IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-46997-z.html
   My bibliography  Save this article

Methyl transfer in psilocybin biosynthesis

Author

Listed:
  • Jesse Hudspeth

    (Medical University of Innsbruck
    Colorado School of Mines)

  • Kai Rogge

    (Friedrich Schiller University
    Leibniz Institute of Natural Product Research and Infection Biology, Hans Knöll Institute)

  • Sebastian Dörner

    (Friedrich Schiller University
    Leibniz Institute of Natural Product Research and Infection Biology, Hans Knöll Institute)

  • Maximilian Müll

    (Leibniz Institute of Natural Product Research and Infection Biology, Hans Knöll Institute)

  • Dirk Hoffmeister

    (Friedrich Schiller University
    Leibniz Institute of Natural Product Research and Infection Biology, Hans Knöll Institute)

  • Bernhard Rupp

    (Medical University of Innsbruck
    k.-k. Hofkristallamt)

  • Sebastiaan Werten

    (Medical University of Innsbruck)

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.

Suggested Citation

  • Jesse Hudspeth & Kai Rogge & Sebastian Dörner & Maximilian Müll & Dirk Hoffmeister & Bernhard Rupp & Sebastiaan Werten, 2024. "Methyl transfer in psilocybin biosynthesis," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46997-z
    DOI: 10.1038/s41467-024-46997-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-46997-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-024-46997-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Sara Reardon, 2023. "Psychedelic treatments are speeding towards approval — but no one knows how they work," Nature, Nature, vol. 623(7985), pages 22-24, November.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.

      More about this item

      Statistics

      Access and download statistics

      Corrections

      All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46997-z. See general information about how to correct material in RePEc.

      If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

      If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

      If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

      For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

      Please note that corrections may take a couple of weeks to filter through the various RePEc services.

      IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.