In silico characterization of the psilocybin biosynthesis pathway.
Computational biology and chemistry June 1, 2023 William Irvine, Marshall Tyler, Rupika Delgoda 11 citations
Psilocybin, the psychoactive alkaloid in Psilocybe mushrooms, is synthesized from L-tryptophan by four enzymes: PsiD, PsiH, PsiK, and PsiM. Because the pathway was only recently defined, structural data for these enzymes were lacking. This work generated homology models for all four Psilocybe cubensis enzymes, refined them with secondary structure prediction, energy minimization, and molecular dynamics simulations, then validated the models by docking their natural substrates. The models produced feasible binding modes for each biotransformation step. Additional docking simulations suggest that the PsiM model can also mediate conversions leading to aeruginascin, norpsilocin, and N,N-dimethyltryptamine, indicating plausible routes for these secondary metabolites. These structural models may aid development of novel substrates, selective inhibitors, and improved in vitro psilocybin production.