Structure, Function and Inhibition of Human O-GlcNAc Transferase

描述(申请人提供)：O-GlcNAc转移酶(OGT)是一种哺乳动物必需的酶，它催化一种独特的翻译后修饰，O-GlcN酰化。O-GlcN酰化已被证明可以调节胰岛素信号、糖异生和其他与葡萄糖代谢有关的途径。Hyper-O-GlcN酰化导致广泛的转录变化，并与糖尿病并发症、癌症和其他病理有关。因此，OGT可能成为治疗的靶点。更好地了解OGT的结构和功能是剖析其生物学作用的关键，小分子抑制剂被科学界广泛寻找。该建议的目标是：1)为分析OGT的生化和细胞功能的合理实验提供结构基础；2)提供有效的小分子抑制剂作为OGT功能的细胞探针；3)发展一种蛋白质组范围的底物图谱方法，以确定底物选择所需的OGT特征。

DESCRIPTION (provided by applicant): O-GlcNAc transferase (OGT) is an essential mammalian enzyme that catalyzes a unique post-translational modification, O-GlcNAcylation. O-GlcNAcylation has been shown to modulate insulin signaling, gluconeogenesis, and other pathways connected to glucose metabolism. Hyper-O-GlcNAcylation leads to widespread transcriptional changes and has been linked to diabetic complications, cancer, and other pathologies. Therefore, it has been suggested that OGT could be a therapeutic target. A better understanding of the structure and function of OGT is critical for dissecting its biological roles, and small molecule inhibitors are widely sought by the scientific community. The goals of this proposal are i) to supply the structural basis for rational experiments to dissect the biochemical and cellular functions of OGT, ii) to provide validated small molecule inhibitors for use as cellular probes of OGT function, and iii) to develop a proteome-wide substrate profiling approach to identify OGT features required for substrate selection.