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射线晶体学研究并结合生化方法来探索。裸盖菇素是所谓“神奇蘑菇”的主要代谢产物。试验令人信服地证明了裸盖菇素在治疗晚期癌症患者的难治性抑郁症和存在性焦虑方面的药物相关性。在高度复杂的反应中使用另外四种酶（PsiD、PsiH、PsiM 和 PsiK）从 L-色氨酸生产裸盖菇素，通过色氨酸合酶 (TrpB) 合成。本项工作的目的是研究和探索这些酶的结构PsiD 和 PsiK 要么代表新的折叠，要么允许分配给具有现有结构模板的三种酶，许多区域和结合位点细节存在显着差异。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还将回答与工程催化剂设计相关的问题，这些结果将为裸盖菇素类似物的有效生物催化生产奠定基础。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，结果将具有基础性。天然产物研究人员和生物医学科学家的兴趣，了解有前途的治疗剂的性质和生物合成。