Structural and Fragment approaches to the modulation of O-GlcNAc in cells
细胞中 O-GlcNAc 调节的结构和片段方法
基本信息
- 批准号:BB/K003836/1
- 负责人:
- 金额:$ 93.05万
- 依托单位:
- 依托单位国家:英国
- 项目类别:Research Grant
- 财政年份:2013
- 资助国家:英国
- 起止时间:2013 至 无数据
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
The function of many of the large macromolecules that control biological processes in a cell can be changed by chemical modification with a sugar called O-GlcNAc. Two enzymes control this chemical modification: a transferase (OGT) that adds the sugar to the protein and a hydrolase (OGA) which removes it. This addition of a sugar is analogous to other mechanisms of control in the cell - such as phosphorylation where a phosphate is added (with a kinase) or removed (with a phosphatase). A great deal is known about how phosphorylation occurs and its consequences on the cell - indeed, many of the more recent drugs that have been discovered are kinase inhibitors that have an impact in conditions such as cancer. However, the O-GlcNAc modification has only recently been discovered and we are only now beginning to discover what happens to cells when the pattern of modification is changed. One recent discovery is that the O-GlcNAc modification has a role in maintaining healthy neurones, and disruption has some impact on neurodegenerative diseases such as Alzheimer's. The aim of our research is to understand more about what these enzymes, OGA and OGT, look like and how they work. This knowledge will be of interest in its own right, but it also provides information which can be used to design small molecule compounds that can bind to the enzymes and change their activity - interestingly, we can both increase and decrease how quickly the enzymes work. It is difficult to find such small molecules by trial and error. One new technique that has been developed recently is the method of fragment-based discovery. Instead of having to find the complete molecule that fits the binding site, this approach begins by identifying smaller pieces of molecule that bind. If the way in which these small fragments bind can be understood, then the chemist can design changes that merge or grow these fragments into the larger compound with the correct properties. We will use these methods to discover small molecules that change the activity of OGA and OGT. These can then be added to cells to see what effect changing the O-GlcNAc has on the way the cells behave. The principle aim is to understand the effect on cell biology, though the compounds may provide a starting place for drug design.
许多控制细胞中生物过程的大分子的功能可以通过一种称为O-GlcNAc的糖的化学修饰来改变。两种酶控制这种化学修饰:一种是将糖添加到蛋白质上的转移酶(OGT),另一种是将糖去除的水解酶(OGA)。这种糖的添加类似于细胞中的其他控制机制-例如磷酸化,其中磷酸盐被添加(用激酶)或去除(用磷酸酶)。关于磷酸化如何发生及其对细胞的后果,人们已经了解了很多--事实上,许多最近发现的药物都是激酶抑制剂,对癌症等疾病有影响。然而,O-GlcNAc修饰最近才被发现,我们现在才开始发现当修饰模式改变时细胞会发生什么。最近的一项发现是,O-GlcNAc修饰在维持健康的神经元中起作用,并且破坏对神经退行性疾病如阿尔茨海默氏症有一定影响。我们研究的目的是更多地了解这些酶,OGA和OGT,看起来像什么,以及它们是如何工作的。这些知识本身就很有趣,但它也提供了可用于设计小分子化合物的信息,这些化合物可以与酶结合并改变它们的活性-有趣的是,我们可以增加和减少酶的工作速度。通过反复试验很难找到这样的小分子。最近开发的一种新技术是基于片段的发现方法。这种方法不需要找到适合结合位点的完整分子,而是从识别结合的较小分子片段开始。如果这些小片段结合的方式可以被理解,那么化学家就可以设计改变,将这些片段合并或生长成具有正确性质的较大化合物。我们将使用这些方法来发现改变OGA和OGT活性的小分子。然后可以将这些添加到细胞中,以观察改变O-GlcNAc对细胞行为方式的影响。主要目的是了解对细胞生物学的影响,尽管这些化合物可能为药物设计提供起点。
项目成果
期刊论文数量(10)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Discovery of selective small-molecule activators of a bacterial glycoside hydrolase.
- DOI:10.1002/anie.201407081
- 发表时间:2014-12-01
- 期刊:
- 影响因子:0
- 作者:Darby JF;Landström J;Roth C;He Y;Davies GJ;Hubbard RE
- 通讯作者:Hubbard RE
Analysis of transition state mimicry by tight binding aminothiazoline inhibitors provides insight into catalysis by human O-GlcNAcase.
