MECHANISM OF ACTION OF VITAMIN K

维生素 K 的作用机制

• 批准号: 2226911
• 负责人: PAUL DOWD
• 金额: $ 17.24万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-04-01 至 1997-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2226911
• 关键词: active sites; blood coagulation; carboxylation; coenzyme analog; enzyme inhibitors; enzyme mechanism; ligase; menadione; oxygen; stable isotope; vitamin K

Vitamin K is required for blood clotting where it is an essential cofactor in the complex enzymic sequence known as the blood clotting cascade. Together with a vitamin K-dependent carboxylase, carbon dioxide and molecular oxygen, vitamin K effects the carboxylation of selected glutamate residues in a number of proteins in the blood clotting sequence. These include: factor II (prothrombin), factor VII, factor IX, factor X and protein C, S and Z; as well as the bone protein osteocalcin. The carboxylation reaction is essential to enable calcium binding to membrane surfaces of zymogen precursors to the blood cascade enzymes. In the absence of carboxylation blood clotting is inhibited. The significance of vitamin K lies in its mechanism of action and its interaction with clinically important anticoagulants. The research proposed in this application will explore enzyme experiments based on a new experimental model for the vitamin K-dependent carboxylation. On the basis of recent model experiments, it is suggested that molecular oxygen triggers the carboxylation event by reacting with the anionic form of vitamin K hydroquinone to produce vitamin K oxide. Formation of the latter provides the energy necessary to furnish a base sufficiently strong to effect the carboxylation. Experiments with 18-O2 will probe the involvement of a special dioxetane intermediate. This experiment will then be extended to define the active site of vitamin K. The mechanism of action of active analogues of the vitamin K-dependent carboxylase will be explored and new potential inhibitors will be synthesized. A new mechanism of action of vitamin K3 in controlling tumor cell growth will be explored.

维生素K是凝血所必需的，它是一种重要的辅助因子 在复杂的酶序列称为血液凝固级联。 与维生素K依赖性羧化酶一起，二氧化碳和 分子氧，维生素K影响选择的羧化 在血液凝固序列中的许多蛋白质中的谷氨酸残基。 这些包括：因子II（凝血酶原），因子VII，因子IX，因子X 和蛋白质C、S和Z;以及骨蛋白骨钙素。的 羧化反应是使钙结合到膜上所必需的 血液级联酶的酶原前体的表面。在 羧化作用的缺乏抑制了血液凝固。的意义 维生素K的作用机制及其与 临床上重要的抗凝剂。 这项申请中提出的研究将探索酶实验 基于一种新的维生素K依赖性的实验模型， 羧化作用根据最近的模型试验，建议 分子氧通过与 阴离子形式的维生素K对苯二酚产生维生素K氧化物。 后者的形成提供了必要的能量， 足够强以实现羧化。18-O2实验 将调查一种特殊的二氧杂环丁烷中间体的参与。 这 实验将扩展到确定维生素K的活性位点。 维生素K依赖性的活性类似物的作用机制 将探索羧化酶，并将开发新的潜在抑制剂。 合成了维生素K_3抗肿瘤作用的新机制 将探索细胞生长。