Glycoengineering: scratching the surface

Abstract

At the surface of many cells is a compendium of glycoconjugates that form an interface between the cell and its surroundings; the glycocalyx. The glycocalyx serves several functions that have captivated the interest of many groups. Given its privileged residence, this meshwork of sugar-rich biomolecules is poised to transmit signals across the cellular membrane, facilitating communication with the extracellular matrix and mediating important signalling cascades. As a product of the glycan biosynthetic machinery, the glycocalyx can serve as a partial mirror that reports on the cell's glycosylation status. The glycocalyx can also serve as an information-rich barrier, withholding the entry of pathogens into the underlying plasma membrane through glycan-rich molecular messages. In this review, we provide an overview of the different approaches devised to engineer glycans at the cell surface, highlighting considerations of each, as well as illuminating the grand challenges that face the next era of ‘glyco-engineers’. While we have learned much from these techniques, it is evident that much is left to be unearthed.

Benefits of Chemical Sugar Modifications Introduced by Click Chemistry for Glycoproteomic Analyses

“…4,22 Metabolic oligosaccharide engineering (MOE), a recent addition to the field of intact O-glycoproteomics, is emerging as an important strategy to profile mucin-type O-glycans. 23,24 In the MOE strategy, monosaccharides are chemically modified with tags that are stable towards the environment in the living cell, but reactive towards methods of bioorthogonal (or "click") chemistry such as copper-mediated azide-alkyne cycloaddition (CuAAC). 25 A collection of bioorthogonal GalNAc-based monosaccharides relevant to this work is shown in Figure 1A.…”

New Opportunities in Glycan Engineering for Therapeutic Proteins

“…In summary, major advances in single-cell transcriptomes and proteomes, precise glycan analytical tools, in silico modeling, vast pathway databases, and mature nuclease-based gene editing have provided an unprecedented opportunity to study the global functions of human glycome. Efficient genetic approaches such as glycoCRISPR (gene targeting for human glycosyltransferase genes [ 124 ]) and cell-based libraries of displayed glycome (GAGOme [ 125 ] and GlycoDisplay [ 126 ]), as well as chemical and metabolic glycoengineering [ 127 ], have offered simple and direct ways to explore and exploit glycosylation. Modularization strategies for the de novo interpretation of glycan structures such as StrucGP [ 128 ] should facilitate in-depth structural and functional studies on glycoproteins.…”

Engineering the Sialome

“…Purely synthetic approaches to glycoengineering have been developed, with landmark advances reported by the Kiessling and Godula groups. − A common theme in this space is conjugation of glycans (natural or synthetic) to lipophilic membrane anchors, such as cholesterol or phospholipids. These reagents can passively intercalate into cell membranes or be formulated into liposomes and thus enable presentation of a specific glycan with tunable control over density.…”