Characterization of Vitamin K Epoxide Reductase

维生素 K 环氧化物还原酶的表征

基本信息

批准号：
8450196
负责人：
DARREL W STAFFORD
金额：
$ 36.87万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-03-01 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8450196
关键词：
Area Biochemical Biological Biological Assay Blood coagulation Bone Density Characteristics Coagulants Coagulation Process Collaborations Development Disease Enzymes Fright Funding Grant Hemorrhage Hydroquinones In Vitro Kinetics Knowledge Lead Malignant Neoplasms Methods Molecular Osteogenesis Osteoporosis Physiological Post-Translational Protein Processing Production Public Health RNA Interference Research Role Stroke Structure Structure-Activity Relationship System Techniques Technology Thrombosis Time Transmembrane Domain Vitamin K Vitamin K Reductase Vitamins Warfarin Work bone metabolism cancer therapy carboxylation computational chemistry electron crystallography enzyme structure expression cloning gamma-glutamyl carboxylase hydroquinone improved in vivo insight mutant prevent public health relevance three dimensional structure vitamin K epoxide reductase

项目摘要

DESCRIPTION (provided by applicant): The long-term objective of this project is to understand, not only the structure and function of the vitamin K epoxide reductase (VKOR), but also the vitamin K cycle as a whole. Vitamin K-dependent carboxylation is an essential post-translational modification for proteins important in several physiologic functions, including blood coagulation and bone metabolism. VKOR is the target of warfarin, the most widely prescribed anti-coagulant for thromboembolic disorders. Although estimated to prevent twenty strokes per induced bleeding episode, warfarin is still under-utilized because of fear of bleeding. It is hoped that research funded by this grant will lead to improved anti- thrombotic therapies that will avoid some of the problems related to warfarin treatment. Specifically, we propose to accomplish the following during the tenure of this grant: (1) using standard purification and enzyme assay methods, RNAi technologies, and modified expression cloning, we will investigate the vitamin K cycle to identify components other than the vitamin K epoxide reductase (VKOR) necessary for the production of vitamin K hydroquinone, (2) employing electron crystallography, biochemical and molecular biological techniques, conduct studies to elucidate the three- dimensional structure of VKOR, and (3) using both in vivo and in vitro methods investigate the structural characteristics necessary for VKOR.

描述（由申请人提供）：该项目的长期目标是了解，不仅要了解维生素K氧化物还原酶（VKOR）的结构和功能，还了解整个维生素K周期。维生素K依赖性羧化是对几种生理功能中重要的蛋白质的基本翻译后修饰，包括血液凝结和骨代谢。 VKOR是华法林（Warfarin）的目标，华法林（Warfarin）是血栓栓塞性疾病最广泛规定的抗凝蛋白剂。尽管据估计，由于担心出血，华法林估计每次诱发的出血发作，但仍未得到充分利用。希望由这笔赠款资助的研究能够改善抗血小板疗法，以避免与华法林治疗有关的一些问题。具体而言，我们建议在此资助期间完成以下内容：（1）使用标准纯化和酶测定方法，RNAi技术和修饰的表达克隆，我们将研究维生素K循环以识别维生素K除了维生素K的循环以外的成分。还原酶（VKOR）生产维生素K氢醌，（2）采用电子晶体学，生化和分子生物学技术，进行研究，以阐明VKOR的三维结构，以及（3）使用体外和体外方法研究VKOR所需的结构特征。