靶向特定蛋白质的O-GlcNAc修饰精准调控工具：疾病机制研究与治疗机遇

doi:10.6023/A25120390

摘要/Abstract

蛋白质O-连接β-N-乙酰葡萄糖胺（O-GlcNAc）糖基化是一种广泛存在于真核细胞中的动态可逆单糖修饰,其修饰和水解过程分别由糖基转移酶（OGT）和糖基水解酶（OGA）催化完成。该修饰参与调控基因转录、表观遗传修饰及信号转导等多种细胞过程。随着研究的推进以及高分辨质谱等技术的应用,O-GlcNAc修饰位点鉴定数量迅速增加,推动了其位点特异性功能研究。然而,直接干预OGT或OGA的策略会扰动细胞中大量蛋白的O-GlcNAc修饰,难以解析特定蛋白修饰位点的功能。为此,开发靶向调控特定蛋白O-GlcNAc修饰的新工具与方法成为研究热点。本文综述了近年来靶向调控蛋白质O-GlcNAc修饰方面的研究进展,介绍了多种新兴化学生物学工具及策略,并探讨了其在揭示O-GlcNAc修饰功能及疾病机制中的潜在应用价值。

关键词: O-GlcNAc糖基化, 化学生物学, 分子工具, 靶向调控, 位点特异性修饰

Protein O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation is a highly dynamic and reversible monosaccharide post-translational modification in eukaryotic cells, playing a critical role in cellular regulation. To date, more than 5,000 O-GlcNAcylated proteins have been identified, distributed in the cytoplasm, nucleus, mitochondria, and membraneless subcellular compartments. O-GlcNAcylation is catalyzed by O-GlcNAc transferase (OGT), which installs a single N-acetylglucosamine moiety onto serine and threonine residues, whereas removal of the modification is mediated by O-GlcNAcase (OGA). UDP-GlcNAc, the end product of the hexosamine biosynthetic pathway (HBP), serves as the sugar donor for this modification. This tightly coupled enzymatic cycle allows O-GlcNAcylation to act as a nutrient-and signal-responsive regulatory modification, linking metabolic state to protein function. O-GlcNAcylation regulates a broad range of fundamental cellular processes, including gene transcription, chromatin remodeling, epigenetic regulation, protein-protein interactions, and diverse intracellular signaling pathways. Dysregulation of global or protein-specific O-GlcNAcylation has been linked to the development and progression of multiple human diseases, including cancer, diabetes, and neurodegenerative disorders. With continuous advances in analytical methodologies, particularly high-resolution mass spectrometry and enrichment strategies, an increasing number of O-GlcNAc modification sites have been identified, allowing the functional roles of target proteins and their specific modification sites to be examined in detail. However, the highly dynamic nature of O-GlcNAcylation causes that chemical or genetic methods targeting OGT or OGA often lead to widespread changes in O-GlcNAc levels across thousands of proteins. Such global alterations complicate the functional interpretation of site-specific modifications and make it challenging to determine the precise role of O-GlcNAc at individual protein sites. Increasing evidence suggests that targeted modulation of specific O-GlcNAc sites on individual proteins provides improved mechanistic insight and greater translational relevance than global modulation approaches. Therefore, developing tools and strategies that allow site-specific modulation of O-GlcNAcylation on individual proteins, without altering overall O-GlcNAc levels, is critical. This review summarizes recent advances in targeted protein O-GlcNAcylation, highlights emerging chemical biology tools and strategies, and discusses their potential to reveal site-specific O-GlcNAc functions and their relevance to human disease.

Key words: O-GlcNAcylation, chemical biology, molecular tools, targeted regulation, site-specific modification

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于恺然, 张娜娜, 刘宇博. 靶向特定蛋白质的O-GlcNAc修饰精准调控工具：疾病机制研究与治疗机遇[J]. 化学学报, doi: 10.6023/A25120390.

Yu, Kairan, Zhang, Nana, Liu, Yubo. Tools for Precise Control of Protein-Specific O-GlcNAcylation: Insights into Disease Mechanisms and Therapeutic Opportunities[J]. Acta Chimica Sinica, doi: 10.6023/A25120390.

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