O-Linked β-N-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.

中文翻译：

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O-GlcNAc 治疗性调节的机会


O-连接 β-N-乙酰氨基葡萄糖 （O-GlcNAc） 是一种必需的动态单糖翻译后修饰 （PTM），存在于数千种核质蛋白的丝氨酸和苏氨酸残基上。O-GlcNAc 的安装和去除分别由一对酶 O-GlcNAc 转移酶 （OGT） 和 O-GlcNAcase （OGA） 控制。自四十年前被发现以来，O-GlcNAc 已存在于不同类别的蛋白质中，在许多细胞过程中发挥着重要的功能作用。O-GlcNAc 稳态失调与疾病的发病机制有关，包括神经退行性变、X 连锁智力障碍 （XLID）、癌症、糖尿病和免疫疾病。O-GlcNAc 在疾病生物学中的这些基础研究推动了 O-GlcNAc 治疗靶向的努力，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 的表征和生物化学、细胞 O-GlcNAc 调节、OGT 和 OGA 抑制剂的开发、O-GlcNAc 在病理生理学中的表现、O-GlcNAc 调节剂的临床进展以及靶向 O-GlcNAc 的新兴机会。这一综合资源应激励对 O-GlcNAc 功能的进一步研究，并激发 O-GlcNAc 治疗调节策略。