Summary: Psilocybin can be produced de novo in yeast. The findings could help with the development of drugs that utilize the psychedelic compound to treat depression and other mental health disorders.
Source: Technical University of Denmark
Psilocybin mushrooms have been found to have minimal harmful effects and could potentially benefit those with depression. But they remain illegal even though they offer a groundbreaking alternative to several under-treated psychological conditions.
Nevertheless, psychedelics are currently riding a wave of positive momentum brought on by cannabis, and if psilocybin gets approved as a pharmaceutical drug, production in yeast appears to be the most commercially viable option.
“It’s infeasible and way too expensive to extract psilocybin from magic mushrooms and the best chemical synthesis methods require expensive and difficult to source starting substrates. Thus, there is a need to bring down the cost of production and to provide a more consistent supply chain,” says Nick Milne, former Postdoc at DTU Biosustain and CSO and Co-founder of Octarine Bio.
Bio-based production of psilocybin has gained big interest and researchers have already proved small-scale production in E. coli. However, production in bacteria comes with a wide range of concerns which can be addressed by using yeast instead.
In yeast, the scientists prove that psilocybin can be produced de novo, which means that you can produce the molecule by simply growing the yeast with sugar and other nutrients, without the need to add any other starting substrates.
Producing psilocybin de novo in E. coli is difficult since a key enzyme in the biosynthetic pathway doesn’t work in bacteria, and so to get around this problem you need to add an expensive starting substrate, making the whole production process too costly.
“Since yeast and Psilocybe mushrooms are quite closely related species, this enzyme works very well in yeast, providing a much more cost-efficient alternative,” says group leader at DTU Biosustain Irina Borodina.
Additionally, yeast also performs better in large-scale fermentation due to its long history in the beer brewing process, and also in the purification process since E. coli produces additional potentially harmful compounds that you would not like to have in your final product.
About this neuroscience research article
Source: Technical University of Denmark Media Contacts: Anders Østerby Mønsted – Technical University of Denmark Image Source: The image is credited to The Novo Nordisk Foundation Center for Biosustainability.
Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives
Psilocybin is a tryptamine-derived psychoactive alkaloid found mainly in the fungal genus Psilocybe, among others, and is the active ingredient in so-called “magic mushrooms”. Although its notoriety originates from its psychotropic properties and popular use as a recreational drug, clinical trials have recently recognized psilocybin as a promising candidate for the treatment of various psychological and neurological afflictions. In this work, we demonstrate the de novo biosynthetic production of psilocybin and related tryptamine derivatives in Saccharomyces cerevisiae by expression of a heterologous biosynthesis pathway sourced from Psilocybe cubensis. Additionally, we achieve improved product titers by supplementing the pathway with a novel cytochrome P450 reductase from P. cubensis. Further rational engineering resulted in a final production strain producing 627 ± 140 mg/L of psilocybin and 580 ± 276 mg/L of the dephosphorylated degradation product psilocin in triplicate controlled fed-batch fermentations in minimal synthetic media. Pathway intermediates baeocystin, nor norbaeocystin as well the dephosphorylated baeocystin degradation product norpsilocin were also detected in strains engineered for psilocybin production. We also demonstrate the biosynthetic production of natural tryptamine derivative aeruginascin as well as the production of a new-to-nature tryptamine derivative N-acetyl-4-hydroxytryptamine. These results lay the foundation for the biotechnological production of psilocybin in a controlled environment for pharmaceutical applications, and provide a starting point for the biosynthetic production of other tryptamine derivatives of therapeutic relevance.