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Role of small molecule interactions and multiprotein assemblies in CYP1B1 disease-associated function and dysfunction

小分子相互作用和多蛋白组装在 CYP1B1 疾病相关功能和功能障碍中的作用

基本信息

批准号：
10389514
负责人：
Edith C Glazer
金额：
$ 12.46万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10389514
关键词：
3-Dimensional Affect Aromatase Aromatase Inhibitors Basic Science Binding Biology CYP17A1 gene CYP1B1 gene Cell Line Cell physiology Cells Chemical Structure Chemicals Chemotherapy-Oncologic Procedure Chimeric Proteins Cisplatin Clinical Research Conflict (Psychology)Cytochrome P450 Data Disease Dose Drug resistance Environment Environmental Risk Factor Enzyme Inhibitor Drugs Enzymes Equipment Functional disorder Genetic Genetic Polymorphism Goals Half-Life Heme Hemeproteins High Pressure Liquid Chromatography Homo Hormones Hydrophobicity Hydrophthalmos Hypoxia Immune response In Vitro Inherited Iron Liver Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Measurement Medical Membrane Metabolic Metabolism Modeling Modification Molecular Conformation Mutation Mycoses Nucleotides Paclitaxel Patients Pharmaceutical Chemistry Pharmacology Phase I Clinical Trials Phenotype Photobleaching Physiologic pulse Play Population Population Distributions Proteins Proteolysis Resistance Role Sampling Scanning Signaling Molecule Single Nucleotide Polymorphism Testing Thermodynamics Time Tissues Tumor Antigens Vesicle Work aqueous cancer cell cancer initiation chemotherapy detection platform enzyme activity epidemiology study experimental study fluorescence lifetime imaging improved in vivo inhibitor/antagonist instrument instrumentation knock-down malignant breast neoplasm mass spectrometer mitochondrial membrane nanoscale novel overexpression protein degradation residence response single molecule small molecule small molecule inhibitor tissue culture tumor tumor progression

项目摘要

Abstract The goal of this project is to determine how mutations, elevated protein levels, and environmental conditions impact the function and dysfunction of Cytochrome P450 1B1 (CYP1B1). The addition of instrumentation is proposed to facilitate characterization of small molecule modulators of CYP1B1, and the metabolic products of this CYP. Selective inhibition of CYPs is an important goal in medicinal chemistry, but these enzymes can chemically modify their inhibitors, resulting in deactivation. The requested High Pressure Liquid Chromatography (HPLC) instrument, along with three orthogonal detection systems, will allow for accurate and rapid determination of chemical structures and enzymatic modifications. This will be accomplished with small amounts of sample, as the analytes will come from cells grown in tissue culture. As CYPs generally increase the polarity of hydrophobic substrates, the instrumentation includes specific modifications that are required for analysis of aqueous media solutions. Such solutions are incompatible with most LC mass spectrometers. This equipment will be also used to evaluate if mutations, protein:protein association, and environmental conditions alter CYP metabolic products, with implications for tissue-selective metabolism under hypoxia or due to the presence of signaling molecules.

抽象的该项目的目标是确定突变、蛋白质水平升高和环境如何影响条件会影响细胞色素 P450 1B1 (CYP1B1) 的功能和功能障碍。添加的建议使用仪器来促进 CYP1B1 小分子调节剂的表征，以及该 CYP 的代谢产物。选择性抑制 CYP 是药物治疗的一个重要目标化学，但这些酶可以化学修饰其抑制剂，导致失活。这要求高压液相色谱 (HPLC) 仪器，以及三个正交检测系统，将能够准确、快速地确定化学结构和酶学修改。这将通过少量样品来完成，因为分析物将来自在组织培养物中生长的细胞。由于 CYP 通常会增加疏水底物的极性，仪器包括水介质分析所需的特定修改解决方案。此类解决方案与大多数 LC 质谱仪不兼容。该设备将也用于评估突变、蛋白质：蛋白质关联和环境条件是否改变 CYP 代谢产物，对缺氧或由于缺氧条件下的组织选择性代谢具有影响信号分子的存在。