Chemical Precision Tools to Understand Glycobiology

Every single cell displays to its environment a layer of carbohydrates (glycans) that are linked to proteins, lipids, cell wall components, and even nucleic acids. Glycans modulate biology at numerous levels, impacting cell-cell interactions, signalling, development, immunology and host-pathogen interactions. Aberrant glycosylation patterns are often observed in diseases and serve crucial functions when a cell becomes malignant. Yet, understanding glycans is all but trivial, requiring elaborate techniques to measure, disrupt and manipulate them. Over the last decades, chemists have stepped up to the challenge. Welcome to the wonderfully exciting world of #glycotime!

On proteins, glycosylation is the most abundant yet least understood posttranslational modification. Modern methods of molecular cell biology are limited in understanding this process since glycans are not encoded in the genome. Instead, the combinatorial activity of more than 200 glycosyltransferases and glycosidases in the secretory pathway manifests the complexity that we know as the cell-surface glyco-code. Knocking out the genes that encode for individual glycosylation enzymes can be a powerful approach but is still limited by their interdependencies - compensation or competition events can mean that knock-outs lead to cellular artifacts. Chemical tools complement these approaches, enabling a detailed view into the process of glycosylation.

Over the years, sugars armed with bioorthogonal tags have been invented, culminating in the 2022 Nobel Prize in Chemistry. These compounds can be used by cellular biosynthesis pathways and incorporated into the glyco-code. Our lab strives to develop such tools that are specific for individual glycosyltransferases, individual glycan types or individual cells. We are also invested in developing inhibitors for glycosylation enzymes and synthetic glycans with bespoke functionalities. For these, we have collectively coined the term of "Chemical Precision Tools", to allow us to tap into the power of quantitative glycobiology.

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