CANCER PRODRUG ACTIVATING ENZYMES

癌症前药激活酶

• 批准号: 8170659
• 负责人: SUBRAMANYAM SWAMINATHAN
• 金额: $ 0.75万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8170659
• 关键词: Complex; Computer Retrieval of Information on Scientific Projects Database; Drug Delivery Systems; Electron Transport; Electrons; Enzymes; Escherichia coli; FMN reductase; Funding; Grant; Hydroquinones; Institution; Ions; Life; Malignant Neoplasms; Metals; NADP; Organism; Pharmaceutical Preparations; Prodrugs; Proteins; Quinones; Research; Research Personnel; Resources; Source; Structure; United States National Institutes of Health; base; enzyme activity; hydroquinone; mutant; nanoparticle

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. NADPH-dependent FMN-reductase is an enzyme that is critical for electron transfer in all living organisms. These enzymes accept electron(s) from NADPH and transfers to substrates such as metal ions and organic compounds like quinones. Reduction of quinone based cancer prodrugs into active hydroquinones has been achieved by these enzymes. We have demonstrated already that the E. Coli FMN-reductase is very effective in cancer prodrug reduction and we are modifing this enzyme to enhance the catalytic activity. This enzyme will be a potential target for cancer prodrug therapy through nanoparticle drug delivery mechanism. This proposal is aimed at determining the wild-type crystal structure and explain the mechanism of the enzyme activity. We propose a hypothesis to optimize the enzymatic activity on the basis of crystal structure and would confirm by studying suitable mutants and protein-drug complexes.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 NADPH 依赖性 FMN 还原酶是一种对所有生物体电子转移至关重要的酶。这些酶接受来自 NADPH 的电子并转移至金属离子和醌等有机化合物等底物。这些酶已实现将基于醌的癌症前药还原为活性氢醌。我们已经证明，大肠杆菌 FMN 还原酶在减少癌症前药方面非常有效，我们正在修改这种酶以增强催化活性。这种酶将成为通过纳米颗粒药物输送机制进行癌症前药治疗的潜在靶点。该提案旨在确定野生型晶体结构并解释酶活性的机制。我们提出了一个基于晶体结构优化酶活性的假设，并将通过研究合适的突变体和蛋白质-药物复合物来证实。