9eto
PsiK from Psilocybe cubensis
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, the natural hallucinogen from Psilocybe (magic) mushrooms, is a highly promising drug candidate for the treatment of depression and several other mental health conditions. Biosynthesis of psilocybin from the amino acid l-tryptophan involves four strictly sequential modifications. The third of these, ATP-dependent phosphorylation of the intermediate 4-hydroxytryptamine, is catalysed by PsiK. Here we present a crystallographic analysis and a structure-based mutagenesis study of this kinase, providing insight into its mode of substrate recognition. The results of our work will support future bioengineering efforts aimed at generating variants of psilocybin with enhanced therapeutic properties. Substrate recognition by the 4-hydroxytryptamine kinase PsiK in psilocybin biosynthesis.,Rogge K, Wagner TJ, Hoffmeister D, Rupp B, Werten S FEBS Lett. 2024 Oct 24. doi: 10.1002/1873-3468.15042. PMID:39449146[5] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||||
