蛋白质甲硫氨酸亚砜化学标记方法研究

蛋白质甲硫氨酸亚砜化（P-S-Me→P-S(O)-Me）是一种重要的蛋白质氧还翻译后修饰，在细胞氧还状态调控、氧还信号转导中扮演了重要的角色。蛋白质甲硫氨酸亚砜及其还原酶Msrs也被发现与衰老和肝脏疾病、癌症、神经退行性疾病、心血管疾病等疾病病理密切相关。然而，具体生理和病理调控机制尚待进一步研究。而该研究的推进极大受限于分析检测工具的缺乏。迄今为止，能进行生理和病理样本蛋白质甲硫氨酸亚砜化位点分析的研究工具仍未见报道。本项目将基于化学选择性偶联反应，发展新型蛋白质甲硫氨酸亚砜化学标记策略尤其是亚砜构型（R/S）专一性的化学标记策略，分析鉴定细胞活性氧敏感蛋白质甲硫氨酸亚砜化位点，揭示甲硫氨酸亚砜还原酶还原底物位点，探讨氧还调控对细胞甲硫氨酸亚砜化的影响。研究成果将为细胞蛋白质甲硫氨酸亚砜化相关生理调控机制、氧还生物学、衰老机制、相关疾病病理研究以及药物设计提供有力的工具。

As a new type of dynamic redox protein post-translational modification, the protein methionine sulfoxidation (P-S-Me→P-S(O)-Me) in the presence of reactive oxygen species(ROS), plays important roles in cellular redox regulation and redox signaling, thus being closely related to biologic activities like ageing，and pathologies of many diseases such as liver diseases, cancers, human degenerative diseases, cardiovascular disease and so on. However, the research to clearly elucidate the physiological and pathological functions of protein methionine sulfoxidation has been confined due to the lack of efficient tools for detection of protein methionine sulfoxides. So far, there is still no report on the tools which enable identification and quantification of protein sulfoxidated sites, and even enantioselective analysis of protein sulfoxidated sites in biological and pathological samples. In this project, we will investigate chemoselective ligation reactions of methionine sulfoxide, and develop the chemical labeling strategy even sulfoxide-enantioselective labeling strategy for global profiling and sulfoxidate sites analysis of protein methionine sulfoxidation in cells. Exploiting these strategies, we also plan to reveal the redox sensitive intracellular protein sulfoxidated sites, as well as the new targets of methionine sulfoxide reductases. These results will provide powerful tools for better understanding the physiological and pathological functions of protein methionine sulfoxidation.