For cells to function correctly within an organism, they need different systems to communicate with each other. One crucial part of cell signaling is the proteoglycans (PGs) and glycosaminoglycans (GAGs), which are macromolecules that bind different signaling molecules and proteins necessary for processes such as growth and proliferation. Therefore, PGs and GAGs are involved in pathological processes like cancer and bacterial or viral infection. A tetrasaccharide linker connects several types of GAGs to the PG core protein, with the first carbohydrate being a xylose. Xylose is, due to its scarcity in mammalian cells, an attractive target for therapeutics. In GAG biosynthesis, the enzyme β4GalT7 galactosylates the xylose. Therefore, this enzyme could be interesting to target using synthetic xylosides that could act as substrates or inhibitors. These xylosides could allow us to understand and control the biosynthesis of GAGs.
This thesis is focused on the design and synthesis of modified xylosides and how we can use these as tools to study the formation of GAGs. We decided to alter the carbohydrate itself to investigate if it is possible to design effective substrates or inhibitors for β4GalT7. We also decided to modify the aglycon, the part attached to the carbohydrate, to answer questions related to how cells process GAGs. This work has resulted in several new substances that, that enter cells, and work well as substrates and inhibitors of β4GalT7 to provide answers to how GAGs are structured, how they move within the cell, and how they interact with other biomolecules such as viral proteins. The results of this work pave the way for the use of synthetic xylosides to answer several questions about GAG-related processes and open up the possibility for creating tools for influencing and studying cells' expression of GAGs.
Place: Kemicentrum, sal K:B. Join via zoom: https://lu-se.zoom.us/j/62142644089
Name: Oscarson, Stefan
Affiliation: University College, Dublin.