Structure and Function of 3-O-sulfation in Heparan Sulfate

硫酸乙酰肝素3-O-硫酸化的结构和功能

基本信息

批准号：
8463564
负责人：
Jeffrey D Esko
金额：
$ 27.06万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-05-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8463564
关键词：
Abbreviations Acetylglucosamine Address Affect Affinity Anabolism Aniline Animal Model Antithrombins Binding Binding Proteins Binding Sites Biochemical Genetics Biological Biological Process Brain Caenorhabditis elegans Carbon Chemicals Chinese Hamster Ovary Cell Chromatography Coupling Development Disaccharides Disease Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Evolution Extracellular Matrix Proteins Family Financial compensation GAG Gene Genes Glucosamine Glucuronic Acids Glycoproteins Glycosaminoglycans Goals Growth Factor Heparin Lyase Heparitin Sulfate Human Hydra Polyps Iduronic Acid In Vitro Inorganic Sulfates Intervention Isoenzymes Isotope Labeling Label Ligand Binding Ligands Maintenance Mass Spectrum Analysis Methods Modeling Modification Mus Nitrous Acid Organism Plant Resins Play Polysaccharides Production Protein Isoforms Proteins Reaction Recombinants Research Personnel Resistance Role Simplexvirus Specificity Structure Study models Techniques Testing Tissue Extracts Tissues Unspecified or Sulfate Ion Sulfates Uronic Acids Vertebrates Viral Wild Type Mouse Work analytical tool chemokine cost cyclophilin B in vivo insight liquid chromatography mass spectrometry member morphogens mutant olfactory lobe public health relevance sulfation sulfotransferase tool

项目摘要

DESCRIPTION (provided by applicant): Heparan sulfate binds many growth factors, chemokines, morphogens, extracellular matrix proteins, enzymes and enzyme inhibitors via relatively short sulfated saccharide sequences. One relatively rare modification to the chains, the addition of sulfate to carbon-3 of glucosamine residues, is poorly understood in terms of its biosynthesis and function. A family of seven glucosaminyl 3-O-sulfotransferases (Hs3st) exists in vertebrates. Although the enzymes have been cloned and partially characterized, little is known about the context in which these modifications occur and even less is known about the endogenous ligands that bind to heparan sulfate chains that contain 3-O-sulfate groups. The central hypothesis of this proposal is that the Hs3sts act selectively on subsequences in heparan sulfate and thereby generate specific binding sites for endogenous protein ligands. This proposal focuses on (i) methods to structurally characterize 3-O-sulfated heparan sulfate, (ii) the specificity of Hs3st-1 and Hs3st-2 as model 3-O-sulfotransferases, (iii) the discovery and characterization of natural ligands that bind to Hs3st modified chains, and (iv) examination of heparan sulfate derived from mice altered in Hs3st-1 and Hs3st-2. Towards these goals, we have the following specific aims: Aim 1: Develop a quantitative method for determining 3-O-sulfation of disaccharide and tetrasaccharide subunits in heparan sulfate. Aim 2: Generate functionally active 3-O-sulfated heparan sulfate using Hs3st-1 and Hs3st-2. Aim 3: Capture and identify protein ligands that bind to 3-O-sulfated heparan sulfate. Aim 4: Examine the formation of binding sites by Hs3st-1 and Hs3st-2 in vivo. We expect that this project will significantly enhance our understanding on how this class of sulfotransferases influences biological processes and pathological states, and validate them as potential targets for pharmacological intervention.

描述（由申请人提供）：硫酸乙酰肝素通过相对较短的硫酸化糖序列结合许多生长因子、趋化因子、形态发生素、细胞外基质蛋白、酶和酶抑制剂。一种相对罕见的链修饰，即在葡萄糖胺残基的碳 3 上添加硫酸盐，其生物合成和功能知之甚少。脊椎动物中存在七种氨基葡萄糖 3-O-磺基转移酶 (Hs3st) 家族。尽管这些酶已被克隆并部分表征，但人们对这些修饰发生的背景知之甚少，甚至对与含有 3-O-硫酸酯基团的硫酸乙酰肝素链结合的内源配体知之甚少。该提议的中心假设是 Hs3sts 选择性地作用于硫酸乙酰肝素中的子序列，从而产生内源蛋白配体的特异性结合位点。该提案重点关注 (i) 结构表征 3-O-硫酸化硫酸乙酰肝素的方法，(ii) Hs3st-1 和 Hs3st-2 作为模型 3-O-磺基转移酶的特异性，(iii) 天然配体的发现和表征与 Hs3st 修饰链结合，以及 (iv) 检查源自 Hs3st-1 和 Hs3st-2 改变的小鼠的硫酸乙酰肝素。为了实现这些目标，我们有以下具体目标：目标 1：开发一种定量方法来测定硫酸乙酰肝素中二糖和四糖亚基的 3-O-硫酸化。目标 2：使用 Hs3st-1 和 Hs3st-2 生成功能活性的 3-O-硫酸化硫酸乙酰肝素。目标 3：捕获并鉴定与 3-O-硫酸化硫酸乙酰肝素结合的蛋白质配体。目标 4：检查 Hs3st-1 和 Hs3st-2 体内结合位点的形成。我们期望该项目将显着增强我们对此类磺基转移酶如何影响生物过程和病理状态的理解，并验证它们作为药理干预的潜在目标。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

WITHDRAWN: Glycan-based biomarkers for mucopolysaccharidoses.

撤回：基于聚糖的粘多糖病生物标志物。

DOI：
发表时间：
2013-02-08
期刊：
影响因子：
0
作者：
Lawrence, Roger;Brown, Jillian R;Lorey, Fred;Dickson, Patricia I;Crawford, Brett E;Esko, Jeffrey D
通讯作者：
Esko, Jeffrey D

A common sugar-nucleotide-mediated mechanism of inhibition of (glycosamino)glycan biosynthesis, as evidenced by 6F-GalNAc (Ac3).

6F-GalNAc (Ac3) 证明了一种常见的糖核苷酸介导的（糖胺）聚糖生物合成抑制机制。

DOI：
发表时间：
2015-07
期刊：
影响因子：
0
作者：
van Wijk, Xander M;Lawrence, Roger;Thijssen, Victor L;van den Broek, Sebastiaan A;Troost, Ran;van Scherpenzeel, Monique;Naidu, Natasha;Oosterhof, Arie;Griffioen, Arjan W;Lefeber, Dirk J;van Delft, Floris L;van Kuppevelt, Toin H
通讯作者：
van Kuppevelt, Toin H

Demystifying heparan sulfate-protein interactions.

揭秘硫酸乙酰肝素-蛋白质相互作用。