Optimized psilocybin production in tryptophan catabolism‐repressed fungi
Slavica Janevska, Sophie Weiser, Ying Huang, Jun Lin, Sandra Hoefgen, Katarina Jojić, Tim Schäfer, Janis Fricke, Dirk Hoffmeister, Lars Regestein, Vito Valiante, Amelia E. Barber, Johann E. Kufs
Microbial Biotechnology November 1, 2024 DOI: 10.1111/1751-7915.70039 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Experimental study Peer reviewed |
|---|---|
| Population | Saccharomyces cerevisiae and Aspergillus nidulans strains |
| Topics | Psilocybin |
| Keywords | Tryptamine Aspergillus nidulans Biochemistry Mutant |
| Citations | 13 |
| Key findings | Deletion of ARO8/9 and BNA2 genes in yeast and their orthologs in A. nidulans dramatically increased psilocybin production, achieving 267 mg/L in optimized batch cultures. |
Abstract
Abstract The high therapeutic potential of psilocybin, a prodrug of the psychotropic psilocin, holds great promise for the treatment of mental disorders such as therapy‐refractory depression, alcohol use disorder and anorexia nervosa. Psilocybin has been designated a ‘Breakthrough Therapy’ by the US Food and Drug Administration, and therefore a sustainable production process must be established to meet future market demands. Here, we present the development of an in vivo psilocybin production chassis based on repression of l ‐tryptophan catabolism. We demonstrate the proof of principle in Saccharomyces cerevisiae expressing the psilocybin biosynthetic genes. Deletion of the two aminotransferase genes ARO8 / 9 and the indoleamine 2,3‐dioxygenase gene BNA2 yielded a fivefold increase of psilocybin titre. We transferred this knowledge to the filamentous fungus Aspergillus nidulans and identified functional ARO8 / 9 orthologs involved in fungal l ‐tryptophan catabolism by genome mining and cross‐complementation. The double deletion mutant of A. nidulans resulted in a 10‐fold increased psilocybin production. Process optimization based on respiratory activity measurements led to a final psilocybin titre of 267 mg/L in batch cultures with a space–time‐yield of 3.7 mg/L/h. These results demonstrate the suitability of our engineered A. nidulans to serve as a production strain for psilocybin and other tryptamine‐derived pharmaceuticals.