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Chemical Tools for the Investigation and Manipulation of Protein Glycosylation

用于研究和操作蛋白质糖基化的化学工具

基本信息

批准号：
10621302
负责人：
Matthew Robert Pratt
金额：
$ 27.23万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-15 至 2026-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10621302
关键词：
Active Sites Affect Affinity Alkynes Anabolism Animals Antibodies Azides Binding Biochemical Reaction Biological Biology California Carbohydrate Chemistry Carbohydrates Cell Communication Cell Culture Techniques Cells Chemicals Chemistry Communities Complex Crosslinker Development Disease Environment Enzymes Event Fucose Future Glucose Glycoproteins Goals Health Hexosamines Human In Vitro Individual Investigation Label Link Mammalian Cell Maps Measures Mediating Metabolic Methods Modification Monitor Monosaccharides Names Nature Outcome Pathway interactions Phosphotransferases Photochemistry Polysaccharides Post-Translational Protein Processing Process Protein Glycosylation Proteins Reaction Reporter Research Role Scientist Serine Sialic Acids Signal Transduction Structure Surface Techniques Technology Tissues Universities Visualization analog analytical tool biological development cell type chemical genetics crosslink design experimental study falls functional group genetic approach glycosylation glycosyltransferase improved inhibitor innovation novel response small molecule sugar technology research and development tool

项目摘要

ABSTRACT - “Chemical Tools for the Investigation and Manipulation of Protein Glycosylation” The broad goal of this proposal is the development of chemical tools that will enable the facile and robust identiﬁcation and inhibition of glycosylation in speciﬁc cells, the mapping of glycosylation-mediated and cell- type speciﬁc interactions, and monitoring and manipulation of carbohydrate biosynthetic pathways. The addition of carbohydrates to proteins, or glycosylation, is one of the most common forms of posttranslational modiﬁcations and is associated with various processes, including protein stability, macromolecular interactions, and cellular signaling. Unfortunately, the currently available tools for interrogating these functions fall short, which limits the study of glycosylation to expert labs. We plan to tackle this unmet need using carbohydrate chemistry, photo-chemistry, and chemical biology in three speciﬁc aims. In Aim 1, we will build on our development of glycosylation probes and inhibitors, with a focus on using chemical genetic approaches to create tools to identify and perturb glycosylation in a cell-speciﬁc fashion. In Aim 2, we will leverage the advantages of chemoenzymatic modiﬁcation of glycosylation to install speciﬁc photocrosslinkers onto living cells, with a focus on identifying biological interactions that are mediated by glycans, as well as mapping cell interactions. Finally, in Aim 3, we will create novel activity-based probes for measuring and inhibiting critical enzymes responsible for monosaccharide biosynthesis. At the conclusion of these independent aims, we will have generated new powerful tools that will have an immediate impact on the types of questions scientists can ask about glycosylation in human health and disease.

摘要：“研究和操纵蛋白质糖基化的化学工具” 这项提议的广泛目标是开发化学工具，使识别ﬁ阳离子和抑制特定ﬁc细胞的糖基化，糖基化介导的定位和细胞- 类型ﬁc相互作用，以及碳水化合物生物合成途径的监测和操作。这个在蛋白质中添加碳水化合物，或糖基化，是翻译后最常见的形式之一 Modiﬁ阳离子，与各种过程有关，包括蛋白质稳定性、大分子相互作用和细胞信号。不幸的是，目前可用来审问这些函数的工具不足之处，这将糖基化的研究限制在专家实验室。我们计划通过以下方式解决这一未得到满足的需求碳水化合物化学、光化学和化学生物学三种ﬁc目标。在目标1中，我们将建立在我们糖基化探针和抑制剂开发的基础上，重点是使用化学遗传以细胞特有的ﬁc方式创建工具来识别和干扰糖基化的方法。在目标2中，我们将利用化学酶修饰ﬁ阳离子糖基化的优点来安装特殊的ﬁc光交联剂到活细胞上，重点是识别由多糖介导的生物相互作用，以及映射细胞间的相互作用。最后，在目标3中，我们将创建新的基于活动的探测器来测量和抑制负责单糖生物合成的关键酶。在这些结束时独立的目标，我们将产生新的强大的工具，将立即影响类型科学家们可以就糖基化对人类健康和疾病的影响提出一系列问题。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Exo-Enzymatic Addition of Diazirine-Modified Sialic Acid to Cell Surfaces Enables Photocrosslinking of Glycoproteins.

DOI：
10.1021/acs.bioconjchem.2c00037
发表时间：
2022-05-18
期刊：
BIOCONJUGATE CHEMISTRY
影响因子：
4.7
作者：
Yarravarapu, Nageswari;Konada, Rohit Sai Reddy;Darabedian, Narek;Pedowitz, Nichole J.;Krishnamurthy, Soumya N.;Pratt, Matthew R.;Kohler, Jennifer J.
通讯作者：
Kohler, Jennifer J.

Azide- and Alkyne-Bearing Metabolic Chemical Reporters of Glycosylation Show Structure-Dependent Feedback Inhibition of the Hexosamine Biosynthetic Pathway.

糖基化的带有叠氮化物和炔烃的代谢化学报告基因显示出己糖胺生物合成途径的结构依赖性反馈抑制。

DOI：
10.1002/cbic.201800280
发表时间：
2018
期刊：
Chembiochem : a European journal of chemical biology
影响因子：
0
作者：
Walter,LisaA;Batt,AnnaR;Darabedian,Narek;Zaro,BalynW;Pratt,MatthewR
通讯作者：
Pratt,MatthewR

4-Deoxy-4-fluoro-GalNAz (4FGalNAz) Is a Metabolic Chemical Reporter of O-GlcNAc Modifications, Highlighting the Notable Substrate Flexibility of O-GlcNAc Transferase.

DOI：
10.1021/acschembio.1c00818
发表时间：
2022-01-21
期刊：
ACS chemical biology
影响因子：
4
作者：
Jackson EG;Cutolo G;Yang B;Yarravarapu N;Burns MWN;Bineva-Todd G;Roustan C;Thoden JB;Lin-Jones HM;van Kuppevelt TH;Holden HM;Schumann B;Kohler JJ;Woo CM;Pratt MR
通讯作者：
Pratt MR

Your mother was right, washing matters: An alkyne-analog of ibuprofen reveals unwanted reactivity of aromatic compounds with proteins during copper-catalyzed click chemistry.