化学生物学解析疾病中O-GlcNAc糖基化功能: 研究工具与策略
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张娜娜, 大连理工大学生物工程专业在读博士生, 研究方向为O-GlcNAc糖基化修饰与肿瘤生物学行为. |
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刘宇博, 大连理工大学生命科学与药学学院副教授, 博士生导师, 主要研究方向为化学糖生物学和肿瘤糖生物学. 以化学生物学和糖生物学交叉融合为手段, 开发高效、低毒糖探针, 发展化学糖组学研究新策略. 2014年大连理工大学生物化工专业博士毕业, 以第一作者或通讯作者在Nature Communications, Journal of Biological Chemistry, Cell death & Disease等期刊发表研究论文30余篇, 主持国家自然科学基金3项, 辽宁省自然科学基金3项. |
收稿日期: 2023-02-19
网络出版日期: 2023-06-07
基金资助
国家自然科学基金(21975163); 国家自然科学基金(32171282)
Application of Chemical Biology to Reveal the Function of O-GlcNAcylation in Diseases: Research Tools and Tactics
Received date: 2023-02-19
Online published: 2023-06-07
Supported by
National Natural Science Foundation of China(21975163); National Natural Science Foundation of China(32171282)
O-连接β-N-乙酰葡糖胺(O-GlcNAc)糖基化是广泛存在于蛋白质丝/苏氨酸残基的翻译后修饰. 这一动态、可逆单糖修饰以位点特异性方式影响底物蛋白的结构和生物学功能, 参与调控几乎所有细胞生理过程和重大疾病的演进过程. 随着研究深入, O-GlcNAc糖基化生物功能的系统解析需要更多特异、精准的研究工具和糖蛋白质组学研究策略. 近年来, 化学生物学领域开发了包括小分子糖探针、生物正交糖代谢标记物、化学酶法、特异性抗体和凝集素等多种O-GlcNAc糖基化分析工具和方法, 以此为基础进一步发展了O-GlcNAc糖蛋白质组学研究策略. 同时, 借助高分辨质谱, 大量蛋白质O-GlcNAc修饰位点得以鉴定, 极大促进了位点特异性O-GlcNAc的生物功能研究. 本文综述了近年来这一领域的研究进展, 以期为更多化学工具的开发提供依据, 为揭示O-GlcNAc糖基化在疾病演进中的功能提供新的研究思路和策略.
关键词： O-GlcNAc糖基化; 化学生物学; 分子工具; 糖蛋白质组学
张娜娜 , 于恺然 , 李际婷 , 张嘉宁 , 刘宇博 . 化学生物学解析疾病中O-GlcNAc糖基化功能: 研究工具与策略[J]. 化学学报, 2023 , 81(7) : 843 -856 . DOI: 10.6023/A23020040
The addition of O-linked-β-N-acetylglucosamine (O-GlcNAc) onto serine and threonine residues of nuclear and cytoplasmic proteins is an abundant and unique post-translational modification that plays a critical role in governing important biological processes. Since its discovery, O-GlcNAcylation has been shown to contribute to numerous cellular processes, including signaling, protein localization and stability, transcription, chromatin remodeling, mitochondrial function, and cell survival. O-GlcNAcylation is a dynamic and reversible post-translational modification that regulates protein function in a site-specific manner, making it an important player in the regulation of diverse biological processes. Dysregulation of O-GlcNAcylation has been implicated in the pathogenesis of various diseases, including cancer, neurodegenerative disorders, and diabetes. To better understand the regulatory roles of O-GlcNAcylation in cellular physiology and disease pathogenesis, O-GlcNAc proteomics strategies and more specialized, more exact research tools are needed to further explore the bio-functional systematization of O-GlcNAcylation. In recent years, the field of chemical biology has developed various tools and methods for analyzing O-GlcNAc glycosylation, including small molecule sugar probes, metabolic labeling reagents, chemoenzymatic techniques, specific antibodies, and lectins. These tools have served as a foundation for the further development of O-GlcNAc glycoproteomic research strategies. O-GlcNAc glycoproteomic strategies, such as high-resolution mass spectrometry-based approaches have been developed to allow for the detection and quantification of O-GlcNAc modifications on specific proteins, enabling site-specific analysis of O-GlcNAc modification patterns. The number of proteins modified by O-GlcNAc is quite extensive, with at least 7000 modification sites identified in human cells. This highlights the importance of O-GlcNAcylation in regulating diverse biological processes. Identification of O-GlcNAcylation sites with specific biological functions is still a remaining problem. Innovative solutions are required to address this challenge in cell models and disease therapy. At the same time, with the aid of high-resolution mass spectrometry, a large number of O-GlcNAc modification sites on proteins have been identified, which has greatly promoted the study of site-specific O-GlcNAc biological functions. This article has reviewed the recent advances in the field of O-GlcNAc research, with the aim of providing a basis for the development of more chemical tools and offering new research ideas and strategies for uncovering the functions of O-GlcNAcylation in disease progression.
Key words： O-GlcNAcylation; chemical biology; molecular tools; glycoproteomics
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