近日，来自中国科学院生物物理所的研究团队在蛋白质组学研究国际顶尖期刊《Molecular and Cellular Proteomics》上发表了他们的最新研究进展，题为“Lysine malonylation is elevated in type 2 diabetic mouse models and enriched in metabolic associated proteins”，在该研究中他们发现赖氨酸丙二酰化修饰在2型糖尿病的发病机理中起着非常重要的作用。
目前2型糖尿病是当前威胁全球人类健康的最重要的慢性非传染性疾病之一。国际糖尿病联盟（IDF）公布的数据显示预计到2035年全球糖尿病人数将高达5.92亿人，而2型糖尿病发病率和人数增加最快的为发展中国家，2015年中国糖尿病的患病率将会突破1.4亿。通常来说糖基化的血红蛋白A1c（HbA1c）作为2型糖尿病的临床检测标准，而蛋白质翻译后修饰在2型糖尿病中还有待揭示。
越来越多的证据表明2型糖尿病及前驱糖尿病中malonyl-CoA水平有显著上调，而malonyl-CoA又作为赖氨酸丙二酰化修饰的丙二酰基供体，其生物功能可能间接影响赖氨酸丙二酰化修饰的生物学意义，所以丙二酰化修饰引起了研究人员的兴趣。
在该项研究中，研究人员利用蛋白质修饰泛抗体对2型糖尿病模型db/db小鼠肝脏组织蛋白进行修饰富集，发现相对于同窝野生型对照组小鼠样本中赖氨酸乙酰化，1,2-甲基化，琥珀酰化，丁酰化，丙酰化以及巴豆酰化修饰只有少量上调，而丙二酰化修饰却显著上调。应用高精度的nano-LC-MS/MS结合抗体免疫亲和富集，在db/db小鼠及同窝野生型对照组小鼠样品中共鉴定到268个蛋白中的573个丙二酰化修饰位点。其中5个赖氨酸丙二酰化修饰上调蛋白质通过免疫共沉淀及Western blot分析的验证。高级生物信息学分析显示丙二酰化修饰的蛋白质在葡萄糖及脂肪酸的代谢过程中起着关键的作用。研究人员同时发现另几个2型糖尿病模型中丙二酰化修饰都有不同层面的上调，而此种上调仅仅发生在肝脏组织中。他们推测，丙二酰化修饰与2型糖尿病相关，在其发病机制中起重要作用。（本研究所用蛋白质泛修饰抗体及其偶联树脂均来自PTM Biolabs, Inc.，即anti-malonyllysine (PTM-901), anti-acetyllysine (PTM-105), anti-1,2-dimethyllysine(PTM-602), anti-succinyllysine (PTM-401), anti-butyryllysine (PTM-301), anti-propionyllysine(PTM-201), anti-crotonyllysine (PTM-502), anti-malonyllysine conjugated agarose beads。
总之，本研究发现了丙二酰化修饰在2型糖尿病动物模型中广泛存在，在调节新陈代谢和不同生物学过程中均发挥重要功能，为2型糖尿病发病机制研究及治疗提供了方向，促进人们对2型糖尿病蛋白质翻译后修饰的认识和研究。
原文链接：Lysine malonylation is elevated in type 2 diabetic mouse models and enriched in metabolic associated proteins.
Protein lysine malonylation, a newly identified protein post-translational modification (PTM), has been proved to be evolutionarily conserved and is present in both eukaryotic and prokaryotic cells. However, its potential roles associated with human diseases remain largely unknown. In the present study, we observed an elevated lysine malonylation in a screening of seven lysine acylations in liver tissues of db/db mice, which is a typical model of type 2 diabetes. We also detected an elevated lysine malonylation in ob/ob mice, which is another model of type 2 diabetes. We then performed affinity enrichment coupled with proteomic analysis on liver tissues of both wild-type (wt) and db/db mice and identified a total of 573 malonylated lysine sites from 268 proteins. There were more malonylated lysine sites and proteins in db/db than in wt mice. Five proteins with elevated malonylation were verified by immunoprecipitation coupled with Western blot analysis. Bioinformatic analysis of the proteomic results revealed the enrichment of malonylated proteins in metabolic pathways, especially those involved in glucose and fatty acid metabolism. In addition, the biological role of lysine malonylation was validated in an enzyme of the glycolysis pathway. Together, our findings support a potential role of protein lysine malonylation in type 2 diabetes with possible implications for its therapy in the future.
