MCB:蛋白質組學中心賴氨酸琥珀醯修飾獲新進展

蛋白翻譯後修飾對蛋白的結構和功能起著非常重要的調節作用，賴氨酸琥珀醯化是上海藥物所和芝加哥大學共同合作在原核和真核細胞中最新發現的蛋白翻譯後修飾通路。研究團隊開創性地對哺乳動物細胞中的去乙醯化修飾酶Sirt5調控的琥珀醯化修飾底物進行了系統的蛋白質組學研究，發現了琥珀醯化修飾對能量代謝中的關鍵酶的調控作用，文章相繼發表在Nature Chemical Biology和Molecular Cell上。但在原核生物中，控制該修飾的琥珀醯化底物及調節酶仍然未知，成為該修飾在原核生物研究的障礙。

上海藥物所化學蛋白質組學中心和芝加哥大學、康納爾大學通過進一步合作，系統研究了大腸桿菌中的琥珀醯化修飾底物，並發現了該修飾的調節酶CobB。此次研究在大腸桿菌中發現了670個蛋白上的2580個賴氨酸琥珀醯修飾位點，是原核生物中賴氨酸琥珀醯修飾研究的第一批數據資料。同時還在782個蛋白中找到了2803個乙醯化修飾位點，獲得了野生型大腸桿菌中最大的賴氨酸乙醯化修飾資料庫。

此項研究首次通過定性定量分析揭示了高糖營養環境的賴氨酸琥珀醯動態變化網絡，表明高糖環境可以導致琥珀醯化和乙醯化修飾的顯著增加，並對琥珀醯化修飾的影響更大，揭示了賴氨酸琥珀醯化在原核生物中為一高豐度修飾。研究還首次發現了原核生物中的去琥珀醯修飾酶-CobB（類Sir2細菌賴氨酸去乙醯化酶），表明該酶具有賴氨酸去琥珀醯化和去乙醯化雙重功能活性，提示其他乙醯化調節酶也可能有多種酶活性。此次研究為原核生物中賴氨酸琥珀醯化和乙醯化功能性研究提供了豐富的資源。

上海藥物所相關研究工作以共同通訊作者單位發表在最新一期Molecular. Cell. Proteomics(IF 7.398)雜誌上。(生物谷Bioon.com)

生物谷推薦的英文摘要：

Molecular & Cellular Proteomics      doi：10.1074/mcp.M113.031567

Identification of Lysine Succinylation Substrates and the Succinylation Regulatory Enzyme CobB in Escherichia coli*

Gozde Colak？§， Zhongyu Xie？§， Anita Y. Zhu§？， Lunzhi Dai？， Zhike Lu？， Yi Zhang‖， Xuelian Wan‖， Yue Chen？， Yoon H. Cha？， Hening Lin？，**， Yingming Zhao？‖，** and Minjia Tan‖，**

Lysine succinylation is a newly identified protein post-translational modification pathway present in both prokaryotic and eukaryotic cells. However， succinylation substrates and regulatory enzyme(s) remain largely unknown， hindering the biological study of this modification. Here we report the identification of 2，580 bacterial lysine succinylation sites in 670 proteins and 2，803 lysine acetylation (Kac) sites in 782 proteins， representing the first lysine succinylation dataset and the largest Kac dataset in wild-type E. coli. We quantified dynamic changes of the lysine succinylation and Kac substrates in response to high glucose. Our data showed that high-glucose conditions led to more lysine-succinylated proteins and enhanced the abundance of succinyllysine peptides more significantly than Kac peptides， suggesting that glucose has a more profound effect on succinylation than on acetylation. We further identified CobB， a known Sir2-like bacterial lysine deacetylase， as the first prokaryotic desuccinylation enzyme. The identification of bacterial CobB as a bifunctional enzyme with lysine desuccinylation and deacetylation activities suggests that the eukaryotic Kac-regulatory enzymes may have enzymatic activities on various lysine acylations with very different structures. In addition， it is highly likely that lysine succinylation could have unique and more profound regulatory roles in cellular metabolism relative to lysine acetylation under some physiological conditions.