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

化学学报 ›› 2026, Vol. 84 ›› Issue (3): 409-424.DOI: 10.6023/A25120390 上一篇下一篇

综述

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

于恺然^a, 张娜娜^b, 刘宇博^b^,^*()

^a 大连理工大学化工海洋与生命学院盘锦 122406
^b 东北大学生命科学与健康学院沈阳 110169

投稿日期:2025-12-01 发布日期:2026-02-10
通讯作者: 刘宇博

作者简介:

于恺然, 大连理工大学化学生物学专业在读博士生, 研究方向为O-GlcNAc糖基化修饰与肿瘤生物学行为.

刘宇博, 博士, 教授, 博士生导师. 现就职于东北大学生命科学与健康学院. 研究工作以化学生物学与糖生物学交叉融合为手段, 通过开发高效、低毒糖探针与化学糖组学新策略, 实现对肿瘤演进过程的多维度、高通量观测; 开发人源化糖链生物合成方法, 构建以糖基转移酶、糖核苷酸合成与转运模块为核心的可编程平台. 在Nature Communications、Science Advances、Oncogene、EMBO Reports等杂志发表论文50余篇. 主持国家自然科学基金, 国家重大科技专项子课题等十余项, 入选国家级青年人才, “兴辽英才”青年拔尖人才.

基金资助:
项目受国家自然科学基金(32471331)

Tools for Precise Control of Protein-Specific O-GlcNAcylation: Insights into Disease Mechanisms and Therapeutic Opportunities

Yu Kairan^a, Zhang Nana^b, Liu Yubo^b^,^*()

^a School of Chemical Engineering, Ocean and Life Sciences, Dalian University of Technology, Panjin 122406, China
^b School of Life Sciences and Health, Northeastern University, Shenyang 110169, China

Received:2025-12-01 Published:2026-02-10
Contact: Liu Yubo
Supported by:
National Natural Science Foundation of China(32471331)

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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 critical roles in cellular regulation. To date, more than 5,000 O-GlcNAc-modified 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). Uridine diphosphate N-acetylglucosamine (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 implies 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

引用此文

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, 2026, 84(3): 409-424.

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, 2026, 84(3): 409-424.

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图/表 10

图1. O-GlcNAc糖基化修饰过程

Figure 1. The O-GlcNAcylation modification process

图2. 基于化学小分子与标记技术的O-GlcNAc修饰研究策略

Figure 2. Chemical and labeling approaches for investigating O-GlcNAc modifications

图3. 功能丧失性O-GlcNAc修饰位点突变

Figure 3. Loss-of-function O-GlcNAc site mutations

图4. S-GlcNAc修饰过程

Figure 4. The S-GlcNAcylation modification process

图5. 功能获得性突变

Figure 5. Gain-of-function O-GlcNAc site mutations

图6. 遗传密码扩展技术流程

Figure 6. Process of genetic code expansion

图7. GECCO策略流程

Figure 7. Process of the GECCO strategy

图8. 基于纳米抗体的O-GlcNAc修饰靶向调控: (a) OGT通过标签纳米抗体空间接近靶蛋白, 使融合表达标签的靶蛋白O-GlcNAc修饰增加. (b) OGA通过标签纳米抗体去除靶蛋白O-GlcNAc修饰. OGA茎和催化结构域的分裂可抑制脱靶活性

Figure 8. Nanobody-based targeted regulation of O-GlcNAcylation. (a) OGT is recruited into proximity of the target protein via a tag-specific nanobody, leading to increased O-GlcNAcylation on the tagged target protein. (b) OGA removes O-GlcNAc from the target protein via the tag-specific nanobody. Splitting the OGA stalk and catalytic domains can suppress off-target activity

图9. 靶向特定蛋白O-GlcNAc修饰的嵌合体分子. (a) FKBP12F36V融合表达的OGT通过OGTAC-1/2/3与融合表达HaloTag的靶蛋白结合, 催化靶蛋白发生O-GlcNAc修饰. (b) FKBP12F36V融合表达的OGT通过OGTAC-4与内源蛋白BRD4直接结合, 催化BRD4发生O-GlcNAc修饰

Figure 9. Chimeric molecules for targeting O-GlcNAcylation to specific proteins. (a) OGT fused to FKBP12F36V is recruited to HaloTag-fused target proteins via OGTAC-1/2/3, resulting in O-GlcNAcylation of the target proteins. (b) OGT fused to FKBP12F36V directly binds the endogenous protein BRD4 through OGTAC-4, leading to O-GlcNAcylation of BRD4

图10. 双特异性RNA适配体

Figure 10. Dual-specificity RNA aptamers

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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

Tools for Precise Control of Protein-Specific O-GlcNAcylation: Insights into Disease Mechanisms and Therapeutic Opportunities

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