350 sequences within modified regions of the heparan sulfate glycosaminoglycan chain and generates internal cleavages. Glucuronic acid was identified at the reducing terminal of newly formed heparanase-digested heparan sulfate chains (Fig. 1a) 7, 13, 14. Hexuronic acid carboxyl groups are required for substrate cleavage but are dispensable for recognition, because carboxyl-reduced heparan sulfate is a potent inhibitor; O-sulfation is not an absolute requirement for cleavage, provided that the glucosamine residue is N-substituted13, 14, 24, 25. The heparanase cleavage recognition site appears to be distinct from the antithrombin III heparan sulfate-binding site, but destroys the heparan sulfate recognition site of the plasma histidinerich glycoprotein11 and the heparan sulfate-interacting protein (HIP) found in endothelial and epithelial cells26. The latter two heparan sulfate-binding proteins have been implicated in the regulation of blood coagulation11, 26. These mutually exclusive recognition properties are bound to play important physiological roles. Sulfated oligosaccharides, such as maltohexaose sulfate and phosphomannopentaose sulfate (PI-88), possess significant inhibitory activity against heparanase degradation of heparan sulfate and thus might serve as potential therapeutic inhibitors27.