Enzymes Involved in Biosynthesis and Degradation of Heparin-Related Polysaccharides

Abstract

Heparin and heparan sulphate (HS) are sulphated polysaccharides of the glycosaminoglycan (GAG) type and parts of proteoglycan (PG) macromolecules. HSs are located at most cell surfaces and in the extracellular matrix, where they bind to various proteins, thereby affecting biological processes. In my thesis two proteins involved in HS metabolism have been studied. One is a mammalian heparanase, which degrades HS, the other is the N-deacetylase/N-sulphotransferase (NDST), taking part in generation of the complex structure of HS.
Heparanases cleave HS only at a few sites, generating HS fragments. Studies on the physiological functions of this partial degradation suggest involvement in biologically important processes such as tumour metastasis, angiogenesis, regulation of cell growth, lipid metabolism and blood coagulation. Heparanases recognise a particular structure in the HS chain, which is characterised in this thesis (1). A novel approach, based on systematic modification of a bacterial polysaccharide was used to generate different model substrates.
HS chains contain several structural elements that are important in binding to different proteins. The generation of such specific structures requires a number of enzymes. NDST determines in what regions of the polysaccharide chain sulphation will occur. Characterisation of this enzyme is the other main topic of this thesis (2-5). In particular, the goal was to elucidate the effect of different NDST isoforms on HS structure.