The structural basis of psilocybin biosynthesis

裸盖菇素生物合成的结构基础

• 批准号: 456463463
• 负责人: Professor Dr. Dirk Hoffmeister
• 金额: --
• 依托单位: Sektion für Genetische Epidemiologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/456463463?language=en
• 关键词: structural; basis; psilocybin; biosynthesis

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.

在这个D-A-CH项目中，裸盖菇素生物合成酶的机制将通过X射线晶体学研究，结合生物化学方法进行探索。具有精神作用的裸盖菇素是裸盖菇的主要代谢物，也就是所谓的“神奇蘑菇”。先进的临床试验已经令人信服地证明了裸盖菇素在治疗难治性抑郁症和晚期癌症患者的存在焦虑方面的药物相关性。蘑菇生产裸盖菇素从L-色氨酸，通过色氨酸合成酶（TrpB）合成，使用另外四种酶（PsiD，PsiH，PsiM和PsiK）在高度复杂的反应。PsiD和PsiK将表示新折叠或将允许分配到折叠族。对于具有现有结构模板的三种酶，将揭示许多区域和结合位点细节的显著差异。除了推断整体三维结构外，底物通道和催化位点的分子结构将回答与工程催化剂设计相关的问题。这些结果将使一个有效的生物催化生产裸盖菇素类似物，并奠定了基础，为未来的生物催化生产裸盖菇素和类似物用于治疗目的。这项工作具有试点性质，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，这些结果将引起天然产物研究人员和生物医学科学家的根本兴趣，为有前途的治疗剂的性质和生物合成提供信息。