Mammalian glycosylation and human disease
Understanding the roles of carbohydrates and carbohydrate-active enzymes in cell physiology and human disease.
Lead researcher: Dr Lianne Willems, Department of Chemistry
Cell-surface proteins and lipids are decorated with a wide variety of carbohydrate structures, named glycans, that play central roles in mammalian biology by regulating, for instance, cell recognition and signalling events.
At the same time, glycan interactions are often hijacked by pathogens to enter host cells, while changes in glycan levels can promote tumorigenesis and cause muscular dystrophy (Figure 1).
The complex and diverse nature of glycan structures mirrors the enormous diversity of cellular enzymes that are involved in synthesising and modifying the many carbohydrate structures in the endoplasmic reticulum (ER) and Golgi apparatus. The complexity of these biosynthetic pathways makes it a challenging task to decipher the exact roles of individual enzymes and glycan structures in cells, knowledge that is essential if we are to understand how malfunctioning leads to disease.
Dr Willems’ research focuses on developing novel chemical tools to study some of these glycans and the enzymes responsible for their biosynthesis. These tools are applied to a range of biochemical, structural and cellular studies to enhance our fundamental understanding of the functioning of the respective glycans and carbohydrate-active enzymes in normal cell physiology and in disease pathology.
Another line of Willems’ research focuses on the degradation of glycolipids by lysosomal glycoside hydrolases. Defects in the activity of these enzymes causes accumulation of their substrates, which leads to lysosomal storage disorders such as Gaucher and Fabry disease. Again, chemical tools are used to provide insights into the molecular and cellular mechanisms of disease.
Figure 1: Cell-surface carbohydrates, linked to proteins or lipids, play key roles in cellular functioning.
- Willems, L. I. et al. Potent and selective activity-based probes for GH27 human retaining α-galactosidases, J. Am. Chem. Soc. 2014, 136, 11622
- Marques, A. R., Willems, L. I. et al. A specific activity-based probe to monitor family GH59 galactosylceramidase - the enzyme deficient in Krabbe disease. Chembiochem 2017, 18 (4), 402
- Willems, L. I.; Li, N.; Florea, B. I.; Ruben, M.; van der Marel, G. A.; Overkleeft, H. S. Triple bioorthogonal ligation strategy for simultaneous labeling of multiple enzymatic activities, Angew. Chem. Int. Ed. 2012, 51, 4431