Structure, Function and Inhibition of Human O-GlcNAc Transferase

人 O-GlcNAc 转移酶的结构、功能和抑制

• 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
• 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

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 - 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相关的途径。超o - glcn酰化导致广泛的转录改变，并与糖尿病并发症、癌症和其他病理有关。因此，有人认为OGT可能是一个治疗靶点。更好地了解OGT的结构和功能对于解剖其生物学作用至关重要，小分子抑制剂被科学界广泛寻求。本提案的目标是i)为合理的实验提供结构基础，以剖析OGT的生化和细胞功能，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)开发一种蛋白质组范围的底物分析方法，以确定底物选择所需的OGT特征。