Ben Schumann Seminar

Abstract

Carbohydrates (glycans) are the most abundant biomass on earth and decorate the surface of every single living cell. Cell surface glycans influence major physiological processes, and changes are strongly associated with the formation of cancer.1 The process of adding glycans to a protein, called glycosylation, is one of the most common and complex ways that proteins can be modified after they are made.

Biomedical research has excelled at investigating the structure and function of nucleic acids (DNA and RNA) and proteins, all of which are made from a ‘template’ in a cell. In contrast, glycans are not produced from templates and are recalcitrant to investigation with classical methods of biochemistry.

About 20 years ago, chemists have started modifying single monosaccharides – the most basic unit of glycans – with chemical tags and subsequently track how these are incorporated into proteins by bioorthogonal (click) chemistry awarded the 2022 Nobel Prize in Chemistry.^2,3 While carrying great potential, this technique is not really specific to particular cells, carbohydrate molecules or biosynthetic enzymes. With the advent of recent technical developments in qualitative and quantitative biology, we would have the opportunity to study the role of glycosylation in health and disease in great detail if our chemical tools were more specific.^4–6

Here, I will give an introduction into chemical precision tools, highlighting what makes them fun to use and how to employ them to tackle complex challenges in the fascinating world of glycobiology.

Fig.: A, cell surface glycans probed by chemical tools containing clickable (bioorthogonal) groups. B, Methods to increase specificity of chemical tools.

References:

1. Schjoldager, K. T., Narimatsu, Y., Joshi, H. J. & Clausen, H. Global view of human protein glycosylation pathways and functions. Nat. Rev. Mol. Cell Biol. 21, 729–749 (2020).

2. Cioce, A., Malaker, S. A. & Schumann, B. Generating orthogonal glycosyltransferase and nucleotide sugar pairs as next-generation glycobiology tools. Curr. Opin. Chem. Biol. 60, 66–78 (2021).

3. Sletten, E. M. & Bertozzi, C. R. Bioorthogonal chemistry: Fishing for selectivity in a sea of functionality. Angew. Chem. Int. Ed. 48, 6974–6998 (2009).

4. Zol-Hanlon, M. I. & Schumann, B. Open questions in chemical glycobiology. Commun. Chem. 3, 1–5 (2020).

5. Cioce, A. et al. Cell-specific Bioorthogonal Tagging of Glycoproteins in Co-culture. In-press, Nat. Commun. (2022).

6. Debets, M. F. et al. Metabolic precision labeling enables selective probing of O-linked N -acetylgalactosamine glycosylation . Proc. Natl. Acad. Sci. U. S. A. 117, 25293–25301 (2020).