The structural basis of psilocybin biosynthesis

在这个D-A-CH项目中，将通过X射线结晶学研究结合生化方法来探索裸盖菇素生物合成酶的机制。精神药物裸盖菇素是裸盖菇菇的主要代谢物，也就是所谓的“神奇蘑菇”。先进的临床试验令人信服地证明，裸盖菇素在治疗难治性抑郁症和晚期癌症患者的生存焦虑方面具有药物相关性。这些蘑菇由L-色氨酸合成裸盖菇素，通过色氨酸合成酶(TrpB)合成，使用另外四种酶(PSID、PSIH、PSIM和PSIK)进行高度复杂的反应。PSID和PSIK将代表新的折叠，或者将允许分配到折叠家族。对于现有结构模板的三种酶，在许多区域和结合部位细节上将显示出显著的差异。除了推断整体的三维结构外，底物通道和催化位置的分子结构还将回答与工程催化剂设计相关的问题。这些结果将使裸盖菇素类似物的生物催化生产成为可能，并为未来用于治疗目的的裸盖菇素及其类似物的生物催化生产奠定基础。这项工作具有先导性，因为它代表了第一个真菌天然产物途径，其整个结构基础将被理解。因此，这些结果将是天然产品研究人员和生物医学科学家的基本兴趣，为一种有前途的治疗剂的性质和生物合成提供信息。

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.