8pb4
PsiM in complex with SAH and norbaeocystin, orthorhombic crystal form
Structural highlights
FunctionPSIM_PSICU N-methyltransferase; part of the gene cluster that mediates the biosynthesis of psilocybin, a psychotropic tryptamine-derived natural product (PubMed:28763571, PubMed:31150155). The first step in the pathway is the decarboxylation of L-tryptophan to tryptamine by the decarboxylase psiD (PubMed:28763571, PubMed:31150155). 4-hydroxy-L-tryptophan is accepted as substrate by psiD as well (PubMed:28763571). The cytochrome P450 monooxygenase psiH then converts tryptamine to 4-hydroxytryptamine (PubMed:28763571). The kinase psiK catalyzes the 4-O-phosphorylation step by converting 4-hydroxytryptamine into norbaeocystin (PubMed:28763571, PubMed:31150155). The methyltransferase psiM then catalyzes iterative methyl transfer to the amino group of norbaeocystin to yield psilocybin via a monomethylated intermediate, baeocystin (PubMed:28763571, PubMed:31150155). 4-hydroxy-6-methyl-l-tryptophancan also be converted the decarboxylase PsiD, kinase PsiK, and methyltransferase PsiM into respectively 6-methyl-norbaeocystin, 6-methylbaeocystin, and 6-methylpsilocybin (PubMed:31150155).[1] [2] Publication Abstract from PubMedPsilocybin, 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 A) 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 N(6)-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. Methyl transfer in psilocybin biosynthesis.,Hudspeth J, Rogge K, Dorner S, Mull M, Hoffmeister D, Rupp B, Werten S Nat Commun. 2024 Mar 28;15(1):2709. doi: 10.1038/s41467-024-46997-z. PMID:38548735[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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