Deciphering and engineering of the molecular diversity of NRPS-derived azacyclic alkaloids in bacteria

细菌中 NRPS 衍生的氮杂环生物碱分子多样性的破译和改造

• 批准号: 446275382
• 负责人: Professor Dr. Helge Björn Bode
• 金额: --
• 依托单位: Muséum national dhistoire naturelle (UMR 7204)
• 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/446275382?language=en
• 关键词: Deciphering; engineering; molecular; diversity; NRPS

While many biosynthetic pathways in bacteria lead to one or a limited number of products, certain systems produce a diversity of metabolites. The pathways to the bacterial pyrrolizidine alkaloids (PAs) represent striking examples of this phenomenon. A common biosynthetic scheme involving a bimodular nonribosomal peptide synthetase (NRPS) and a monooxygenase, in combination with accessory enzymes and/or spontaneous chemical reactions, leads to diverse azacycles such as pyrrolizidines and cyclocarbamates. In recent work, several of these compounds have been found to attenuate virulence of the producing bacteria during interaction with its host. The molecular mechanisms governing such diversification and underlying their biological activity remain unknown. Given the high interest and broad pharmaceutical potential of azacycle-containing molecules, this project proposes to decipher the molecular basis for the chemical diversity of pyrrolizidine and related alkaloids in bacteria, to elucidate structure-function relationships for key enzymes in the pathways, and to apply the obtained knowledge to generate new-to-nature derivatives with interesting bioactivity, notably as anti-virulence compounds of a major human pathogen, Pseudomonas aeruginosa.

虽然细菌中的许多生物合成途径产生一种或有限数量的产物，但某些系统产生多种代谢产物。细菌吡咯里西啶生物碱（PA）的途径代表了这种现象的突出例子。一个常见的生物合成方案涉及一个双模非核糖体肽合成酶（NRPS）和单加氧酶，与辅助酶和/或自发的化学反应，导致不同的氮杂环，如吡咯烷和环氨基甲酸酯。在最近的工作中，已经发现这些化合物中的几种在与其宿主相互作用期间减弱产毒细菌的毒力。管理这种多样化及其生物活性的分子机制仍然未知。考虑到含氮杂环分子的高度兴趣和广泛的药学潜力，该项目提出破译细菌中吡咯里西啶和相关生物碱的化学多样性的分子基础，阐明途径中关键酶的结构-功能关系，并应用所获得的知识产生具有有趣生物活性的新天然衍生物，特别是作为主要人类病原体的抗毒性化合物，绿脓杆菌。