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Structural and Biochemical Basis of the Vitamin K cycle

维生素 K 循环的结构和生化基础

基本信息

批准号：
8228021
负责人：
Weikai Li
金额：
$ 24.9万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8228021
关键词：
Active Sites Address Amino Acids Anticoagulants Anticoagulation Archaea Bacteria Binding Biochemical Biochemistry Blood Coagulation Factor Blood coagulation Catalysis Cells Cellular biology Complex Coumarins Coupled Couples Coupling Crystallization Cysteine Deep Vein Thrombosis Detergents Disease Disulfides Drug Design Electron Transport Electrons Environment Enzymes Glutamic Acid Goals Hemorrhage Homologous Gene Human Hydroquinones In Vitro Injury Instruction Knowledge Laboratories Lead Membrane Mutation Myocardial Infarction Natural regeneration Nature Oral Oxidation-Reduction Pathway interactions Pharmaceutical Preparations Phase Positioning Attribute Post-Translational Protein Processing Protein Biochemistry Proteins Pulmonary Embolism Reaction Research Research Personnel Schools Site Stroke Structure Testing Therapeutic Thioredoxin Thrombosis Time Universities Vitamin K Warfarin Washington X-Ray Crystallography alpha benzopyrone base carboxylation cofactor design drug mechanism gamma-glutamyl carboxylase high risk hydroquinone improved inhibitor/antagonist luminal membrane mutant oxidation prevent professor reconstitution reduced vitamin K research study resistance mutation vitamin K epoxide reductase vitamin K1 oxide

项目摘要

The vitamin K cycle supports blood coagulation and is a major target for anticoagulation drugs. Coagulation factors require Dcarboxylation of glutamic acids for activation at sites of injury. The vitamin K dependent ¿ carboxylase (VKGG) is driven by the oxidation of a vitamin K cofactor. The vitamin K epoxide reductase (VKOR) regenerates this cofactor; the reducing equivalent comes from a thioredoxin-like partner. VKOR is the target of warfarin, the most commonly used oral anticoagulant for treating and preventing thrombosis diseases including deep vein thrombosis, pulmonary embolism, stroke, and myocardial infarction. Warfarin has a narrow therapeutic window due to the high risk of hemorrhage. The design of safer VKOR inhibitors was impeded by the complete absence of structural knowledge of VKOR. During the K99 phase, we determined the structure of a bacterial homolog of VKOR in association with its reducing partner, a thioredoxin domain (Li etal.. Nature 2010). The structure reveals a binding pocket for warfarin and a pathway of electron transfer from the thioredoxin domain to VKOR. For the ROO phase, 1) we will determine the crystal structures of VKOR in complex with warfarin and other coumarin drugs. We will also use purified VKOR proteins to study the biochemistry of VKOR catalysis and warfarin inhibition. The studies will provide the basis for rational drug design. 2) We will determine structures of reaction intermediates to elucidate the pathway by which electrons flow from the thioredoxin domain to VKOR. We will also study the function of human VKOR with its reducing partners. 3) We will conduct structural studies ofthe gamma-glutamyl carboxylase (VKGC). I have obtained a full-time, tenure-track assistant professor position in the Washington University at St. Louis. The school has an excellent research environment with well-equipped laboratories and top researchers. Future research in my group will use a combination of X-ray crystallography, protein biochemistry, and cell biology. My long-term goal is to understand the entire vitamin K pathway that sustains blood coagulation.

维生素K循环支持血液凝固，是抗凝药物的主要靶点。凝固