转录因子AtrA介导的巴豆酰化修饰调控链霉菌次级代谢的分子机制

次级代谢是链霉菌非常重要也是非常复杂的生理过程，期间合成的天然产物是药物开发的重要来源，因此深刻理解次级代谢调控的分子机制是充分开发链霉菌天然产物资源的基础。经典链霉菌次级代谢调控研究主要集中在多层次的级联转录调控，而蛋白质翻译后修饰调控链霉菌次级代谢的分子机制鲜有报道。前期研究发现链霉菌次级代谢关键转录调控因子AtrA上存在巴豆酰化修饰。本课题将通过多组学，蛋白晶体等技术深入解析在次级代谢过程中，巴豆酰化修饰调控AtrA活性，及其与靶基因启动子结合变化的分子机制；解析AtrA修饰的酶学机制、动态变化与次级代谢的偶联性，以及AtrA对细胞修饰状态、修饰系统的反馈调控，从而阐明巴豆酰化修饰精准调控次级代谢的分子机制。本课题从新的视角理解链霉菌次级代谢调控分子机制，将进一步丰富次级代谢多层次复杂调控理论体系，并为从蛋白修饰层次人工设计与改造调控网络、提升微生物药物的生物合成效率奠定理论基础。

Secondary metabolism is one of the important and complex physiological processes of Streptomyces, during which numerous natural products are produced as the main sources for pharmaceutical development. So thorough understanding of the molecular mechanism on secondary metabolism regulation is the basis for full exploitation of Streptomyces natural products. Traditional studies on regulation of Streptomyces secondary metabolism mainly focus on the transcriptional cascades, but the regulatory mechanism of protein post-translational modifications (PTMs) on Streptomyces secondary metabolism is rarely reported. We have shown that a novel PTM crotonylation occurs on AtrA, a critical transcriptional regulator for Streptomyces secondary metabolism. Here, based on multi-omics, protein crystallization, etc, we will reveal the molecular mechanisms of crotonylation on AtrA to regulate its transcriptional activity and the dynamic interaction with its regulon promoters during secondary metabolism. We will also investigate the modification enzymology of AtrA, the coupling of AtrA crotonylation dynamics with secondary metabolism, and also the feedback regulation of AtrA on the crotonylation system and crotonylation status for secondary metabolism development, thus showing the molecular mechanisms that crotonylation elaborately regulates Streptomyces secondary metabolism. Our work will shed new light on the precise regulatory mechanisms of Streptomyces secondary metabolism based on protein PTMs. This study will also enrich our understanding of the hieratical complex regulation of secondary metabolism, and pave the way for possible reconfiguration of regulatory networks based on PTMs for enhancement of biosynthetic efficiency of microbial pharmaceuticals.