The structural basis of psilocybin biosynthesis

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In this D-A-CH project, the mechanism of psilocybin biosynthesis enzymes will be explored through X-ray crystallographic studies, combined with biochemical methods. The psychotropic psilocybin represents the principal metabolite of Psilocybe mushrooms, the so-called “magic mushrooms”. Advanced clinical trials have convincingly demonstrated psilocybin’s pharmaceutical relevance in the treatment of therapy-refractory depression and of existential anxiety of advanced-stage cancer patients. The mushrooms produce psilocybin from L-tryptophan, synthesized via tryptophan synthase (TrpB), using another four enzymes (PsiD, PsiH, PsiM, and PsiK) in highly sophisticated reactions.It is the objective of the proposed work to investigate and explore the structures of these enzymes. PsiD and PsiK will either represent new folds or will allow assignment to a fold family. For the three enzymes with existing structure templates, significant differences in numerous regions and binding site details will be revealed. In addition to inferring the overall three dimensional structures, the molecular architecture of substrate channels and the catalytic sites will answer questions relevant for the design of engineered catalysts. These results will enable an efficient biocatalytic production of psilocybin analogs and lay the foundation for future biocatalytic production of psilocybin and analogues for therapeutic purposes. This work has pilot character as it represents the first fungal natural product pathway whose entire structural basis will be understood. Hence, the results will be of fundamental interest to natural product researchers as well as biomedical scientists, informing about the nature and biosynthesis of a promising therapeutic agent.