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）：乙酰硫酸盐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，形成剂，细胞外基质蛋白，酶和酶抑制剂。一种相对罕见的对链的修饰，是在葡萄糖残基的碳-3中添加硫酸盐，就其生物合成和功能而言，对葡萄糖残基的碳-3添加很少。脊椎动物中存在一个七个葡萄糖氨基3-O-硫代转移酶（HS3ST）的家族。尽管酶已经被克隆并部分表征，但对这些修饰发生的背景知之甚少，甚至了解与含有3-O硫酸盐基团的硫酸乙酰肝素链结合的内源性配体。该提议的中心假设是HS3ST在硫酸乙酰肝素的子序列中有选择性作用，从而生成内源性蛋白配体的特定结合位点。该提议的重点是（i）在结构上表征3-O硫酸乙酰肝素的方法，（ii）HS3ST-1和HS3ST-2作为3-O-Sulfotrans酶的模型的特异性，（III）发现和与HS3ST修改的固定链的自然配体的发现和表征，以及Heparan的（HS3ST修改）的sulan和Heparant-iv sulf and-iv sulff and Heparff，hsparfient and Heparf。 HS3st-2。朝向这些目标，我们具有以下具体目标：目标1：开发一种定量方法来确定硫酸乙酰肝素中二糖和四糖亚基的3-O硫化。 AIM 2：使用HS3ST-1和HS3ST-2生成功能活性的3-O硫酸乙酰肝素。 AIM 3：捕获和鉴定与3-O硫酸乙酰肝素结合的蛋白质配体。 AIM 4：检查体内HS3ST-1和HS3ST-2的结合位点的形成。我们预计，该项目将显着增强我们对这类硫代转移酶如何影响生物学过程和病理状态的理解，并验证它们作为药理学干预的潜在目标。

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：
10.3233/dma-130970
发表时间：
2013
期刊：
Disease markers
影响因子：
0
作者：
Lawrence,Roger;Brown,JillianR;Lorey,Fred;Dickson,PatriciaI;Crawford,BrettE;Esko,JeffreyD
通讯作者：
Esko,JeffreyD

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：
10.1096/fj.14-264226
发表时间：
2015
期刊：
FASEB journal : official publication of the Federation of American Societies for Experimental Biology
影响因子：
0
作者：
vanWijk,XanderM;Lawrence,Roger;Thijssen,VictorL;vandenBroek,SebastiaanA;Troost,Ran;vanScherpenzeel,Monique;Naidu,Natasha;Oosterhof,Arie;Griffioen,ArjanW;Lefeber,DirkJ;vanDelft,FlorisL;vanKuppevelt,ToinH
通讯作者：
vanKuppevelt,ToinH

Demystifying heparan sulfate-protein interactions.