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Structure complex of 4-hydroxytryptamine kinase PsiK complexed with Mg2+ and Tryptamine
Structural highlights
FunctionPSIK_PSICU 4-hydroxytryptamine kinase; part of the gene cluster that mediates the biosynthesis of psilocybin, a psychotropic tryptamine-derived natural product (PubMed:28763571, PubMed:31150155, PubMed:32101345). 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, PubMed:32101345, PubMed:35583969). 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). PsiK kinase can also turn psilocin into psilocybin (PubMed:28763571, PubMed:35583969). This activity may represent a protective mechanism to rephosphorylate the unstable psilocin to the stable psilocybin in case of intracellular ester cleavage (PubMed:28763571, PubMed:35583969). Moreover, psiK is able to O-phosphorylate the quaternary amine 4-hydroxy-N,N,N-trimethyltryptamine (4-OH-TMT) to yield aeruginascin, another bioactive compound found in Psilocybe species (PubMed:35583969).[1] [2] [3] [4] Publication Abstract from PubMedPsilocybin shows significant therapeutic potential for psilocybin-assisted psychotherapy in addressing various psychiatric conditions. The biosynthetic approach promises rapid and efficient production of psilocybin. Understanding the enzymes that contribute to the biosynthesis of psilocybin can enhance its production process. In this study, we elucidate the crystal structures of L-tryptophan-specific decarboxylase PsiD in both its apo and tryptamine-bound states, the 4-hydroxytryptamine kinase PsiK bound to its substrate, and several forms of the methyltransferase PsiM in either apo or substrate-bound forms derived from the psychedelic mushroom. Structure-based evaluations reveal the mechanisms of self-cleavage and self-inhibition in PsiD, along with the sequential catalytic steps from 4-hydroxytryptamine to the final compound, psilocybin. Additionally, we showcase the antidepressant properties of biosynthetic intermediates of psilocybin on female mice experiencing depression-like behaviors induced by sub-chronic variable stress. Our studies establish a structural basis for the future biosynthetic production of psilocybin using these enzymes and emphasize the clinical potential of norbaeocystin. Structural basis for psilocybin biosynthesis.,Meng C, Guo W, Xiao C, Wen Y, Zhu X, Zhang Q, Liang Y, Li H, Xu S, Qiu Y, Chen H, Lin WJ, Wu B Nat Commun. 2025 Mar 22;16(1):2827. doi: 10.1038/s41467-025-58239-x. PMID:40121242[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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