3-O-sulfation of heparan sulfate as a regular of protein function

硫酸乙酰肝素的 3-O-硫酸化作为蛋白质功能的调节

• 批准号: 10615737
• 负责人: Geert-Jan Boons
• 金额: $ 45.17万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10615737
• 关键词: Address; Anticoagulants; Binding; Binding Proteins; Biological; Biological Process; Biology; Blood Coagulation Factor; Blood coagulation; Carbohydrates; Cell Adhesion; Cell surface; Cells; Chemicals; Code; Collection; Complement Activation; Complex; Deep Vein Thrombosis; Disaccharides; Disease; Endothelial Cells; Endothelium; Engineering; Enzymatic Biochemistry; Enzymes; Epitopes; Extracellular Matrix; Gene Family; Goals; Growth Factor; Heparin; Heparitin Sulfate; Human; Infection; Inflammation; Inflammatory; Isoenzymes; Lead; Libraries; Life; Ligands; Malignant Neoplasms; Mammalian Cell; Mediating; Methodology; Methods; Micro Array Data; Modality; Modification; Nerve Degeneration; Oligosaccharides; Polysaccharides; Printing; Protein Isoforms; Proteins; Pulmonary Embolism; Recombinants; Signal Transduction; Signaling Protein; Site; Specificity; Structure; Structure-Activity Relationship; Substrate Specificity; Sulfate; Surface; Technology; Therapeutic; Thromboembolism; Vascular Diseases; Vertebral column; cell type; chemokine; cytokine; gain of function; human disease; interest; mast cell; morphogens; pathogen; prevent; programs; protein function; recruit; sulfotransferase; therapeutic lead compound

Project summary/abstract Heparin is a highly sulfated carbohydrate produced by mast cells that is widely used as an anticoagulant to prevent deep vein thrombosis, pulmonary embolism and arterial thromboembolism. Heparan sulfate (HS) is structurally related to heparin and decorates the surface of all most all human cells. It interacts with a multitude of proteins including chemokines and cytokines; blood coagulation factors; growth factors and morphogens, proteins involved in complement activation, and cell adhesion and signaling proteins. HS has been implicated in human diseases such as vascular diseases, inflammation, infections and neurodegeneration. It has been postulated that HS encodes information by an ability to recruit proteins in a context-dependent manner. Although the “HS-sulfate code” hypothesis is conceptually appealing, little is known about the ligand specificities of HS binding proteins and the substrate specificities of HS-biosynthetic enzymes. As a result, it is not known whether isoforms of HS biosynthetic enzymes can create distinctive epitopes that in a cellular context can recruit specific HS- binding proteins. An understanding of the specificities of HS binding also offers opportunities to develop therapeutic modalities. In this program, chemical and chemo-enzymatic methodologies will be developed that will make it possible to prepare a focused library of biologically relevant HS epitopes with and without a 3-O-sulfate moiety. These compounds will be used to develop an HS-microarray to establish ligand requirement of HS-binding proteins. Compounds of interest will be further explored for their ability to interfere in the binding and cellular activation of endothelial cells. We will focus on HS-binding proteins involved in blood coagulation, inflammation and vascular disease. The established structure-activity relationships are expected to provide therapeutic lead compounds. The HS-microarray will also be used as a general platform to discover and characterize HS-binding proteins requiring a 3-O-sulfate. In addition, the synthetic compounds will be used to define substrate requirements of the various 3-O-sulfotransferases. Collectively, our studies will address the question of whether isoforms of 3-O-sulfotransferases can create distinctive epitopes that can recruit specific HS-binding proteins, to mediate various biological processes. 1

项目摘要/摘要 肝素是由肥大细胞产生的高度硫酸盐，被广泛用作抗凝剂 硫酸乙酰肝素可预防深静脉血栓形成，肺栓塞和动脉血栓主义。 （HS）在结构上与肝素相关，并装饰了所有大多数人类细胞的表面。它相互作用 具有多种蛋白质，包括趋化因子和细胞因子；血液凝血因子；生长 因子和形态剂，涉及完成激活的蛋白质以及细胞粘合剂和信号传导 蛋白质。 HS已在人类疾病中浸渍，例如血管疾病，炎症， 感染和神经变性。有人认为，HS通过能力编码信息 以上下文的方式募集蛋白质。尽管“ HS硫酸盐代码”假设是 从概念上看，关于HS结合蛋白的配体规范和 HS生物合成酶的底物规范。结果，尚不清楚HS的同工型是否 生物合成酶可以产生独特的表位，在细胞环境中可以募集特定的HS- 结合蛋白。对HS约束的特异性的理解也为发展提供了机会 治疗方式。 在该计划中，将开发化学和化学酶方法，以使其成为 有可能，有或没有3-O硫酸盐的生物学相关的HS表位图书馆 部分。这些化合物将用于开发HS微阶层，以建立配体要求 HS结合蛋白。感兴趣的化合物将进一步探讨其干扰能力 内皮细胞的结合和细胞活化。我们将专注于血液中涉及的HS结合蛋白 凝血，感染和血管疾病。建立的结构活动关系是 预计提供热铅化合物。 HS微阵列也将用作一般 发现和表征需要3-O硫酸盐的HS结合蛋白的平台。另外， 合成化合物将用于定义各种3-O-硫代转移酶的底物需求。 总的来说，我们的研究将解决3-O-硫代转移酶的同工型的问题 创建独特的表位，可以募集特定的HS结合蛋白，以培养各种生物学 过程。 1