金核霉素和杀草菌素的生物合成研究

Nucleoside antibiotics (NAs) are a large class of nucleoside or nucleotide derivatives which display excellent biological activities. NAs are widely used as agricultural antibiotics as well as molecular tools in biological researches. Aureonuclemycin and herbicidins constitute a group of adenine nucleoside antibiotics that unite novel structures and good application futures. The novel structures include, for example, the unique undecose skeleton, tricyclic furano-pyrano-pyran moiety and nine stereogenic centers, opposite hydroxyl group at C-3' position, (E)-2-(methyl)-2-butenoic acid group that is rare in microbes, and so on. Aureonuclemycin is also a new generation of agricultural agent with large-scale application prospect that was independently developed in China. In this proposal, we plan to study the biosynthesis of aureonuclemycin and herbicidins, elucidate the natural mechanisms in the synthesis of these complicated structures, and obtain novel biosynthetic pathways for NA skeletons. The study has great importance to the combinatorial biosynthesis of NAs. Meanwhile we will perform the rational alteration of the biosynthetic pathway for by-product 5'-DI, combining with systematical metabolic engineering. These genetic manipulations will enhance the production of aureonuclemycin by eliminating the 5'-DI accumulation, and will certainly promote the industrialization and application of this antibiotic.

核苷类抗生素是一大类具有良好生物活性的核苷或核苷酸衍生物，它们作为农用抗生素和生物学研究的小分子工具被广泛使用。金核霉素及杀草菌素是兼具新颖结构和实际应用前景的腺嘌呤核苷类抗生素：它包含独特的十一碳糖核苷衍生骨架、呋喃并-吡喃并-吡喃三环结构及9个手性中心、与天然腺苷戊糖相反的3'-羟基构型、以及微生物中少见的反式-2-甲基-2-丁烯酸酯修饰等；金核霉素同时也是我国自主研发的新一代生物农药，具有大规模应用前景。本项目通过金核霉素和杀草菌素的生物合成研究，将首次阐明这些复杂结构在自然界中的合成机制，获得核苷类抗生素核心骨架的新合成途径，对于核苷类抗生素的组合生物合成具有重要意义；通过对金核霉素产生菌中副产物生物合成途径的理性改造，结合全局性代谢工程手段，消除副产物5'-DI的累积并提高金核霉素产量，有助于金核霉素的产业化和推广应用。

金核霉素及杀草菌素是兼具新颖结构和实际应用前景的腺嘌呤核苷类抗生素。本项目通过金核霉素和杀草菌素的生物合成研究，发现了他们的生物合成途径，初步阐明了这些复杂结构在自然界中的合成机制，获得高碳糖骨架的新合成途径，完全解析了莎草菌素的后修饰过程，对于核苷类抗生素的组合生物合成具有重要意义。同时，通过对杀草菌素生物合成途径的改造，获得了若干莎草菌素新类似物，为分子多样性提供了帮助。