Collections > Electronic Theses and Dissertations > Biological and Chemoenzymatic Synthesis of Anticoagulant Heparan Sulfate
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Heparan sulfate (HS) is a linear, heterogeneously sulfated polysaccharide that is ubiquitous to most mammalian tissues. The roles played by HS on the cell surface and in the extracellular matrix (ECM) are diverse in function. A number of HS/protein interactions have been studied and have led to a more detailed understanding of signal transduction pathways, enzyme activation, and ligand presentation. Accumulating evidence has supported the role of the fine structure of HS in high-affinity interactions with serine protease inhibitors, growth factors, and microbial coat proteins. These findings have led to a great deal of interest in understanding how specific HS structures are generated and the mechanisms that regulate HS biosynthesis. Complex HS sequences are generated by a number of biosynthetic enzyme families, including the N-deacteylase N-sulfotransferases, epimerase, 2-O-, 6-O-, and 3-Osulfotransferases. Herein, studies are presented that explore the functions of N-deacetylase N-sulfotransferase and the 3-O-sulfotransferases. In addition, we report a chemoenzymatic approach to synthesizing anticoagulant heparin, a structural analogue of HS. The anticoagulant effects of heparin, derived from natural sources, have been exploited in the clinic for over seventy years. A synthetic approach to heparin production could provide the anticoagulant with reduced side effects. It would also allow for the investigation of other therapeutic benefits of heparin and HS. In conclusion, the work presented herein provides detail into the biosynthetic machinery and biological properties of HS, as well as strategies to control the assembly of heparin and HS polysaccharides.