Optimized psilocybin production in tryptophan catabolism‐repressed fungi
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...
Saved in:
| Main Authors: | , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2024-11-01
|
| Series: | Microbial Biotechnology |
| Online Access: | https://doi.org/10.1111/1751-7915.70039 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850146837282947072 |
|---|---|
| author | Slavica Janevska Sophie Weiser Ying Huang Jun Lin Sandra Hoefgen Katarina Jojić Amelia E. Barber Tim Schäfer Janis Fricke Dirk Hoffmeister Lars Regestein Vito Valiante Johann E. Kufs |
| author_facet | Slavica Janevska Sophie Weiser Ying Huang Jun Lin Sandra Hoefgen Katarina Jojić Amelia E. Barber Tim Schäfer Janis Fricke Dirk Hoffmeister Lars Regestein Vito Valiante Johann E. Kufs |
| author_sort | Slavica Janevska |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-53d44d76fc64408d9d6a7f5b39599526 |
| institution | OA Journals |
| issn | 1751-7915 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Microbial Biotechnology |
| spelling | doaj-art-53d44d76fc64408d9d6a7f5b395995262025-08-20T02:27:43ZengWileyMicrobial Biotechnology1751-79152024-11-011711n/an/a10.1111/1751-7915.70039Optimized psilocybin production in tryptophan catabolism‐repressed fungiSlavica Janevska0Sophie Weiser1Ying Huang2Jun Lin3Sandra Hoefgen4Katarina Jojić5Amelia E. Barber6Tim Schäfer7Janis Fricke8Dirk Hoffmeister9Lars Regestein10Vito Valiante11Johann E. Kufs12(Epi‐)Genetic Regulation of Fungal Virulence Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute Jena GermanyBio Pilot Plant Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute Jena GermanyBiobricks of Microbial Natural Product Syntheses Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute Jena GermanyBiobricks of Microbial Natural Product Syntheses Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute Jena GermanyBiobricks of Microbial Natural Product Syntheses Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute Jena GermanyBiobricks of Microbial Natural Product Syntheses Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute Jena GermanyFungal Informatics Friedrich Schiller University Jena GermanyPharmaceutical Microbiology Friedrich Schiller University Jena GermanyPharmaceutical Microbiology Friedrich Schiller University Jena GermanyPharmaceutical Microbiology Friedrich Schiller University Jena GermanyBio Pilot Plant Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute Jena GermanyBiobricks of Microbial Natural Product Syntheses Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute Jena GermanyBio Pilot Plant Leibniz Institute for Natural Product Research and Infection Biology–Hans Knöll Institute Jena GermanyAbstract 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.https://doi.org/10.1111/1751-7915.70039 |
| spellingShingle | Slavica Janevska Sophie Weiser Ying Huang Jun Lin Sandra Hoefgen Katarina Jojić Amelia E. Barber Tim Schäfer Janis Fricke Dirk Hoffmeister Lars Regestein Vito Valiante Johann E. Kufs Optimized psilocybin production in tryptophan catabolism‐repressed fungi Microbial Biotechnology |
| title | Optimized psilocybin production in tryptophan catabolism‐repressed fungi |
| title_full | Optimized psilocybin production in tryptophan catabolism‐repressed fungi |
| title_fullStr | Optimized psilocybin production in tryptophan catabolism‐repressed fungi |
| title_full_unstemmed | Optimized psilocybin production in tryptophan catabolism‐repressed fungi |
| title_short | Optimized psilocybin production in tryptophan catabolism‐repressed fungi |
| title_sort | optimized psilocybin production in tryptophan catabolism repressed fungi |
| url | https://doi.org/10.1111/1751-7915.70039 |
| work_keys_str_mv | AT slavicajanevska optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT sophieweiser optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT yinghuang optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT junlin optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT sandrahoefgen optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT katarinajojic optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT ameliaebarber optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT timschafer optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT janisfricke optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT dirkhoffmeister optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT larsregestein optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT vitovaliante optimizedpsilocybinproductionintryptophancatabolismrepressedfungi AT johannekufs optimizedpsilocybinproductionintryptophancatabolismrepressedfungi |