Structure, Function and Inhibition of Human O-GlcNAc Transferase

人 O-GlcNAc 转移酶的结构、功能和抑制

基本信息

批准号：
8234495
负责人：
Suzanne Walker
金额：
$ 53.03万
依托单位：
HARVARD MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-02-01 至 2016-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8234495
关键词：
Active Sites Address Attenuated Binding Biochemical Biological Cell Extracts Cell division Cell physiology Cells Communities Complex Complications of Diabetes Mellitus Cysteine Development Diphosphates Disease Elements Enzymes Family Foundations Gluconeogenesis Glycopeptides Goals Hand Health Human Inhibitory Concentration 50 Laboratories Lead Light Link Lysine Malignant Neoplasms Mediating Methods Modification Molecular Nutrient O-GlcNAc transferase Pathology Pathway interactions Pattern Peptides Play Post-Translational Protein Processing Process Protein Microchips Protein Profiling Microarrays Proteins Proteome Quinolones Research Role Stress Response Signaling Structure Structure-Activity Relationship Sulfonamides Work analog base crosslink design enzyme structure enzyme substrate glucose metabolism glycosylation improved inhibitor/antagonist insulin signaling interest mutant novel protein protein interaction research study small molecule sugar therapeutic target tool

项目摘要

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. PUBLIC HEALTH RELEVANCE: O-GlcNAc transferase (OGT) is an essential mammalian enzyme that catalyzes a unique post-translational modification, O-GlcNAcylation. This modification mediates critical cellular processes involved in nutrient signaling, stress responses, and cell division. Aberrant O-GlcNAcylation has been linked to many diseases, and the work proposed here will lead to the development of small molecule inhibitors to probe OGT's biological roles and potential as a therapeutic target.

描述（由申请人提供）：O-GlcNAc 转移酶 (OGT) 是一种重要的哺乳动物酶，可催化独特的翻译后修饰 O-GlcNAc 酰化。 O-GlcNAc 酰化已被证明可以调节胰岛素信号传导、糖异生以及与葡萄糖代谢相关的其他途径。高 O-GlcNAc 酰化会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，有人建议OGT可以作为治疗靶点。更好地了解 OGT 的结构和功能对于剖析其生物学作用至关重要，小分子抑制剂受到科学界的广泛寻求。该提案的目标是 i) 为剖析 OGT 的生化和细胞功能的合理实验提供结构基础，ii) 提供经过验证的小分子抑制剂，用作 OGT 功能的细胞探针，以及 iii) 开发蛋白质组- 广泛的底物分析方法，用于识别底物选择所需的 OGT 特征。公共健康相关性：O-GlcNAc 转移酶 (OGT) 是一种重要的哺乳动物酶，可催化独特的翻译后修饰 O-GlcNAc 酰化。这种修饰介导涉及营养信号、应激反应和细胞分裂的关键细胞过程。异常的 O-GlcNAc 酰化与许多疾病有关，本文提出的工作将导致小分子抑制剂的开发，以探索 OGT 的生物学作用和作为治疗靶点的潜力。