放线菌转录调控因子的酰基化修饰与红霉素合成代谢调控研究

酰基CoA既是酰基化修饰的供体也是许多抗生素合成的前体，揭示基于酰基CoA介导的酰基化修饰在抗生素合成的调控作用极其重要。我们前期研究发现酰基化修饰抑制丙酰CoA代谢及红霉素合成途径一些关键酶的活性。本项目针对转录因子的酰基化调控胞内基础营养代谢、酰基CoA平衡、次级代谢产物合成机制展开研究。利用合成生物学理念和翻译后修饰代谢工程（PTM-ME）策略筛选由于酰基化抑制效应影响红霉素合成的关键调控蛋白；从翻译后修饰角度解析转录调控因子与细胞整体代谢网络的互作机制；通过精准调节和改造转录调控因子的酰基化水平提高红霉素合成代谢途径的相对代谢流及其与本底代谢途径的适配性；拓展基于翻译后修饰调控机理的改造靶点，强化PTM-ME策略的应用；为复杂型、高商业价值型放线菌合成代谢调控分子机制的完善和理性改造提供理论基础。

Acyl-CoAs function as key precursors for the biosynthesis of various natural products as well as the dominant donors for protein acylation. It is critical to reveal the role of acyl-CoA-mediated acylation in the regulation of antibiotic synthesis. Our previous study found that acylation inhibits the activity of some key enzymes in the propionyl-CoA metabolism and erythromycin synthesis. On the basis of our early research, this study concentrated on the regulatory mechanism among intracellular nutrition metabolism, acyl-CoA homeostasis and secondary metabolism via acylation of transcription factors. Using the synthetic biology method and post-translational metabolic engineering (PTM-ME) strategy, we will try to screen the key regulatory proteins whose acylation inhibits erythromycin synthesis, and reveal the interaction mechanism between transcriptional regulators and global metabolic network in view of post-translational modification. Furthermore, the improvement of relative metabolic flow of erythromycin anabolism and its compatibility in the chassis cell will be obtained through accurate regulation of the acylation level of transcriptional regulators. Our study will provide new modification targets based on the PTM regulation mechanism and contribute to the optimization of PTM-ME strategy. In particular, this system-level understanding of protein PTM will offer a conceptual and technological framework to create new metabolic enzymes/ pathways for the optimal production in actinomycetes.