Chemoenzymatic modular assembly of O-GalNAc glycans for functional glycomics

Author:

Wang ShuaishuaiORCID,Chen Congcong,Gadi Madhusudhan Reddy,Saikam Varma,Liu Ding,Zhu He,Bollag RoniORCID,Liu KebinORCID,Chen XiORCID,Wang Fengshan,Wang Peng GeorgeORCID,Ling PeixueORCID,Guan WanyiORCID,Li LeiORCID

Abstract

AbstractO-GalNAc glycans (or mucin O-glycans) play pivotal roles in diverse biological and pathological processes, including tumor growth and progression. Structurally defined O-GalNAc glycans are essential for functional studies but synthetic challenges and their inherent structural diversity and complexity have limited access to these compounds. Herein, we report an efficient and robust chemoenzymatic modular assembly (CEMA) strategy to construct structurally diverse O-GalNAc glycans. The key to this strategy is the convergent assembly of O-GalNAc cores 1–4 and 6 from three chemical building blocks, followed by enzymatic diversification of the cores by 13 well-tailored enzyme modules. A total of 83 O-GalNAc glycans presenting various natural glycan epitopes are obtained and used to generate a unique synthetic mucin O-glycan microarray. Binding specificities of glycan-binding proteins (GBPs) including plant lectins and selected anti-glycan antibodies towards these O-GalNAc glycans are revealed by this microarray, promoting their applicability in functional O-glycomics. Serum samples from colorectal cancer patients and healthy controls are assayed using the array reveal higher bindings towards less common cores 3, 4, and 6 than abundant cores 1 and 2, providing insights into O-GalNAc glycan structure-activity relationships.

Funder

U.S. Department of Health & Human Services | NIH | National Institute of General Medical Sciences

U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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