VITAMIN K EPOXIDE REDUCTASE--MECHANISM AND INHIBITION

维生素 K 环氧还原酶——机理和抑制

• 批准号: 3448860
• 负责人: Peter Preusch
• 金额: $ 4.79万
• 依托单位: UNIVERSITY OF AKRON
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-09-01 至 1988-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3448860
• 关键词: affinity labeling; alpha benzopyrone; anticoagulants; chemical synthesis; epoxides; high performance liquid chromatography; liver; microsomes; quinones; vitamin K; warfarin

Experiments are proposed to determine the mechanism of the related vitamin K epoxide and quinone reductase(s) and the mechanism of their inhibition by the coumarin anticoagulants and other compounds. These enzymes play a key role in the ability of vitamin K to promote blood coagulation factor biosynthesis, appear to be the pharmacologically important site of coumarin anticoagulant action, and are suitable target enzymes for the development of new classes of anticoagulants. Anticoagulants have found application in the management of stroke, cardiovascular disease, pulmonary embolism, vascular implant and heart valve replacement survival, and have recently shown promise as antineoplastic agents. Anticoagulants have also been effective rodentocides important in control of rodent born human diseases. Clinical use of coumarin anticoagulants, most commonly sodium warfarin (Coumadin), is complicated by a large number of drug potentiation interactions and undesirable side effects. Some side effects of current anticoagulants may relate to a lack of specificity of the inhibitors for the target enzyme, others may relate to inhibition of vitamin K function in extrahepatic tissues and may point to new potential applications for tissue directed vitamin K epoxide reductase inhibitors. The long term goal of these studies is the development of new classes of vitamin K epoxide reductase inhibitors. A first step is the complete elucidation of the reaction mechanism of the target enzyme. This work will involve purification and characterization of the enzyme, clarification of the relationship between the vitamin K epoxide and quinone reductase(s), chemical modification and enzyme kinetic studies, examination of known inhibitors as mechanistic probes, and the application of known reactions expected to yield site specific covalent inactivation of the enzyme. A second project will examine the tissue distribution of vitamin K epoxide reductase activity and its sensitivity to coumarin anticoagulants. Differences in the properties of the enzyme in different tissues that are detected will for a basis for segregation of anticoagulant activity from side effects and may permit application of vitamin K antagonists in situations where their anticoagulant activity is undesirable.

提出了实验以确定相关维生素的机制 K环氧化物和喹酮还原酶及其抑制的机制 香豆素抗凝剂和其他化合物。 这些酶可以发挥钥匙 维生素K促进血液凝血因子的能力中的作用 生物合成似乎是香豆素的药理重要部位 抗凝作用，是适合开发的靶酶 新的抗凝剂。 抗凝剂已在 中风，心血管疾病，肺栓塞的管理， 血管植入物和心脏瓣膜的替代生存期，最近 显示为抗肿瘤剂的承诺。 抗凝剂也已经 有效的啮齿动物对控制啮齿动物出生的人类疾病很重要。 香豆素抗凝剂的临床使用，最常见的是华法林钠 （香豆素），大量药物增强很复杂 相互作用和不良副作用。 电流的某些副作用 抗凝剂可能与缺乏抑制剂的特异性有关 靶酶，其他酶可能与抑制维生素K功能有关 肝外组织，可能指出组织的新潜在应用 定向维生素K环氧还原酶抑制剂。 这些研究的长期目标是开发新类 维生素K环氧还原酶抑制剂。 第一步是完整 阐明靶酶的反应机理。 这项工作将 涉及酶的纯化和表征，澄清 维生素K环氧化物和喹酮还原酶（S）的关系， 化学修饰和酶动力学研究，研究已知 抑制剂作为机械探针，并应用已知反应 预计将产生特定的酶的共价失活。 第二个项目将检查维生素K环氧的组织分布 还原酶活性及其对香豆素抗凝剂的敏感性。 不同组织中酶的性质的差异 检测到的抗凝活性将于隔离 副作用，可能允许在维生素K拮抗剂中应用 其抗凝活性的情况是不可取的。