Chemistry - A European Journal
April 9, 2025
Tim Schäfer, Thomas Krüger, Jakob Worbs et al.
2 citations
A reusable solid-phase resin coated with five enzymes—three from Psilocybe mushrooms and two from E. coli—converts 4-hydroxy-L-tryptophan into psilocybin quantitatively in a proof-of-principle in vitro experiment. This biocatalytic approach offers a sustainable, selective alternative to synthetic production for the drug candidate being tested in advanced clinical trials for major depressive disorder.
Biotechnology and Bioengineering
December 30, 2025
Sophie Weiser, Sidney Jung, Bettina Bardl et al.
1 citation
A bioprocess using a genetically modified strain of the fungus Aspergillus nidulans produced 542 mg per liter of psilocybin from glucose in 68 hours. The filamentous culture broth was sensitive to oxygen availability and power input, which affected viscosity and mass transfer. Scaling up from shake flasks to a 7-liter stirred tank reactor based on specific power input, along with enhanced oxygen supply in a pressure reactor and nitrogen limitation addressed by adding ammonium sulfate, yielded a robust batch process. This biotechnological approach could supplement chemical synthesis for supplying psilocybin for pharmaceutical use and demonstrates pressurized bioprocessing to overcome oxygen limitations for shear-sensitive filamentous organisms.
ChemBioChem
May 3, 2025
Nick Zschoche, Markus Gressler, Stefan Bartram et al.
1 citation
Psilocybe cubensis mushrooms, famous for producing the psychedelic compound psilocybin, also possess enzymes that synthesize a variety of other small, potentially bioactive molecules. Four newly identified sesquiterpene synthases, CubB through CubE, are expressed differently in the mushroom's fruiting bodies versus its vegetative mycelium. CubB produces a single compound, nerolidol, while CubC generates multiple sesquiterpenes including β-caryophyllene and α-humulene. CubD and CubE nearly exclusively produce sterpurene. The presence of nerolidol was confirmed in young fruiting bodies and vegetative mycelium. These findings expand understanding of the secondary metabolome of Psilocybe species.
ChemBioChem
October 16, 2024
Jesse Hudspeth, Kai Rogge, Tobias Wagner et al.
1 citation
The enzyme PsiM from the mushroom Psilocybe cubensis catalyzes the final step in psilocybin biosynthesis, adding two methyl groups to the substrate norbaeocystin. A single amino acid change, M247N, allowed this enzyme to evolve from ancestral monomethylating RNA methyltransferases into a dimethylating enzyme. Mutating this asparagine back to methionine (N247M) or alanine (N247A) eliminated the ability to perform the second methylation. High-resolution crystal structures and kinetic measurements show that Asn247 provides necessary space in the active site for multiple methylations and stabilizes nearby secondary structures through hydrogen bonds, enabling efficient substrate binding and catalysis.
ChemBioChem
April 1, 2026
Sebastian Schober, Lisa Dorfmann, Karl Walther et al.
Psilocybe cubensis magic mushrooms produce not only the psychedelic psilocybin but also a range of sesquiterpenes, natural products that can modulate biological receptors. Five sesquiterpene synthases were characterized: CubF makes α-muurolol, CubG1 and CubG2 produce mainly epi-isozizaene and β-duprezianene, CubH yields dauca-4(11),8-diene, and CubI forms β-barbatene. Gas chromatography revealed that vegetative mycelium and fruiting bodies have different sesquiterpene profiles, with sterpurene prominent in mycelium and dauca-4(11),8-diene in fruiting bodies. This knowledge may help separate the pharmacological effects of whole magic mushrooms from those of pure psilocybin.
Angewandte Chemie
September 21, 2025
Tim Schäfer, Fabian Haun, Bernhard Rupp et al.
Psilocybin, the main psychoactive alkaloid in magic mushrooms, is produced by several fungal genera. In Psilocybe species the biosynthetic pathway from L-tryptophan is well characterized. This work examined the pathway in Inocybe corydalina, a distantly related mushroom that also makes psilocybin. Four recombinant enzymes from I. corydalina were characterized in vitro: a decarboxylase (IpsD), a kinase (IpsK), and two methyltransferases (IpsM1 and IpsM2); a fifth monooxygenase (IpsH) was analyzed in silico. None of the reactions matched those in Psilocybe. The Inocybe pathway is branched and also produces baeocystin as a second end product. The findings indicate that psilocybin biosynthesis evolved twice independently using unrelated enzymes.