Worth Matthew, Li Hao, Jiang Jiaoyang
Pharmaceutical Sciences Division, School of Pharmacy, and ‡Department of Chemistry, University of Wisconsin-Madison , Madison, Wisconsin 53705, United States.
ACS Chem Biol. 2017 Feb 17;12(2):326-335. doi: 10.1021/acschembio.6b01065. Epub 2017 Jan 19.
O-GlcNAcylation is the modification of serine and threonine residues with β-N-acetylglucosamine (O-GlcNAc) on intracellular proteins. This dynamic modification is attached by O-GlcNAc transferase (OGT) and removed by O-GlcNAcase (OGA) and is a critical regulator of various cellular processes. Furthermore, O-GlcNAcylation is dysregulated in many diseases, such as diabetes, cancer, and Alzheimer's disease. However, the precise role of this modification and its cycling enzymes (OGT and OGA) in normal and disease states remains elusive. This is partially due to the difficulty in studying O-GlcNAcylation with traditional genetic and biochemical techniques. In this review, we will summarize recent progress in chemical approaches to overcome these obstacles. We will cover new inhibitors of OGT and OGA, advances in metabolic labeling and cellular imaging, synthetic approaches to access homogeneous O-GlcNAcylated proteins, and cross-linking methods to identify O-GlcNAc-protein interactions. We will also discuss remaining gaps in our toolbox for studying O-GlcNAcylation and questions of high interest that are yet to be answered.
O-连接的N-乙酰葡糖胺化（O-GlcNAcylation）是指细胞内蛋白质上的丝氨酸和苏氨酸残基被β-N-乙酰葡糖胺（O-GlcNAc）修饰。这种动态修饰由O-GlcNAc转移酶（OGT）添加，并由O-GlcNAcase（OGA）去除，是各种细胞过程的关键调节因子。此外，O-GlcNAcylation在许多疾病中失调，如糖尿病、癌症和阿尔茨海默病。然而，这种修饰及其循环酶（OGT和OGA）在正常和疾病状态下的确切作用仍然难以捉摸。部分原因在于用传统的遗传和生化技术研究O-GlcNAcylation存在困难。在这篇综述中，我们将总结在克服这些障碍的化学方法方面的最新进展。我们将涵盖OGT和OGA的新型抑制剂、代谢标记和细胞成像的进展、获取均一O-GlcNAc化蛋白质的合成方法以及用于鉴定O-GlcNAc-蛋白质相互作用的交联方法。我们还将讨论我们研究O-GlcNAcylation的工具包中仍然存在空白以及尚未解答的高关注度问题。
