Understanding degradation of heparan sulphate with implications for disease. (360G-Wellcome-095828_Z_11_Z)

Glycosaminoglycans are essential components of the extracellular matrix, with roles in inflammation, development and cell signalling. One glycosaminoglycan, heparan sulphate, consists of repeating units of disaccharides, which are modified with acetyl or sulphate moieties. I am interested in how enzymes degrade heparan sulphate. Heparanase is a glycoside hydrolase that cleaves heparan sulphate to produce shorter oligosaccharides. Remodelling of heparan sulphate in the extracellular matrix is imp ortant in cancer invasion; increased heparanase levels correlate with increased metastasis in cancer cell lines and patients. Inhibition of heparanase may, therefore, be an effective approach to slow cancer progression. Nine lysosomal enzymes completely degrade heparan sulphate to regenerate its components. Mutations in these enzymes can affect their stability, preventing them from reaching the lysosome where they function. The reduced enzyme activity limits heparan sulphate degradation, causing accumulation of fragments, and results in a lysosomal storage disorder. One approach for treating these disorders uses molecular chaperones, which are inhibitors that stabilise the enzyme, enabling it to be targeted to the lysosome where it can function. I aim to investigate the mechanistic, structural and functional characteristics of the human enzymes involved in heparan sulphate degradation to enable development of therapeutics for cancer and lysosomal storage disorders.