“In vivo biosynthesis of N,N-dimethyltryptamine, 5-MeO-N,N-dimethyltryptamine, and bufotenine in E. coli”
Lucas M. Friedberg, Abhishek K. Sen, Quynh Nguyen, Gabriel P. Tonucci, Elle B. Hellwarth, William E. Gibbons, J. Andrew Jones
Metabolic Engineering May 23, 2023 DOI: 10.1016/j.ymben.2023.05.006 via OpenAlex
Summary
AI-generated from the abstractPsychedelic 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.
Study at a glance
| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Escherichia coli |
| Interventions | genetic optimization process optimization tryptophan supplementation |
| Keywords | Tryptamine Escherichia coli Fermentation Metabolic engineering Biochemistry |
| Citations | 22 |
| Key finding | Biosynthetic production of DMT, 5-MeO-DMT, and bufotenine was achieved in Escherichia coli, with DMT titers reaching 74.7 ± 10.5 mg/L under fed-batch conditions. |
Abstract
N,N-dimethyltryptamine (DMT), 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) and 5-hydroxy-N,N-dimethyltryptamine (bufotenine) are psychedelic tryptamines found naturally in both plants and animals and have shown clinical potential to help treat mental disorders, such as anxiety and depression. Advances in both metabolic and genetic engineering make it possible to engineer microbes as cell factories to produce DMT and its aforementioned derivatives to meet demand for ongoing clinical study. Here, we present the development of a biosynthetic production pathway for DMT, 5-MeO-DMT, and bufotenine in the model microbe Escherichia coli. Through the application of genetic optimization techniques and process optimization in benchtop fermenters, the in vivo production of DMT in E. coli was observed. DMT production with tryptophan supplementation reached maximum titers of 74.7 ± 10.5 mg/L under fed batch conditions in a 2-L bioreactor. Additionally, we show the first reported case of de novo production of DMT (from glucose) in E. coli at a maximum titer of 14.0 mg/L and report the first example of microbial 5-MeO-DMT and bufotenine production in vivo. This work provides a starting point for further genetic and fermentation optimization studies with the goal to increase methylated tryptamine production metrics to industrially competitive levels.