MECHANISM OF OROTIDINE-5'-MONOPHOSPHATE DECARBOXYLASE

乳清苷-5-单磷酸脱羧酶的作用机制

• 批准号: 6505250
• 负责人: Weiming Wu
• 金额: $ 20.08万
• 依托单位: SAN FRANCISCO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-30 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6505250
• 关键词: active sites; decarboxylases; enzyme mechanism; enzyme substrate analog; enzyme substrate complex; nuclear magnetic resonance spectroscopy; nucleic acid biosynthesis; site directed mutagenesis; uridine monophosphate

The enzyme orotidine-5'-monophosphate decarboxylase (ODCase) is involved in the biosynthesis of nucleic acid building blocks and thus represents a potential target for development of anti-tumor drugs. Developing a clear understanding of the fundamental mechanisms of key enzymes has already proven an important contribution to the discovery of new drug therapies. The goal of the proposed research is to understand how the enzyme catalyzes the conversion of the substrate orotidine-5'- monophosphate (OMP) to product uridine-5'-monophosphate (UMP) and to probe the positioning of amino acid residues in the active site of the enzyme. Substrate analogs will be synthesized and studied. NMR spectroscopy will be used to investigate substrate analog-enzyme complexes to probe the structural change of the substrate upon binding in the active site. Chemical method and site-directed mutagenesis will be used to determine the role of active-site residues. The proposed work will be carried out in collaboration with Professor Susan M. Miller at the Department of Pharmaceutical Chemistry, University of California at San Francisco.

涉及乳清苷-5'-单磷酸脱羧酶 (ODCase) 在核酸构件的生物合成中，因此代表 是开发抗肿瘤药物的潜在靶点。开发一个 清楚地了解关键酶的基本机制 已被证明对新药发现的重要贡献 疗法。拟议研究的目标是了解如何 酶催化底物orotidine-5'-的转化 单磷酸（OMP）生成尿苷-5'-单磷酸（UMP）并 探测氨基酸残基在活性位点的定位 酶。将合成和研究底物类似物。核磁共振 光谱学将用于研究底物类似物酶 复合物以探测结合后底物的结构变化 在活动站点中。化学方法和定点诱变将 用于确定活性位点残基的作用。拟议的工作 将与 Susan M. Miller 教授合作进行 加州大学药物化学系 旧金山。