Heparanase in cancer progression: Structure, substrate recognition and therapeutic potential

Abstract

Heparanase, a member of the carbohydrate-active enzyme (CAZy) GH79 family, is an endo-β-glucuronidase capable of degrading the carbohydrate moiety of heparan sulphate proteoglycans, thus modulating and facilitating remodeling of the extracellular matrix. Heparanase activity is strongly associated with major human pathological complications, including but not limited to tumour progress, angiogenesis and inflammation, which make heparanase a valuable therapeutic target. Long-due crystallographic structures of human and bacterial heparanases have been recently determined. Though the overall architecture of human heparanase is generally comparable to that of bacterial glucuronidases, remarkable differences exist in their substrate recognition mode. Better understanding of regulatory mechanisms of heparanase in substrate recognition would provide novel insight into the anti-heparanase inhibitor development as well as potential clinical applications.

Heparin, Heparan Sulphate and Sepsis: Potential New Options for Treatment

“…The endoglucuronidase heparanase-1 (HPase) has been the subject of much recent interest. Though the literature has in the past been principally concerned with the identification of HPase as a target in the development of anti-cancer therapies (for example see [ 165 ]), several recent reviews have emphasised its role in the degradation of endothelial glycocalyx, particularly in sepsis [ 166 , 167 , 168 , 169 , 170 ]. HPase 1 is the only mammalian enzyme that breaks down heparin/HS; Heparanase-2 is a protein homologous to HPase, but in spite of its name it acts as an inhibitor of HPase and therefore has a protective effect on the glycocalyx by preventing the shedding of HS fragments [ 171 ].…”

“…HPase cleaves the heparin/HS chain at the reducing side of GlcA between two N-sulphated, preferably also 6- O -sulphated glucosamine residues [ 165 ]. This yields moderately large oligosaccharides consisting of about 10–20 monosaccharides [ 172 , 173 ].…”

Role of heparanase in pulmonary hypertension

“…The HPA gene is located on human chromosome 4q22, spanning approximately 50 kb and consisting of 14 exons and 13 introns ( Vlodavsky et al, 1999 ). Human HPA comprises an α (β/α)8 domain and an αβ three-dimensional domain ( Yuan et al, 2022 ). In the three-dimensional structure of HPA, the C-terminal region plays a critical role in its enzymatic activity and secretion ( Cruz et al, 2020 ).…”