Heparanase - Discovery and Targets

Heparanase was discovered during a study of the heparin proteoglycan (serglycin) in mast cells. Newly synthesized polysaccharide chains, kDa 60-100 x 10³, were rapidly degraded to fragments similar in size to commercially available heparin (averaging 15 x 10³). Analysis of the degradation products identified reducing-terminal glucuronic acid residues, shown by studies of heparin biosynthesis to be of ßD-configuration in the intact polymer. Heparanase, thus identified as an endo-ßD-glucuronidase, was subsequently identified in a variety of tissues and cells. The enzyme was subsequently implicated with a variety of pathophysiological processes, including in particular cancer, inflammatory diseases, and amyloidosis, as detailed in subsequent chapters of this volume. The target for enzyme action in these settings is primarily extracellular heparan sulfate proteoglycans; furthermore, intracellular cleavage initiates degradation of heparan sulfate chains by exolytic hydrolases and sulfatases, as part of normal turnover of the polysaccharide. More unexpectedly, heparanase also influences heparan sulfate biosynthesis, such that overexpression of the enzyme results in generation of highly sulfated, heparin-like oligosaccharides. The mechanism behind this effect remains unclear - along with the overall design of the molecular machinery in control of proteoglycan biosynthesis.