MECHANISM OF ACTION OF VITAMIN K

维生素K是凝血所必需的，因为它是一种重要的辅因子 在被称为血液凝固级联的复杂的酶序列中。 再加上依赖维生素K的羧基酶、二氧化碳和 分子氧、维生素K对所选化合物的羧化作用 谷氨酸残基存在于血液凝结序列中的许多蛋白质中。 这些包括：凝血因子II(凝血酶原)、因子VII、因子IX、因子X 和蛋白C、S和Z，以及骨蛋白骨钙素。这个 羧化反应是钙与膜结合所必需的 血级联酶的酶原前体表面。在 缺乏羧化作用的血液凝结受到抑制。的重要意义。 维生素K在于其作用机制及其与 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依赖实验模型 羧化作用。在近期模型试验的基础上，提出了一种新的模型试验方法。 分子氧通过与之发生反应来触发羧化反应 维生素K对苯二酚的阴离子形式，以产生维生素K氧化物。 后者的形成提供了提供基础所需的能量 足够强，足以实现羧化作用。用18-O2进行实验 将调查一种特殊的二氧杂环己烷中间体的牵连。这 然后将扩大实验范围，以确定维生素K的活性部位。 维生素K依赖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 合成的。维生素K3抗肿瘤作用的新机制 我们将探索细胞的生长。

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.