高碳糖核苷类抗生素miharamycins和amipurimycin的生物合成机制解析

核苷类抗生素是一大类具有广泛生物活性的核苷衍生物，它们作为农业抗生素被广泛使用且在临床应用方面也极具潜力。Miharamycins和amipurimycin是链霉菌产生的两种高碳糖核苷类抗生素，具有罕见的支链九碳糖氨基酸骨架和2-氨基嘌呤结构。我们成功地获取了miharamycins和amipurimycin的生物合成基因簇，同时构建了高产菌株并建立了高效的体内遗传操作方法，初步提出了它们的生物合成途径。本项目拟以miharamycins和amipurimycin生物合成中新颖的酶催化机制研究为切入点，完全阐明微生物合成这类抗生素的生物化学过程，并扩展人们对于非核糖体肽合成酶和聚酮合酶催化机理的认识。在此基础上，我们将通过组合生物合成有针对性地挖掘新的高碳糖核苷类天然产物，扩充这个独特抗生素家族的成员数量，为核苷类抗生素的药物开发提供新的候选分子。

Nucleoside antibiotics are a large class of nucleoside derivatives with a wide range of biological activities. Nucleoside antibiotics are widely used as agricultural antibiotics and have great potential in clinical applications. Miharamycins and amipurimycin are two high-carbon sugar nucleoside antibiotics produced by Streptomyces, containing a unique branched C9 pyranosyl amino acid core and a rare 2-aminopurine moiety. We have successfully obtained the biosynthetic gene clusters of miharamycins and amipurimycin and proposed their biosynthetic pathways. The high-yield mutant strains were constructed and efficient in vivo genetic manipulation methods were established. In this project, we are going to study the mechanism of several novel steps in the formation of miharamycins and amipurimycin. We will completely elucidate the biochemical process for the biosynthesis of this family of antibiotics in microorganisms, and expand the understanding of the catalytic mechanism of nonribosomal peptide synthetase and polyketide synthase. In addition, we are going to develop new C9 nucleoside compounds through combinatorial biosynthesis, expanding the members of this unique family and providing new candidates for pharmaceutical research of nucleoside antibiotics.