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）是一种必不可少的哺乳动物酶，可催化独特的翻译后修饰，O-Glcnacylation。 O-Glcnacylation已显示可调节胰岛素信号传导，糖异生和其他与葡萄糖代谢相关的途径。超O-Glcnacylation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，已经提出OGT可能是一个治疗靶标。更好地理解OGT的结构和功能对于剖析其生物学作用至关重要，而科学界广泛寻求小分子抑制剂。该提案的目标是i）为理性实验提供结构性基础，以剖析OGT的生化和细胞功能，ii）提供了有效的小分子抑制剂，以用作OGT功能的细胞探针，以及III），以开发全蛋白质组的蛋白质组底物分析方法，以确定所需的OGT特征。公共卫生相关性：O-GLCNAC转移酶（OGT）是一种必不可少的哺乳动物酶，它催化了独特的翻译后修饰，O-Glcnacylation。这种修饰介导了涉及营养信号，应力反应和细胞分裂的关键细胞过程。异常的O-Glcnacylation与许多疾病有关，此处提出的工作将导致小分子抑制剂的发展以探测OGT的生物学作用和作为治疗靶点的潜力。