Shotgun functional glycomics of heparan sulphate saccharides: generating diverse libraries to decode biological selectivity

硫酸乙酰肝素糖的鸟枪式功能糖组学：生成多样化的文库来解码生物选择性

• 批准号: BB/I004343/1
• 负责人: Jeremy Turnbull
• 金额: $ 44.98万
• 依托单位: University of Liverpool
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2011
• 资助国家: 英国
• 起止时间: 2011 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FI004343%2F1
• 关键词: Shotgun; functional; glycomics; heparan; sulphate

Complex sugars (glycans) are a highly diverse family of molecules with a broad range of functions in biological processes including cell recognition, adhesion, cell-cell communication and signalling. The study of the glycome - the entire set of glycans expressed by particular cells or tissues - is an emerging field which aims to understand how glycan functions underpin the complexity of human biology, and their involvement in disease processes. The selective interaction of proteins with glycans is one of the keys to their biological functions. A number of new technologies have emerged to support the development of 'glycomics' studies - large-scale studies of glycan structural diversity and the selective interactions of glycans with their matching protein partners which underpins their functions. However, these approaches do not directly reveal functional properties, especially for some complex classes of glycans like the heparan sulphate (HS) family of sulphated glycans which are responsible for regulation of a wide range of biological processes including growth factor signalling, enzyme activity and cell adhesion. We now need to have the tools to ask how specific structures control specific proteins to control biological systems. In this project we propose to develop a new approach to address this question by generating a large library of novel HS glycans with a wide range of structures, and screening them in biological assays, followed by analysis of selected structures. This will permit us to evaluate the structure-activity relationships of HS at higher throughput for the first time. This 'shotgun' library approach will provide a powerful and generic new tool for decoding the function of the HS glycome by allowing specific glycan structures to be matched to specific biological functions. In the future this strategy could provide new information that could be translated into applications in biotechnology and drug development.

复合糖（聚糖）是一个高度多样化的分子家族，在生物过程中具有广泛的功能，包括细胞识别，粘附，细胞间通讯和信号传导。对糖组（由特定细胞或组织表达的整套聚糖）的研究是一个新兴领域，旨在了解聚糖功能如何支撑人类生物学的复杂性，以及它们如何参与疾病过程。蛋白质与聚糖的选择性相互作用是其生物学功能的关键之一。出现了许多新技术来支持“糖组学”研究的发展-大规模研究聚糖结构多样性和聚糖与其匹配蛋白质伴侣的选择性相互作用，这是其功能的基础。然而，这些方法不能直接揭示功能特性，特别是对于一些复杂类别的聚糖，如硫酸化聚糖的硫酸乙酰肝素（HS）家族，其负责调节广泛的生物过程，包括生长因子信号传导、酶活性和细胞粘附。我们现在需要有工具来研究特定的结构如何控制特定的蛋白质来控制生物系统。在这个项目中，我们建议开发一种新的方法来解决这个问题，通过产生一个大的库的新的HS聚糖具有广泛的结构，并筛选它们在生物测定，然后分析选定的结构。这将使我们能够首次以更高的通量评估HS的结构-活性关系。这种“鸟枪”文库方法将通过允许特定聚糖结构与特定生物学功能相匹配，为解码HS糖组的功能提供强大且通用的新工具。在未来，这一战略可以提供新的信息，可以转化为生物技术和药物开发的应用。

项目成果

Composition, sequencing and ion mobility mass spectrometry of heparan sulfate-like octasaccharide isomers differing in glucuronic and iduronic acid content.

葡萄糖醛酸和艾杜糖醛酸含量不同的硫酸乙酰肝素类八糖异构体的组成、测序和离子淌度质谱分析。

• DOI: 10.1255/ejms.1337
• 发表时间: 2015
• 期刊: European journal of mass spectrometry (Chichester, England)
• 作者: Leary JA

Sulf1 and Sulf2 Differentially Modulate Heparan Sulfate Proteoglycan Sulfation during Postnatal Cerebellum Development: Evidence for Neuroprotective and Neurite Outgrowth Promoting Functions.

• DOI: 10.1371/journal.pone.0139853
• 发表时间: 2015
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Kalus I;Rohn S;Puvirajesinghe TM;Guimond SE;Eyckerman-Kölln PJ;Ten Dam G;van Kuppevelt TH;Turnbull JE;Dierks T
• 通讯作者: Dierks T

Cryogenic Infrared Spectroscopy Reveals Structural Modularity in the Vibrational Fingerprints of Heparan Sulfate Diastereomers

• DOI: 10.1021/acs.analchem.0c02048
• 发表时间: 2020-08-04
• 期刊: ANALYTICAL CHEMISTRY
• 影响因子: 7.4
• 作者: Lettow, Maike;Grabarics, Marko;Pagel, Kevin
• 通讯作者: Pagel, Kevin

Panels of chemically-modified heparin polysaccharides and natural heparan sulfate saccharides both exhibit differences in binding to Slit and Robo, as well as variation between protein binding and cellular activity.

• DOI: 10.1039/c6mb00432f
• 发表时间: 2016-10-20
• 期刊: Molecular bioSystems
• 作者: Ahmed YA;Yates EA;Moss DJ;Loeven MA;Hussain SA;Hohenester E;Turnbull JE;Powell AK
• 通讯作者: Powell AK

Nanoscale self-assembled multivalent (SAMul) heparin binders in highly competitive, biologically relevant, aqueous media

• DOI: 10.1039/c4sc00298a
• 发表时间: 2014-01-01
• 期刊: CHEMICAL SCIENCE
• 影响因子: 8.4
• 作者: Bromfield, Stephen M.;Posocco, Paola;Smith, David K.
• 通讯作者: Smith, David K.