Integrated chemoenzymatic synthesis of a comprehensive sulfated ganglioside glycan library to decipher functional sulfoglycomics and sialoglycomics

IF 19.2 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY Nature chemistry Pub Date : 2024-06-06 DOI:10.1038/s41557-024-01540-x
Zhuojia Xu, Yating Liu, Jialin Liu, Wenjing Ma, Zhumin Zhang, Digantkumar G. Chapla, Liuqing Wen, Kelley W. Moremen, Wen Yi, Tiehai Li
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Abstract

Ganglioside glycans are ubiquitous and complex biomolecules that are involved in a wide range of biological functions and disease processes. Variations in sialylation and sulfation render the structural complexity and diversity of ganglioside glycans, and influence protein–carbohydrate interactions. Structural and functional insights into the biological roles of these glycans are impeded due to the limited accessibility of well-defined structures. Here we report an integrated chemoenzymatic strategy for expeditious and systematic synthesis of a comprehensive 65-membered ganglioside glycan library covering all possible patterns of sulfation and sialylation. This strategy relies on the streamlined modular assembly of three common sialylated precursors by highly stereoselective iterative sialylation, modular site-specific sulfation through flexible orthogonal protecting-group manipulations and enzymatic-catalysed diversification using three sialyltransferase modules and a galactosidase module. These diverse ganglioside glycans enable exploration into their structure–function relationships using high-throughput glycan microarray technology, which reveals that different patterns of sulfation and sialylation on these glycans mediate their unique binding specificities. Deciphering the sulfation and sialylation codes of ganglioside glycans is impeded by the limited accessibility of well-defined structures. Now, an integrated chemoenzymatic strategy has been developed for efficient synthesis of a comprehensive 65-membered ganglioside glycan library, enabling an extensive exploration into their structure–function relationships using glycan microarray technology.

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综合化学酶法合成硫酸化神经节苷脂糖库,破译功能性硫酸化甘聚物和硫酸化甘聚物
神经节苷脂糖是一种无处不在的复杂生物大分子,参与了多种生物功能和疾病过程。硅烷基化和硫酸化的变化使神经节苷脂聚糖的结构变得复杂多样,并影响蛋白质与碳水化合物之间的相互作用。由于难以获得定义明确的结构,因此无法从结构和功能上深入了解这些聚糖的生物学作用。在此,我们报告了一种综合化学酶法策略,可快速、系统地合成一个全面的 65 元神经节苷脂聚糖库,涵盖所有可能的硫酸化和硅烷基化模式。这种策略依赖于通过高度立体选择性的迭代糖苷化来简化三种常见糖苷化前体的模块化组装,通过灵活的正交保护基团操作来进行特定位点的模块化硫酸化,以及使用三种糖苷基转移酶模块和一种半乳糖苷酶模块进行酶催化的多样化。这些多样化的神经节苷脂聚糖有助于利用高通量聚糖芯片技术探索它们的结构-功能关系,从而发现这些聚糖上不同的硫酸化和硅烷基化模式介导了它们独特的结合特异性。
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来源期刊
Nature chemistry
Nature chemistry 化学-化学综合
CiteScore
29.60
自引率
1.40%
发文量
226
审稿时长
1.7 months
期刊介绍: Nature Chemistry is a monthly journal that publishes groundbreaking and significant research in all areas of chemistry. It covers traditional subjects such as analytical, inorganic, organic, and physical chemistry, as well as a wide range of other topics including catalysis, computational and theoretical chemistry, and environmental chemistry. The journal also features interdisciplinary research at the interface of chemistry with biology, materials science, nanotechnology, and physics. Manuscripts detailing such multidisciplinary work are encouraged, as long as the central theme pertains to chemistry. Aside from primary research, Nature Chemistry publishes review articles, news and views, research highlights from other journals, commentaries, book reviews, correspondence, and analysis of the broader chemical landscape. It also addresses crucial issues related to education, funding, policy, intellectual property, and the societal impact of chemistry. Nature Chemistry is dedicated to ensuring the highest standards of original research through a fair and rigorous review process. It offers authors maximum visibility for their papers, access to a broad readership, exceptional copy editing and production standards, rapid publication, and independence from academic societies and other vested interests. Overall, Nature Chemistry aims to be the authoritative voice of the global chemical community.
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