Skip to content

Metabolic engineering of Saccharomyces cerevisiae for the de novo production of psilocybin and related tryptamine derivatives

N. Milne, Philip Tinggaard Thomsen, Niels Aage Tvis Knudsen, P. Rubaszka, Mette Kristensen, Irina Borodina

Metabolic Engineering March 26, 2020 DOI: 10.1016/j.ymben.2019.12.007 (opens in new tab)

Relevant Not relevant

Study at a glance

AI-extracted from the abstract
Characteristics Experimental study Peer reviewed
Population Saccharomyces cerevisiae (baker's yeast) engineered with genes from Psilocybe cubensis
Topics Psilocybin
Keywords Tryptamine Saccharomyces cerevisiae Metabolic engineering Biochemistry
Citations 126
Key findings De novo biosynthetic production of psilocybin and related tryptamine derivatives in Saccharomyces cerevisiae was achieved, with final titers of 627 ± 140 mg/L psilocybin and 580 ± 276 mg/L psilocin in fed-batch fermentations.

Abstract

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.

Comparable studies

Other experimental studies on psilocybin, most cited first.

Study Year Design Participants
Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action Healthy human volunteers 1998 Experimental study
Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin Participants in controlled laboratory experiments receiving a moderate to high oral... 2015 Validation study using pooled data from five laboratory experiments n = 184
Broadband Cortical Desynchronization Underlies the Human Psychedelic State Healthy human participants 2013 Experimental study
Long-term follow-up of psilocybin-assisted psychotherapy for psychiatric and existential distress in patients with life-threatening cancer Participants with cancer-related psychiatric distress who completed a parent randomized... 2020 Long-term within-subjects follow-up analysis n = 15
Enzymatic Synthesis of Psilocybin 2017 Laboratory study

Citations in the library

Cited by 47

and 42 more in the library

Cites 20

and 15 more in the library

Related reading

Explore topics

Psilocybin