乙酰化修饰调控氨同化的机制及对沙门氏菌致病性的影响

氨同化为氨基酸合成代谢提供氨基供体，通过调节胞内谷氨酸和谷氨酰胺水平影响沙门氏菌的生理及病理。谷氨酸脱氢酶（Glutamate dehydrogenase, GDH）和谷氨酰胺合成酶（Glutamine synthetase, GS）是氨同化关键酶，腺苷酰化修饰调控GS酶活力。申请者在国际上首次报道蛋白的乙酰化修饰是一种保守和全局的代谢调控机制，且预实验结果表明乙酰化可以改变GDH和GS的酶活力，但乙酰化的GDH和GS如何参与氨同化，并进而调控沙门氏菌致病性及其相关机理尚不清楚。基于此，本研究拟解析乙酰化调控沙门氏菌GDH和GS酶活力的机制，揭示GS乙酰化修饰和腺苷酰化修饰的相互作用模式，并阐明乙酰化修饰调控沙门氏菌氨同化的生理和病理意义。项目研究成果有望进一步完善乙酰化参与微生物代谢调控的基础理论，为沙门氏菌的致病性提供新的作用机制，也将为沙门氏菌感染导致的临床相关疾病的干预提供新靶点。

The metabolism of ammonia assimilation can provide the ammonia moiety for the amino acid synthesis, by balancing the level of glutamate and glutamine for the regulation of physiology and expression of the virulent proteins, and then having effect on the virulence of the Salmonella. Glutamate dehydrogenase (GDH) and glutamine synthetase (GS) are the key metabolic enzymes responsible for this process, and the adenylylation modification is the well-known protein translational modification for the GS and further ammonia assimilation regulation. We firstly reported that the acetylation is a conserved and global regulation mechanism from prokaryotes to eukaryotes. In preliminary study, we found that the enzymatic activities of GDH and GS are regulated by acetylation. However, the mechanism of how the acetylation modulates the enzymatic activities of GDH and GS for the ammonia assimilation and then regulates Salmonella virulence is not clear. In this study, we will uncover the molecular mechanism how the acetylation coordinating the enzymatic activities of GDH and GS, and discover the crosstalk mechanism between the acetylation and the adenylylation, and then demonstrate the role of acetylation in regulating Salmonella ammonia assimilation for its physiology and virulence. If it is well done, we can expand the basic theory how acetylation in participating in regulation of microbial metabolism, which can provide the new concept of Salmonella virulence and the new targets for the Salmonella-mediated diseases in clinic.