蛋白质O-GlcNAc糖基化的探针

Probes for Studying Protein O-GlcNAcylation

生物大分子包括蛋白质、核酸、糖脂等的动态化学修饰与病理变化的关系,是当今生物医学研究最为重要的前沿领域之一。细胞内蛋白质丝氨酸和苏氨酸侧链羟基的O连N-乙酰葡糖胺(O-GlcNAc)糖基化修饰,参与了基因表达、信号转导、细胞周期等关键生物学过程的精密调控。异常的O-GlcNAc糖基化与肿瘤、糖尿病、神经退行性疾病等慢性疾病的发生发展密切相关。随着质谱检测技术和蛋白质组学的快速发展,目前已经有大量O-GlcNAc糖基化修饰靶蛋白质和位点得到鉴定。而其中多数蛋白质O-GlcNAc糖基化修饰的生理功能亟需通过探针进一步研究。本文对基于抗体、凝集素、代谢途径、化学酶法的O-GlcNAc糖基化探针研究进行归纳总结,发现未来对O-GlcNAc糖基化的研究急需开发针对特定位点的动态化研究探针,其对进一步揭示O-GlcNAc在疾病发生发展过程中的作用至关重要,也是实现临床分子诊断并进行靶向干预的关键。

The development and progression of many diseases are mostly associated with the dynamic chemical modifications of bio-macromolecules such as protein,nuclear acid,and glycolipid.Therefore,the association of a disease state with the abnormal chemical modification of bio-macromolecules has been one of the frontier areas of biomedical research in these years.Posttranslational modification of proteins with O-GlcNAc is one of the most important dynamic chemical modifications that plays vital roles in regulating cellular events such as gene expression,signal transduction and cell cycle.The abnormal OGlcNAcylation has been strongly linked to chronic diseases such as cancer,diabetes and neurodegenerative diseases.In the past few years,modern mass spectrometry and proteomics methods have greatly advanced the study of O-GlcNAcylation and numerous O-GlcNAcylated proteins have been identified and mapped with modification site.However,in many cases the relevant physiological role of those modifications is not fully understood yet because of limited availability of efficient tools for probing O-GlcNAc specifically.Here,we summarize the current probes and strategies for studying O-GlcNAc using antibodies,O-GlcNAc binding proteins,metabolic and chemoenzymatic labeling.We propose that future studies should be focused on developing probes capable of monitoring the dynamic O-GlcNAc modification at specific proteins in living cells.Developing novel probes is a key step for elucidating the pathophysiological role of this modification in disease state and the related studies will also provide basis for developing O-GlcNAcylation-based molecular diagnostic reagents and the target-specific therapeutic strategy.