Ganglioside glycans, sialic acid-containing oligosaccharides, play important roles in numerous biological processes. Variations in sialylation and sulfation make structures of ganglioside glycans complex and diverse. Limited access to well-defined glycans has resulted in poor understanding of their biological roles and structure-function relationships.
In a study published in Nature Chemistry, a research team led by LI Tiehai from the Shanghai Institute of Materia Medica (SIMM) of the Chinese Academy of Sciences developed an integrated chemoenzymatic strategy for modular synthesis of a comprehensive 65-membered ganglioside glycan library. This library enables extensive exploration into structure-function relationships between these glycans and disease-associated proteins. Researchers first developed an efficient modular approach to streamline the assembly of three common sialylated precursors via stereoselectively iterative sialylation using a versatile sialic acid donor. They then adopted flexible orthogonal protecting-group manipulations to achieve the site-specific sulfation facilely. Taking advantage of three robust sialyltransferase modules and a galactosidase module, they performed enzymatic-catalyzed diversification to provide a wide variety of sulfated ganglioside glycans.
In addition, researchers developed an easy-to-implement approach for divergent chemoenzymatic synthesis of all series of nonsulfated ganglioside glycans via reprogramming biosynthetic assembly-lines.
This collection of well-defined ganglioside glycans provided insights into their functional sulfoglycomics and sialoglycomics using glycan microarray technology. Researchers mapped fingerprint binding profiles of these diverse glycans towards disease-associated Siglecs, and elucidated ligand requirements of infection-related virus proteins and bacteria toxins. The results revealed that different patterns of sulfation and sialylation on glycans mediated unique binding specificities.
This study provides an approach for expeditious synthesis of the ganglioside glycan library that covers all possible patterns of sulfation and sialylation. This synthetic approach expands the chemical space and enzyme toolbox of ganglioside glycan synthesis, which could be adopted to synthesize other sialylated and sulfated glycans. Furthermore, the ability to decipher glyco-code of this glycan library with high-throughput microarray screening offers new opportunities for biomedical discovery and facilitates the development of carbohydrate-based drugs.
