Methyl transfer in psilocybin biosynthesis
Atomic-resolution (0.9 Å) crystal structures of PsiM at multiple reaction stages reveal the SAM-dependent dimethylation mechanism and show that its substrates physicochemically mimic RNA, while structural and phylogenetic analyses indicate PsiM derives from METTL16-family m6A writers. The study also shows inherent limitations of the ancestral monomethyltransferase scaffold that reduce psilocybin assembly efficiency and prevent trimethylation to aeruginascin, informing bioengineering efforts to create improved psilocybin variants.
Authors
- Hudspeth, J.
- Rogge, K.
- Dörner, S.
Published
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.
Research Summary of 'Methyl transfer in psilocybin biosynthesis'
Introduction
Hudspeth and colleagues introduce PsiM as the SAM-dependent methyltransferase that performs the final biosynthetic step generating psilocybin from norbaeocystin via the monomethylated intermediate baeocystin. The authors situate psilocybin in a therapeutic context, noting its clinical promise and recent efforts to produce it biotechnologically, and highlight that the four genes required for the pathway (psiD, psiH, psiK and psiM) have enabled heterologous production in several microbial hosts. This study set out to determine high-resolution crystal structures of PsiM at successive stages of its catalytic cycle, to characterise its enzymology and substrate specificity, and to investigate its evolutionary origins. The aims included explaining why PsiM dimethylates its small-molecule substrate, whether it can perform a third methylation to yield aeruginascin, and how the enzyme’s structure relates to related RNA methyltransferases, with the practical goal of informing bioengineering of psilocybin analogues.
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Study Details
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- APA Citation
Hudspeth, J., Rogge, K., Dörner, S., Müll, M., Hoffmeister, D., Rupp, B., & Werten, S. (2024). Methyl transfer in psilocybin biosynthesis. Nature Communications, 15(1). https://doi.org/10.1038/s41467-024-46997-z
References (5)
Papers cited by this study that are also in Blossom
Geiger, H. A., Wurst, M. G., Daniels, R. N. · ACS Chemical Neuroscience (2018)
Fricke, J., Lenz, C., Wick, J. et al. · Chemistry A European Journal (2018)
Halberstadt, A. L., Geyer, M. A. · Neuropharmacology (2011)
Yang, F., Yang, S., Tseng, P. et al. · Psychiatry Investigation (2021)
Adams, A. M., Kaplan, N. A., Wei, Z. et al. · Metabolic Engineering (2019)
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