Exploration of the biosynthesis of glucosaminoglycans

Session: 
S8.4 Glycosaminoglycans
Code: 
OL8.4.3
Location (hall): 
Fucose
Start/end time: 
Thursday, July 4, 2019 - 12:15 to 12:30
Ulf
Ellervik

Ulf Ellervik1

1Lund University, Lund, Sweden

Proteoglycans (PG) are large macromolecules that consist of a core protein decorated by glycosaminoglycans (GAG), i.e. large linear, negatively charged polymers of repeating disaccharide units. The PGs are found on the cell surface as well as in the extracellular matrix with important roles in the regulation of growth factor signaling, and cell-cell interactions. 

The biosynthesis of GAG chains is initiated by xylosylation of a serine residue in the PG protein. The xylosylated protein is then further glycosylated to form a linker tetrasaccharide. This linker is then polymerized to form the full-length GAGs. The variable lengths of GAGs together with post-synthetic modifications result in extensive diversity.

Interestingly, the biosynthesis of GAG chains can also be initiated by xylosides that act as acceptors in the first galactosylation step by the enzyme β4GalT7, and thus provide a simplified model system for GAG biosynthesis.

In this lecture we will present our recent findings on the key enzymes β4GalT7 and DS-epi1 (Figure 1), the use of xylosides as tools for understanding the biosynthesis of GAGs, and engineering of specific GAG-chains for use as anticoagulants. [1-4]

Figure 1: Proteoglycans are composed of glycosaminoglycan chains linked to a core protein via the carbohydrate xylose

References: 
  1. D. Willen, et al. J. Org. Chem. 2018, 83, 1259-1277. 
  2. E. Tykesson et al. J. Biol. Chem. 2018, 293, 13725-13735.
  3. Y.-H. Chen, et al., Nature Meth. 2018, 15, 881-888. 
  4. A. Persson, et al. J. Biol. Chem. 2018, 293, 10202-10219

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