Aspects on dermatan sulfate metabolism

The functions of proteoglycans often depend on the fine structure of the covalently attached glycosaminoglycan (GAG) side-chains. The process leading to the mature GAG is complex and involves a multitude of different enzymatic steps. GAG synthesis is initiated on serine residues, where a xylose residue is transferred to the protein core, a reaction catalyzed by a xylosyltransferase (XT). It thereafter continues with the additions of two galactose residues and one glucuronic acid. These four sugar units comprise the so called link region on which either chondroitin sulfate/dermatan sulfate (CS/DS) or heparan sulfate/heparin are synthesized. This thesis focuses on the metabolism of (CS/DS). In three of the papers different aspects of the biosynthesis are investigated. The first one deals with questions concerning the initiation of GAG synthesis and the role of the core protein thereof. The second paper address questions concerning the regulation of the enzyme responsible for DS formation, the C-5 epimerase. The effect of different cytokines/growth factors on the enzyme activity was investigated and correlations to the structure of the GAG chain are made. In the third paper the delicate interplay of 4-O-sulfation and epimerization was thoroughly investigated and it is suggested that epimerization enhance the possibilities to 4-O-sulfation. Another way to regulate the functions of GAG chains in the tissues is to control their degradation. In the last paper a novel CS/DS degrading enzyme, functioning in the extracellular environment, is described.