Groenevelt Jessica M, Corey Daniel J, Fehl Charlie
Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, MI, 48202, USA.
Chembiochem. 2021 Jun 2;22(11):1854-1870. doi: 10.1002/cbic.202000843. Epub 2021 Mar 3.
All human cells use O-GlcNAc protein modifications (O-linked N-acetylglucosamine) to rapidly adapt to changing nutrient and stress conditions through signaling, epigenetic, and proteostasis mechanisms. A key challenge for biologists in defining precise roles for specific O-GlcNAc sites is synthetic access to homogenous isoforms of O-GlcNAc proteins, a result of the non-genetically templated, transient, and heterogeneous nature of O-GlcNAc modifications. Toward a solution, this review details the state of the art of two strategies for O-GlcNAc protein modification: advances in "bottom-up" O-GlcNAc peptide synthesis and direct "top-down" installation of O-GlcNAc on full proteins. We also describe key applications of synthetic O-GlcNAc peptide and protein tools as therapeutics, biophysical structure-function studies, biomarkers, and as disease mechanistic probes to advance translational O-GlcNAc biology.
所有人类细胞都利用O-连接的N-乙酰葡糖胺（O-GlcNAc）蛋白修饰，通过信号传导、表观遗传和蛋白质稳态机制快速适应不断变化的营养和应激条件。生物学家在确定特定O-GlcNAc位点的精确作用时面临的一个关键挑战是如何合成获得O-GlcNAc蛋白的同质异构体，这是由于O-GlcNAc修饰具有非基因模板化、瞬时性和异质性的特点。为了解决这个问题，本综述详细介绍了O-GlcNAc蛋白修饰的两种策略的现状：“自下而上”的O-GlcNAc肽合成进展以及在完整蛋白质上直接“自上而下”安装O-GlcNAc。我们还描述了合成O-GlcNAc肽和蛋白质工具作为治疗药物、生物物理结构功能研究、生物标志物以及作为推进转化性O-GlcNAc生物学的疾病机制探针的关键应用。