- DOI:10.1039/c6sc00370b
- 发表时间:2016-06-01
- 期刊:
- 影响因子:8.4
- 作者:Cekic N;Heinonen JE;Stubbs KA;Roth C;He Y;Bennet AJ;McEachern EJ;Davies GJ;Vocadlo DJ
- 通讯作者:Vocadlo DJ
Discovery of Selective Small-Molecule Activators of a Bacterial Glycoside Hydrolase
细菌糖苷水解酶选择性小分子激活剂的发现
- DOI:10.1002/ange.201407081
- 发表时间:2014
- 期刊:
- 影响因子:0
- 作者:Darby J
- 通讯作者:Darby J
Increase of enzyme activity through specific covalent modification with fragments.
- DOI:10.1039/c7sc01966a
- 发表时间:2017-11-01
- 期刊:
- 影响因子:8.4
- 作者:Darby JF;Atobe M;Firth JD;Bond P;Davies GJ;O'Brien P;Hubbard RE
- 通讯作者:Hubbard RE
A Convenient Approach to Stereoisomeric Iminocyclitols: Generation of Potent Brain-Permeable OGA Inhibitors
立体异构亚氨基环醇的便捷方法:生成有效的脑渗透性 OGA 抑制剂
- DOI:10.1002/ange.201507985
- 发表时间:2015
- 期刊:
- 影响因子:0
- 作者:Bergeron-Brlek M
- 通讯作者:Bergeron-Brlek M
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Gideon Davies其他文献
Gideon Davies的其他文献
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{{ truncateString('Gideon Davies', 18)}}的其他基金
Exploring New Pathways of Sulfoquinovose degradation in the biosphere
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BB/W003805/1 - 财政年份:2022
- 资助金额:
$ 93.05万 - 项目类别:
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Dissection of the Leishmania mannogen biosynthetic pathway: beta 1-2 mannan in pathogens and beyond
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$ 93.05万 - 项目类别:
Research Grant
X-ray Diffraction Equipment for Macromolecular Crystallography at York
约克高分子晶体学 X 射线衍射设备
- 批准号:
BB/T017805/1 - 财政年份:2020
- 资助金额:
$ 93.05万 - 项目类别:
Research Grant
Application of activity-based glycosidase probes for mechanism, enzyme discovery and clinical diagnosis
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- 批准号:
BB/R001162/1 - 财政年份:2018
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$ 93.05万 - 项目类别:
Research Grant
GLYCONEER-An automated oligosaccharide synthesiser to transform glycobiology research within the University of York, and the UK glycoscience community
GLYCONEER - 一款自动化寡糖合成仪,旨在改变约克大学和英国糖科学界的糖生物学研究
- 批准号:
BB/M012697/1 - 财政年份:2015
- 资助金额:
$ 93.05万 - 项目类别:
Research Grant
Dissecting and Exploiting Lytic Polysaccharide Monooxygenases
剖析和利用裂解多糖单加氧酶
- 批准号:
BB/L021633/1 - 财政年份:2014
- 资助金额:
$ 93.05万 - 项目类别:
Research Grant
Xyloglucan degradation systems: dissection and exploitation
木葡聚糖降解系统:剖析和利用
- 批准号:
BB/I014802/1 - 财政年份:2012
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$ 93.05万 - 项目类别:
Research Grant
Dissection of alpha mannosidases: from reaction coordinate to inhibition
α甘露糖苷酶剖析:从反应坐标到抑制
- 批准号:
BB/G016127/1 - 财政年份:2009
- 资助金额:
$ 93.05万 - 项目类别:
Research Grant
Studies of the O-GlcNAc Modification
O-GlcNAc 修饰的研究
- 批准号:
BB/F007124/1 - 财政年份:2008
- 资助金额:
$ 93.05万 - 项目类别:
Research Grant
Dissecting the mechanism by which glycosyltransferases calalyse mannosyl transfer
剖析糖基转移酶催化甘露糖基转移的机制
- 批准号:
BB/E001696/1 - 财政年份:2007
- 资助金额:
$ 93.05万 - 项目类别:
Research Grant
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