Mammalian Glycosyltransferases for use in Chemistry and Biology

描述(申请人提供)：复杂的碳水化合物或多聚糖参与几乎所有的生理或病理过程。了解多糖的生物学作用以及影响或改变其功能的因素的进展将为新的疗法和诊断的发展提供重要途径。为了认识到推进糖科学对人类健康影响的机会，我们组建了一个由五名高级研究人员组成的团队，他们将在三个相关研究项目上合作，以利用核心的独特能力来生产重组哺乳动物糖基转移酶。这些研究项目将1)研究糖基转移酶的生化和结构方面，以确定其在分子和结构水平上的受体特异性；2)在一种新的化学酶学方法中利用这些酶来为构效关系研究提供葡聚糖，帮助开发下一代糖链微阵列并作为分析标准；3)开发经化学记者修饰的糖核苷酸供体，以标记糖偶联物的亚群，用于可视化、捕获和鉴定疾病细胞模型中的糖聚糖。这三个项目具有很强的协同性。每一种都需要一组相对较大的糖基转移酶，这些糖基转移酶将由一个核心产生。此外，它们还将产生互惠的知识和资源。项目1和3将进行补充研究，以揭示糖基转移酶的糖基受体特异性。关于糖基转移酶的糖基受体特异性的信息将被项目2用来制备以其他方式无法通过化学-酶合成获得的多糖。项目2将产生合成多糖，项目1将利用这些合成多糖深入研究糖基受体的特异性。项目1的结构研究将为设计用化学报告分子修饰的糖核苷酸供体的项目提供重要信息，用于人类疾病的细胞学研究。

DESCRIPTION (provided by applicant): Complex carbohydrates or glycans are involved in almost every physiological or pathological process. Advances in understanding the biological roles played by glycans, along with the factors that influence or alter their functions will provid important avenues for the development of new therapeutics, and diagnostics. In recognition of opportunities to advance the impact of glycoscience on human health, we have assembled a team of five senior investigators that will work cooperatively on three related research projects to exploit unique capabilities of a Core to produce recombinant mammalian glycosyltransferases. The research projects will 1) study biochemical and structural aspects of glycosyltransferase to define their acceptor specificities at a molecular and structural level 2) exploit the enzymes in a novel chemoenzymatic approach to provide glycans for structure activity relationship studies, aid in the development of the next generation of glycan microarray and as analytical standards; 3) develop sugar nucleotide donors modified by a chemical reporters to label subsets of glycoconjugates for visualization, capture and identification of glycans in cellular models of disease. The three projects have high synergy. Each requires a relatively large panel of glycosyltransferases that will be produced by a core. In addition, they will generate reciprocal knowledge and resources. Project 1 and 3 will perform complementary studies to uncover glycosyl acceptor specificities of glycosyltransferases. Information about glycosyl acceptor specificities of glycosyltransferases will be employed by Project 2 to prepare glycans that otherwise are not accessible by chemo-enzymatic synthesis. Project 2 will generate synthetic glycans that will be employed by Project 1 for in depth studies of glycosyl acceptor specificities. Structural studies by Project 1 will provide important information for project to design of sugar nucleotide donors modified with a chemical reporter for cellular studies in the context of human disease.