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Tools for understanding the glycosaminoglycan biosynthesis

Willén, Daniel LU (2021)
Abstract
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... (More)
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. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Oscarson, Stefan, University College, Dublin.
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Xylosides, Glycosaminoglycans, Proteoglycans, β4GalT7, Carbohydrate synthesis, GAG priming, GAG inhibition
pages
204 pages
publisher
Lund University, Faculty of Science, Department of Chemistry, Centre for Analysis and Synthesis
defense location
Kemicentrum, sal K:B. Join via zoom: https://lu-se.zoom.us/j/62142644089
defense date
2021-12-02 09:00:00
ISBN
978-91-7422-846-5
978-91-7422-847-2
language
English
LU publication?
yes
id
7700a7e1-b057-4bc8-b298-f2652735c56d
date added to LUP
2021-10-27 09:23:34
date last changed
2022-04-12 15:08:53
@phdthesis{7700a7e1-b057-4bc8-b298-f2652735c56d,
  abstract     = {{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. <br/><br/><br/>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.}},
  author       = {{Willén, Daniel}},
  isbn         = {{978-91-7422-846-5}},
  keywords     = {{Xylosides; Glycosaminoglycans; Proteoglycans; β4GalT7; Carbohydrate synthesis; GAG priming; GAG inhibition}},
  language     = {{eng}},
  publisher    = {{Lund University, Faculty of Science, Department of Chemistry, Centre for Analysis and Synthesis}},
  school       = {{Lund University}},
  title        = {{Tools for understanding the glycosaminoglycan biosynthesis}},
  url          = {{https://lup.lub.lu.se/search/files/109313978/Daniel_Willen_web.pdf}},
  year         = {{2021}},
}