Chemical biology tools for studying carbohydrate processing enzymes

用于研究碳水化合物加工酶的化学生物学工具

• 批准号: RGPIN-2015-05426
• 负责人: Vocadlo, David
• 金额: $ 6.48万
• 依托单位: Simon Fraser University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613544
• 关键词: Chemical; biology; tools; studying; carbohydrate

The modification of proteins with sugars is known as protein glycosylation and is a common modification of cellular proteins in all kingdoms of life. Glycosylation is particularly abundant in multicellular eukaryotes, where over half of all proteins are thought to be modified by sugars linked together for form what are known as glycans. The dedication of approximately 300 genes within the human genome to the regulation of glycoconjugates highlights the important roles played by these species. The enzymes responsible for building of glycoconjugates are glycosyltransferases and those that break them down are known as glycosidases. The importance of these enzymes rests in the roles they play in regulating the structures and abundance of glycoconjugates, which have been found to alter protein function, mediate molecular interactions, and alter the stability of proteins. Striking findings in the past few years have also shown that protein glycosylation acts directly to regulate signaling and transcription. Recently, the National Academy of Sciences and National Research Council (USA) identified the area of glycoscience as a promising and emerging area of research that merits significant investment. Indeed, the field of protein glycosylation lags somewhat behind the study of other, more prominent, classes of biomolecules such as phosphorylation. Several reasons to account for this difference in progress have been made. Among the rationales proposed is that there is a limited repertoire of chemical tools available that can be used by the wider research community to study relevant glycans structures as well as the enzymes that process these species. To address this gap, a major thrust of our research program is directed toward developing chemical tools that will greatly facilitate research into understanding less appreciated and poorly understood forms of eukaryotic protein glycosylation. In this proposal we outlined a principally carbohydrate chemistry and enzymology-based program of research comprising three aims. We will create probes to monitor glycosidase and glycosyltransferase and to create inhibitors of these enzymes. The molecules resulting from these efforts will be validated in cells to identify those which are active in cells. The resulting new chemical tools will enable the field to improve our understanding of how the enzymes that regulate these glycan structures function within cells. The tools developed here should therefore help access knowledge that could help researchers in other fields develop new diagnostics or therapeutics.

用糖修饰蛋白质被称为蛋白质糖基化，是所有生命王国中细胞蛋白质的常见修饰。糖基化在多细胞真核生物中特别丰富，其中一半以上的蛋白质被认为是通过连接在一起的糖来修饰的，形成了所谓的聚糖。人类基因组中大约有300个基因参与糖缀合物的调控，这突出了这些物种所起的重要作用。负责构建糖缀合物的酶是糖基转移酶，而分解它们的酶被称为糖苷酶。这些酶的重要性在于它们在调节糖缀合物的结构和丰度方面所起的作用，糖缀合物已被发现可以改变蛋白质功能，介导分子相互作用，并改变蛋白质的稳定性。在过去的几年里，惊人的发现也表明，蛋白质糖基化直接调节信号和转录。最近，美国国家科学院和国家研究委员会（美国）将糖科学领域确定为一个有前途的新兴研究领域，值得大量投资。