Methyl transfer in psilocybin biosynthesis

Jesse Hudspeth, Kai Rogge, Sebastian Dörner, Maximilian Müll, Dirk Hoffmeister, Bernhard Rupp and Sebastiaan Werten ()
Additional contact information
Jesse Hudspeth: Medical University of Innsbruck
Kai Rogge: Friedrich Schiller University
Sebastian Dörner: Friedrich Schiller University
Maximilian Müll: Leibniz Institute of Natural Product Research and Infection Biology, Hans Knöll Institute
Dirk Hoffmeister: Friedrich Schiller University
Bernhard Rupp: Medical University of Innsbruck
Sebastiaan Werten: Medical University of Innsbruck

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract Psilocybin, the natural hallucinogen produced by Psilocybe (“magic”) mushrooms, holds great promise for the treatment of depression and several other mental health conditions. The final step in the psilocybin biosynthetic pathway, dimethylation of the tryptophan-derived intermediate norbaeocystin, is catalysed by PsiM. Here we present atomic resolution (0.9 Å) crystal structures of PsiM trapped at various stages of its reaction cycle, providing detailed insight into the SAM-dependent methylation mechanism. Structural and phylogenetic analyses suggest that PsiM derives from epitranscriptomic N6-methyladenosine writers of the METTL16 family, which is further supported by the observation that bound substrates physicochemically mimic RNA. Inherent limitations of the ancestral monomethyltransferase scaffold hamper the efficiency of psilocybin assembly and leave PsiM incapable of catalysing trimethylation to aeruginascin. The results of our study will support bioengineering efforts aiming to create novel variants of psilocybin with improved therapeutic properties.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-46997-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46997-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-46997-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().