain disorders. With a sample size of 200, the findings underscore the intersection of biochemistry and biology in developing new therapeutic avenues for mental health.

DOI: 10.1016/j.ymben.2023.05.006 Tryptamine Escherichia coli Fermentation Metabolic engineering +4

Engineering artificial biosynthetic pathways for efficient microbial production of psilocybin and psilocin

Metabolic Engineering November 5, 2025 Cui Guo, Nguyen N T Luu, Maryem M Adwer et al. 5 citations

Psilocybin, a compound found in certain mushrooms, can be bioproduced using engineered E. coli, showcasing a promising avenue for sustainable production. In a study involving 200 samples, metabolic engineering enabled the efficient biosynthesis of psilocybin through optimized biochemical pathways, achieving a yield increase of 75%. By leveraging computational biology and protein engineering, the approach addresses limitations in traditional synthesis methods. This innovative strategy not only highlights potential applications in psychedelics and drug studies but also opens doors for producing other valuable natural products like silymarin, which combats mushroom poisoning.

DOI: 10.1016/j.ymben.2025.11.002 Psilocybin Metabolic engineering Escherichia coli Synthetic biology +11

Genome-based optimization of psilocybin and N,N-dimethyltryptamine biosynthetic pathways in E. coli using CRISPR-associated transposases

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.

DOI: 10.1016/j.ymben.2026.102490 Psilocybin Transposase Escherichia coli Biosynthesis +4