Chemoenzymatic Synthesis and Biochemical Studies of Glycosphingolipids

鞘糖脂的化学酶法合成及生化研究

• 批准号: 1800279
• 负责人: Zhongwu Guo
• 金额: $ 45万
• 依托单位: University of Florida
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1800279&HistoricalAwards=false
• 关键词: Chemoenzymatic; Synthesis; Biochemical; Studies; Glycosphingolipids

With funding from the Chemical Synthesis Program of the NSF Division of Chemistry, Dr. Zhongwu Guo of the University of Florida is developing a new, efficient, and widely applicable strategy for the synthesis of molecules called "glycosphingolipids" (GSLs). GSLs are components of the cell membrane and play a vital role in biological processes such as the regulation cell division, recognition,and adhesion, as well as nerve system development and drug resistance. Abnormal GSLs were demonstrated to be closely associated with diseases such as cancer, bacterial and viral infections, diabetes, Alzheimer?s disease, and Fabry disease. Detailed investigations of GSLs are critical for understanding their fundamental functions and for the development of new biotechnologies. To this end, a major hurdle in understanding GSLs is obtaining pure and well-defined samples. In the current project, Dr. Guo is developing new strategies to make GSLs, as well as making GSL derivatives for use as tools to study their biochemical properties. This project explores the fundamental reactivity of GSLs in biology, especially diseases related to the human brain. Other activities supported by this award include undergraduate student engagement in scientific research. New curriculum development targeted at improving chemical education, and interest in carbohydrate chemistry and glycobiology is also a focus of Dr. Guo's outreach and educational activities. This project advances human health while supporting education at the interface of chemistry and biology.Dr. Guo's strategy for the synthesis of glycosphingolipids (GSLs) consists of enzymatic carbohydrate assembly of a substrate bearing a truncated lipid followed by chemoselective lipid elongation via olefin cross-metathesis and other reactions. This approach is addressing issues with the limited water solubility of the fully elongated GSLs and allowing for access to these compounds in pure and structurally defined forms. Dr. Guo is also applying this synthetic strategy to preparing GSL libraries that contain different glycans, lipids, and functional groups. He is employing the functionalized GSLs, especially those with fluorescent labels, to probe their distribution in the cell membrane. This project has a significant and broad impact on many scientific areas including GSL-related biology and biomedical sciences through the use of GSLs as molecular tools. The application of these tools is providing insights into the functions, functional mechanisms, and structure-activity relationships of GSLs. In addition, Dr. Guo is also actively engaged in establishing and enriching the Chemical Biology program at the University of Florida. He train graduate and undergraduate students at the interface of chemistry and biology.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在NSF化学部化学合成计划的资助下，佛罗里达大学的Zhongwu Guo博士正在开发一种新的，有效的，广泛适用的合成称为“鞘糖脂”（GSL）的分子的策略。GSL是细胞膜的组成部分，在调节细胞分裂、识别和粘附以及神经系统发育和耐药性等生物学过程中起着至关重要的作用。 异常GSL被证明与癌症、细菌和病毒感染、糖尿病、阿尔茨海默病等疾病密切相关。和Fabry病。对GSL的详细研究对于了解其基本功能和开发新的生物技术至关重要。为此，理解GSL的一个主要障碍是获得纯净和定义明确的样品。在目前的项目中，郭博士正在开发新的策略来制造GSL，以及制造GSL衍生物作为研究其生化特性的工具。该项目探讨了GSL在生物学中的基本反应性，特别是与人类大脑相关的疾病。该奖项支持的其他活动包括本科生参与科学研究。 新课程开发旨在改善化学教育，对碳水化合物化学和糖生物学的兴趣也是郭博士推广和教育活动的重点。 该项目促进人类健康，同时支持化学和生物学的界面教育。郭博士的鞘糖脂（GSL）合成策略包括酶促碳水化合物组装带有截短脂质的底物，然后通过烯烃交叉复分解和其他反应进行化学选择性脂质延长。这种方法解决了完全延长的GSL的水溶性有限的问题，并允许以纯的和结构确定的形式获得这些化合物。Guo博士还将这种合成策略应用于制备含有不同聚糖、脂质和官能团的GSL文库。他正在使用功能化的GSL，特别是那些带有荧光标记的GSL，来探测它们在细胞膜中的分布。该项目通过使用GSL作为分子工具，对许多科学领域，包括GSL相关生物学和生物医学科学产生了重大而广泛的影响。这些工具的应用提供了深入了解GSL的功能，功能机制和结构-活性关系。此外，郭博士还积极参与建立和丰富佛罗里达大学的化学生物学项目。 该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

项目成果

A Diversity-Oriented Strategy for Chemoenzymatic Synthesis of Glycosphingolipids and Related Derivatives

• DOI: 10.1021/acs.orglett.0c02847
• 发表时间: 2020-11-06
• 期刊: ORGANIC LETTERS
• 影响因子: 5.2
• 作者: Li, Qingjiang;Jaiswal, Mohit;Guo, Zhongwu
• 通讯作者: Guo, Zhongwu

A Diversity-Oriented Strategy for Chemical Synthesis of Glycosphingolipids: Synthesis of Glycosphingolipid LcGg4 and Its Analogues and Derivatives

面向多样性的鞘糖脂化学合成策略：鞘糖脂LcGg4及其类似物和衍生物的合成

• DOI: 10.1021/acs.joc.0c02490
• 发表时间: 2021
• 期刊: The Journal of Organic Chemistry
• 作者: Rohokale, Rajendra S.;Li, Qingjiang;Guo, Zhongwu
• 通讯作者: Guo, Zhongwu