Mammalian Glycosyltransferases for use in Chemistry and Biology

描述（由申请人提供）：复合碳水化合物或聚糖几乎参与所有生理或病理过程。对聚糖所起生物学作用以及影响或改变其功能的因素的理解的进展沿着将为开发新的治疗剂和诊断剂提供重要途径。认识到有机会推动糖科学对人类健康的影响，我们组建了一个由五名高级研究人员组成的团队，他们将在三个相关的研究项目上合作，以利用核心的独特能力来生产重组哺乳动物糖基转移酶。研究项目包括：1）研究糖基转移酶的生化和结构，以确定其在分子和结构水平上的受体特异性; 2）以一种新的化学酶方法开发糖基转移酶，为结构活性关系研究提供聚糖，帮助开发下一代聚糖微阵列和作为分析标准; 3）开发由化学报告分子修饰的糖核苷酸供体，以标记糖缀合物的子集，用于疾病的细胞模型中聚糖的可视化、捕获和鉴定。这三个项目具有很高的协同性。每一种都需要一个相对较大的糖基转移酶组，这些糖基转移酶将由核心产生。此外，它们将产生互惠的知识和资源。项目1和3将进行互补研究，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由项目2用于制备否则无法通过化学-酶促合成获得的聚糖。项目2将生成合成聚糖，项目1将采用这些聚糖对糖基受体特异性进行深入研究。项目1的结构研究将为项目设计用化学报告分子修饰的糖核苷酸供体提供重要信息，用于人类疾病背景下的细胞研究。

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.