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Methyl transfer in psilocybin biosynthesis.
Hudspeth, Jesse; Rogge, Kai; Dörner, Sebastian; Müll, Maximilian; Hoffmeister, Dirk; Rupp, Bernhard; Werten, Sebastiaan.
Afiliación
  • Hudspeth J; Institute of Genetic Epidemiology, Medical University of Innsbruck, Innsbruck, Austria.
  • Rogge K; Department of Chemistry, Colorado School of Mines, Golden, CO, USA.
  • Dörner S; Institute of Pharmacy, Friedrich Schiller University, Jena, Germany.
  • Müll M; Research Group Pharmaceutical Microbiology, Leibniz Institute of Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany.
  • Hoffmeister D; Institute of Pharmacy, Friedrich Schiller University, Jena, Germany.
  • Rupp B; Research Group Pharmaceutical Microbiology, Leibniz Institute of Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany.
  • Werten S; Research Group Biosynthetic Design of Natural Products, Leibniz Institute of Natural Product Research and Infection Biology, Hans Knöll Institute, Jena, Germany.
Nat Commun ; 15(1): 2709, 2024 Mar 28.
Article en En | MEDLINE | ID: mdl-38548735
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Agaricales / Psilocybe / Alucinógenos Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Reino Unido
Texto completo
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XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Agaricales / Psilocybe / Alucinógenos Idioma: En Revista: Nat Commun Asunto de la revista: BIOLOGIA / CIENCIA Año: 2024 Tipo del documento: Article País de afiliación: Austria Pais de publicación: Reino Unido