Department of Chemistry and Chemical Biology, Harvard University, Cambridge, Massachusetts 02138, United States.
Affiliate member of the Broad Institute, Cambridge, Massachusetts 02142, United States.
Chem Rev. 2024 Nov 27;124(22):12918-13019. doi: 10.1021/acs.chemrev.4c00417. Epub 2024 Nov 7.
-Linked β--acetylglucosamine (O-GlcNAc) is an essential, dynamic monosaccharide post-translational modification (PTM) found on serine and threonine residues of thousands of nucleocytoplasmic proteins. The installation and removal of O-GlcNAc is controlled by a single pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Since its discovery four decades ago, O-GlcNAc has been found on diverse classes of proteins, playing important functional roles in many cellular processes. Dysregulation of O-GlcNAc homeostasis has been implicated in the pathogenesis of disease, including neurodegeneration, X-linked intellectual disability (XLID), cancer, diabetes, and immunological disorders. These foundational studies of O-GlcNAc in disease biology have motivated efforts to target O-GlcNAc therapeutically, with multiple clinical candidates under evaluation. In this review, we describe the characterization and biochemistry of OGT and OGA, cellular O-GlcNAc regulation, development of OGT and OGA inhibitors, O-GlcNAc in pathophysiology, clinical progress of O-GlcNAc modulators, and emerging opportunities for targeting O-GlcNAc. This comprehensive resource should motivate further study into O-GlcNAc function and inspire strategies for therapeutic modulation of O-GlcNAc.
-O-连接β-N-乙酰氨基葡萄糖（O-GlcNAc）是一种必需的、动态的单糖，存在于数千种核细胞质蛋白的丝氨酸和苏氨酸残基上。O-GlcNAc 的安装和去除由一对酶分别控制，即 O-连接 N-乙酰氨基葡萄糖转移酶（OGT）和 O-连接 N-乙酰氨基葡萄糖苷酶（OGA）。自四十年前发现以来，O-GlcNAc 已在多种蛋白质类别中被发现，在许多细胞过程中发挥着重要的功能作用。O-GlcNAc 动态平衡的失调与疾病的发病机制有关，包括神经退行性疾病、X 连锁智力障碍（XLID）、癌症、糖尿病和免疫性疾病。这些关于 O-GlcNAc 在疾病生物学中的基础研究激发了人们努力通过靶向 O-GlcNAc 进行治疗，目前有多种临床候选药物正在评估中。在这篇综述中，我们描述了 OGT 和 OGA 的特征和生物化学、细胞内 O-GlcNAc 调控、OGT 和 OGA 抑制剂的开发、O-GlcNAc 在病理生理学中的作用、O-GlcNAc 调节剂的临床进展以及靶向 O-GlcNAc 的新机会。这个全面的资源应该会激励进一步研究 O-GlcNAc 的功能，并激发对 O-GlcNAc 进行治疗性调节的策略。
