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首页> 外文期刊>Applied Microbiology >Comparative Investigation into Formycin A and Pyrazofurin A Biosynthesis Reveals Branch Pathways for the Construction of C-Nucleoside Scaffolds
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Comparative Investigation into Formycin A and Pyrazofurin A Biosynthesis Reveals Branch Pathways for the Construction of C-Nucleoside Scaffolds

机译：比较调查对甲酰霉霉素A和吡唑脲素生物合成揭示了C-核苷支架构建的分支途径

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Formycin A (FOR-A) and pyrazofurin A (PRF-A) are purine-related C -nucleoside antibiotics in which ribose and a pyrazole-derived base are linked by a C -glycosidic bond. However, the logic underlying the biosynthesis of these molecules has remained largely unexplored. Here, we report the discovery of the pathways for FOR-A and PRF-A biosynthesis from diverse actinobacteria and propose that their biosynthesis is likely initiated by a lysine N ~(6)-monooxygenase. Moreover, we show that forT and prfT (involved in FOR-A and PRF-A biosynthesis, respectively) mutants are correspondingly capable of accumulating the unexpected pyrazole-related intermediates 4-amino-3,5-dicarboxypyrazole and 3,5-dicarboxy-4-oxo-4,5-dihydropyrazole. We also decipher the enzymatic mechanism of ForT/PrfT for C -glycosidic bond formation in FOR-A/PRF-A biosynthesis. To our knowledge, ForT/PrfT represents an example of β-RFA-P (β-ribofuranosyl-aminobenzene 5?-phosphate) synthase-like enzymes governing C -nucleoside scaffold construction in natural product biosynthesis. These data establish a foundation for combinatorial biosynthesis of related purine nucleoside antibiotics and also open the way for target-directed genome mining of PRF-A/FOR-A-related antibiotics.IMPORTANCE FOR-A and PRF-A are C -nucleoside antibiotics known for their unusual chemical structures and remarkable biological activities. Deciphering the enzymatic mechanism for the construction of a C -nucleoside scaffold during FOR-A/PRF-A biosynthesis will not only expand the biochemical repertoire for novel enzymatic reactions but also permit target-oriented genome mining of FOR-A/PRF-A-related C -nucleoside antibiotics. Moreover, the availability of FOR-A/PRF-A biosynthetic gene clusters will pave the way for the rational generation of designer FOR-A/PRF-A derivatives with enhanced/selective bioactivity via synthetic biology strategies.
机译：甲酰霉素A（for-a）和吡脲脲a（prf-a）是嘌呤相关的c-核苷抗生素，其中核糖和吡唑衍生的碱通过c凝糖键连接。然而，这些分子的生物合成的逻辑依赖性在很大程度上是未探索的。在这里，我们报告了从不同的肌动菌菌的FOR-A和PRF-A生物合成的途径发现，并提出它们的生物合成可能由赖氨酸N〜（6） - 肟酶引发。此外，我们展示了堡和PRFT（分别参与了A和PRF-A生物合成），相应地能够积累意外的吡唑相关的中间体4-氨基-3,5-二羧酸甲唑和3,5-二羧基 - 4-氧代-4,5-二氢吡唑。我们还破译了For-A / PRF-A生物合成中的C糖苷键形成的Fort / Prft的酶机机理。据我们所知，Fort / PRFT表示天然产物生物合成中的C-核苷支架结构的β-RFA-P（β-核糖糖基 - 氨基苯甲酸氨基苯甲酸氨基苯甲酸酯5→相似的酶。这些数据建立了相关嘌呤核苷抗生素的组合生物合成的基础，并且还对PRF-A / for-A相关抗生素的靶向基因组开采的方式进行了途径。称为A和PRF-A是C-核​​苷抗生素已知为了他们不寻常的化学结构和显着的生物活动。在A / PRF-B生物合成期间解密用于构建C-核苷支架的酶促机理将不仅将生物化学曲目扩展为新的酶促反应，而且允许针对A / PRF-A-的靶向导向的基因组挖掘相关的C-核苷抗生素。此外，FOR-A / PRF-A生物合成基因集群的可用性将使A / PRF-A衍生物的理性产生具有增强/选择性生物活性的衍生物的理性产生的方法。

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