Chemical Immunology Lab, Centre for Cooperative Research in Biosciences, CIC-bioGUNE, Basque Research and Technology Alliance (BRTA), Derio 48160, Biscay, Spain.
Ikerbasque, Basque Foundation for Science, Bilbao 48013, Spain.
Chem Soc Rev. 2021 Sep 20;50(18):10451-10485. doi: 10.1039/d0cs01275k.
The addition of -linked-β-D--acetylglucosamine (-GlcNAc) onto serine and threonine residues of nuclear and cytoplasmic proteins is an abundant, unique post-translational modification governing important biological processes. -GlcNAc dysregulation underlies several metabolic disorders leading to human diseases, including cancer, neurodegeneration and diabetes. This review provides an extensive summary of the recent progress in probing -GlcNAcylation using mainly chemical methods, with a special focus on discussing mechanistic insights and the structural role of -GlcNAc at the molecular level. We highlight key aspects of the -GlcNAc enzymes, including development of OGT and OGA small-molecule inhibitors, and describe a variety of chemoenzymatic and chemical biology approaches for the study of -GlcNAcylation. Special emphasis is placed on the power of chemistry in the form of synthetic glycopeptide and glycoprotein tools for investigating the site-specific functional consequences of the modification. Finally, we discuss in detail the conformational effects of -GlcNAc glycosylation on protein structure and stability, relevant -GlcNAc-mediated protein interactions and its molecular recognition features by biological receptors. Future research in this field will provide novel, more effective chemical strategies and probes for the molecular interrogation of -GlcNAcylation, elucidating new mechanisms and functional roles of -GlcNAc with potential therapeutic applications in human health.
在核蛋白和细胞质蛋白的丝氨酸和苏氨酸残基上添加β-D-N-乙酰氨基葡萄糖（β-GlcNAc）是一种丰富的、独特的翻译后修饰，可调节重要的生物学过程。β-GlcNAc 的失调是几种代谢紊乱的基础，可导致人类疾病，包括癌症、神经退行性疾病和糖尿病。本综述广泛总结了近年来主要采用化学方法探测β-GlcNAcylation 的最新进展，特别关注讨论分子水平上的机制见解和β-GlcNAc 的结构作用。我们强调了β-GlcNAc 酶的关键方面，包括 OGT 和 OGA 小分子抑制剂的开发，并描述了用于研究β-GlcNAcylation 的各种化学酶和化学生物学方法。特别强调了化学形式的合成糖肽和糖蛋白工具在研究修饰的特异性功能后果方面的强大功能。最后，我们详细讨论了β-GlcNAc 糖基化对蛋白质结构和稳定性的构象影响、相关的β-GlcNAc 介导的蛋白质相互作用及其生物受体的分子识别特征。该领域的未来研究将为β-GlcNAcylation 的分子研究提供新的、更有效的化学策略和探针，阐明β-GlcNAc 的新机制和功能作用，为人类健康提供潜在的治疗应用。
