Magic pathways: the genes and enzymes of psilocybin biosynthesis

SUMMARYSpecies of several mushroom genera, among them Psilocybe and Inocybe, biosynthesize psilocybin, the prodrug to the powerful psychotropic and perception-altering analog, psilocin. While "magic" mushrooms are popular as recreational drugs, advanced clinical trials have shown that psilocybin is a valuable future (and, in some countries, available) medication against depression and anxiety. In this review article, we focus on the metabolic processes leading to psilocybin in the fungal cell and present the biosynthetic enzymes, their structures, and the reactions catalyzed. Remarkably, mushrooms have evolved psilocybin biosynthesis twice independently, involving genes and enzymes that are only distantly related or unrelated altogether. We also present routes on how this iconic natural product can be made biocatalytically in vitro or in heterologous hosts in vivo. Despite substantial progress in psilocybin research over the past decade, we present unsolved questions that remain for the current and the next generation of researchers.