Chemical precision tools to dissect protein glycosylation

Ben Schumann / Imperial College London, United Kingdom

May 8, 2024



The composition of glycoproteins is an undisputed corollary of their function. Understanding the glycoproteome in health and disease is paramount but hampered by the complexity of glycan modifications: hundreds of biosynthetic enzymes in the secretory pathway manifest the cell surface glyco-code. Interdependencies of these enzymes can impact the applicability of classical methods in molecular and cell biology, for instance through compensation or competition events.

Here, I describe our work that complements approaches in molecular cell biology by generating chemical “precision tools” to understand the activities of individual glycosyltransferase enzymes. A key technology is the bump-and-hole tactic in which glycosyltransferases are engineered to accept a chemically modified, bulky nucleotide-sugar substrate. The tactic is applicable to living cells, allowing to trace protein glycosylation introduced in the secretory pathway by bioorthogonal chemistry. We have produced precision tools for a variety of glycosyltransferases, glycan subtypes, and cell types to shed light on the complexity of the secretory pathway.

Ben Schumann

studied Biochemistry in Tübingen before entering the world of carbohydrate chemistry with Peter H. Seeberger at the Max Planck Institute of Colloids and Interfaces Potsdam and the FU Berlin. Developing vaccines against pathogenic bacteria based on synthetic glycans, Ben learnt to apply his compounds in biological settings in vivo and in vitro, receiving the Award for Excellence in Glycosciences and the Otto Hahn Medal by the Max Planck Society.During his postdoctoral work in the lab of Carolyn R. Bertozzi at Stanford University as an Alexander von Humboldt Foundation fellow, Ben developed an interest for “precision tools” to study glycosylation of human cells in great detail. He started as a Group Leader at the Francis Crick Institute and Imperial College London in 2018 to develop such tools, using a combination of organic and chemo-enzymatic synthesis, molecular and cell biology. His work routinely incorporates recent methods of genome engineering and glycoproteomics. The lab was part of a large international team that received the 2021 Rita and John Cornforth RSC Horizon Prize in Chemical Biology. Ben has been awarded an Imperial College London Outstanding Early Career Researcher Award and is an EMBO Young Investigator. He received an ERC Starting Grant in 2023, now covered by a Guarantee scheme by UK Research and Innovation, the 2023 Royal Society of Chemistry Dextra Award and the 2024 Biochemical Society Early Career Research Award. He aims to foster a positive, inclusive atmosphere in research.