WHY DO SUBSTRATES REQUIRE CYTOCHROME B5 FOR OXIDATION BY CYTOCHROME P 450?

为什么底物需要细胞色素 B5 才能被细胞色素 P 450 氧化？

• 批准号: 6347878
• 负责人: KELLIE HOM
• 金额: $ 2.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6347878
• 关键词: bioengineering /biomedical engineering; biomaterials; biomedical resource; biotechnology; computers

The overall long-term goal of our research is to understand the molecular basis of the effect of cytochrome b5 (cyt b5) on the metabolism of certain substrates by cytochrome P-450 (cyt P-450), and to determine the physiological significance of this reaction. In particular, we are interested in elucidating the molecular basis of the marked stimulatory effect of cyt b5 on the metabolism of the volatile anesthetic, methoxyflurane, by cyt P-450 LM2 (2B4). These studies may lead up the delineation of the etiology and patho-physiology of the post-operative hepatotoxicity attributed to the volatile anesthetics and to the development of safer anesthetics. These studies should also provide important information about the mechanism by which cyt P-450 oxidizes its numerous endogenous and xenobiotic substrates. This knowledge should prove valuable in facilitating the design of clinically useful inhibitors of cytochrome P-450 for therapeutic applications in fungal diseases, hyper-aldosteronism, prostate cancer, benign prostatic hypertrophy and breast cancer. Cyt b5-cytochrome c (cyt c) complex is used as a model for the larger (72,000 dalton) hydrophobic cyt b5-cyt P-450 complex for use with high resolution NMR. The cytochrome b5-cytochrome c complex is a relevant model for the larger hydrophobic complex because cytochrome b5 uses approximately the same site to interact with both cytochrome c and cytochrome P-450. Knowledge of the structure of the by b5-cyt c complex will provide insights, into 1) the mechanism, 2) pathway of electron transfer, between cyt b5 and its redox partners and 3) macromolecular recognition and protein dynamics. These NMR experiments have provided important structural details about how certain amino acids of cyt b5 might facilitate electron transfer with its redox partners, cyt P-450, cyt b5 reductase and cyt c. The computing, graphics and programming facilities at the UCSF Computer Graphics Laboratory have been used to construct three-dimensional molecular models based on results from our NMR studies, to display and examine these models, and to calculate the dynamics and interactions of the components in the models. These results should lead to a greater understanding of the structural basis for the requirement for cyt b5 for the metabolism of some substrates by cyt P-450.

我们研究的总体长期目标是了解 细胞色素B5（Cyt B5）对效果的分子基础 通过细胞色素P-450（CYT P-450）和某些底物的代谢 确定该反应的生理意义。 在 特别是，我们有兴趣阐明 Cyt B5对刺激作用的明显刺激作用对 Cyt P-450 LM2（2B4）挥发性麻醉，甲氧基氟烷。 这些 研究可能会导致病因的描述和 术后肝毒性的病理生理学归因于 挥发性麻醉和开发更安全的麻醉药。 这些研究还应提供有关 Cyt P-450氧化其众多内源性和 异种生物底物。 这些知识应该证明有价值 促进细胞色素的临床有用抑制剂的设计 P-450用于真菌疾病的治疗应用， 高醛固型，前列腺癌，良性前列腺肥大和 乳腺癌。 Cyt B5-Cytochrome C（Cyt C）复合物用作模型 对于较大（72,000道尔顿）疏水Cyt B5-Cyt P-450复合物 用于高分辨率NMR。 细胞色素b5-cytoochrome c 复合物是较大疏水复合物的相关模型，因为 细胞色素B5使用大约同一地点与两者相互作用 细胞色素C和细胞色素P-450。 了解结构 B5-Cyt C复合物将提供洞察力，分为1）机制，2） 电子传输的途径，在Cyt B5及其氧化还原伙伴之间 3）大分子识别和蛋白质动力学。 这些NMR 实验提供了有关如何 Cyt B5的某些氨基酸可能会促进电子转移 它的氧化还原伙伴Cyt P-450，Cyt B5还原酶和Cyt c。这 UCSF计算机上的计算，图形和编程设施 图形实验室已用于构建三维 分子模型基于我们的NMR研究结果，显示和显示 检查这些模型，并计算动力学和相互作用 模型中的组件。 这些结果应导致 对需求的结构基础有更深入的了解 Cyt B5用于Cyt P-450的某些底物的代谢。