Glycoside hydrolases (glycosidases/GHs) are widely abundant enzymes in all kingdoms of life and are important biocatalysts that catalyze the hydrolysis of glycosidic linkages in oligo... Show moreGlycoside hydrolases (glycosidases/GHs) are widely abundant enzymes in all kingdoms of life and are important biocatalysts that catalyze the hydrolysis of glycosidic linkages in oligo/polysaccharides, glycoproteins and glycolipids with tremendous efficiency. Abnormal glycosidase activity is intimately associated with a variety of human diseases. Overexpression of heparanase, for example, is implicated in almost all cancers examined, and correlates with increased tumor size, tumor angiogenesis, enhanced metastasis and poor prognosis. Specific inhibitors of glycosidases are of great value, not only because they can serve as useful biological tools to study the catalytic machinery, mechanism and itinerary of target enzymes by crystal structure analysis of (covalent) inhibitor-enzyme complexes, but also because they may act as starting points for the development of therapeutic drugs for the treatment of glycosidase-mediated diseases. Additionally, covalent mechanism-based inhibitors have been used as scaffolds for the development of activity-based probes (ABPs) which allow profiling of glycosidases in complex biological systems. The research described in this dissertation focus on the development and biochemical evaluation of covalent inhibitors and ABPs for retaining endo- and exo-glycosidases including starch-degrading enzymes and human lysosomal β-glucocerebrosidase (GBA), as well as the synthesis of a panel of uronic acid-type 1-N-iminosugars as potential competitive heparanase inhibitors. Show less
