Lysosomal beta-glucuronidase (GUSB)

Lysosomal beta-glucuronidase (GUSB) is a critical lysosomal enzyme that functions as an exoglycosidase, hydrolyzing β-D-glucuronic acid residues from the non-reducing ends of glycosaminoglycans (GAGs) including heparan sulfate, dermatan sulfate, and chondroitin sulfate, enabling their stepwise degradation within lysosomes. Encoded by the GUSB gene on chromosome 7, it is synthesized as an 80 kDa monomer (653 amino acids) that undergoes C-terminal proteolysis to a 78 kDa form and assembles into a functional 332 kDa homotetramer with three distinct domains: a jelly roll barrel, an immunoglobulin-like domain, and a TIM barrel. Catalysis involves key residues Glu540 (nucleophile), Glu451 (acid-base catalyst), and Tyr504, supporting a retaining glycosidase mechanism with structural similarities to bacterial β-glucuronidase and other glycosyl hydrolases. The enzyme features four N-glycosylation sites (Asn173, Asn272, Asn402, Asn631) essential for folding, tetramer stability, and lysosomal targeting via mannose-6-phosphate recognition, facilitated by surface lysine residues like Lys197 in a β-hairpin motif. Deficiency in GUSB activity causes mucopolysaccharidosis type VII (MPS VII, Sly syndrome), a lysosomal storage disorder characterized by GAG accumulation leading to progressive multisystem damage including skeletal dysplasia, intellectual disability, and organomegaly. While enzyme replacement therapy has been explored to restore GUSB function and mitigate lysosomal storage, detailed drug interactions remain limited in structural studies.

Other names

beta-glucuronidaseβ-glucuronidasehuman β-glucuronidaseGUS