Abstract
Glycans play essential roles in a range of cellular processes and have been shown to contribute to various pathologies. The diversity and dynamic nature of glycan structures and the complexities of glycan biosynthetic pathways make it challenging to study the roles of specific glycans in normal cellular function and disease. Chemical reporters have emerged as powerful tools to characterise glycan structures and monitor dynamic changes in glycan levels in a native context. A variety of tags can be introduced onto specific monosaccharides via the chemical modification of endogenous glycan structures or by metabolic or enzymatic incorporation of unnatural monosaccharides into cellular glycans. These chemical reporter strategies offer unique opportunities to study and manipulate glycan functions in living cells or whole organisms. In this review, we discuss recent advances in metabolic oligosaccharide engineering and chemoenzymatic glycan labelling, focusing on their application to the study of mammalian O-linked glycans. We describe current barriers to achieving glycan labelling specificity and highlight innovations that have started to pave the way to overcome these challenges.
Highlights
Glycans play crucial roles in a diversity of cellular processes
N-linked glycans consist of a universal core structure that starts with an N-acetylglucosamine (GlcNAc) and is further extended and edited by networks of glycosyltransferases and other glycan-modifying enzymes, resulting in a large diversity of mature N-glycan structures [2]
As an alternative to the direct chemical modification of native glycan structures, metabolic oligosaccharide engineering (MOE) exploits the flexibility in the cell’s own metabolic machinery for the introduction of tagged monosaccharides into desired glycans (Figure 3). This approach was pioneered by Reutter and co-workers who showed that cells fed with unnatural derivatives of N-acetylmannosamine (ManNAc) are able to convert them into the corresponding cytidine monophosphate (CMP)-sialic acid donors and incorporate the unnatural substrates into cell surface glycans [29]
Summary
The diversity and dynamic nature of glycan structures and the complexities of glycan biosynthetic pathways make it challenging to study the roles of specific glycans in normal cellular function and disease. A variety of tags can be introduced onto specific monosaccharides via the chemical modification of endogenous glycan structures or by metabolic or enzymatic incorporation of unnatural monosaccharides into cellular glycans. These chemical reporter strategies offer unique opportunities to study and manipulate glycan functions in living cells or whole organisms. We describe current barriers to achieving glycan labelling specificity and highlight innovations that have started to pave the way to overcome these challenges
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