Lysosomal acid β-glucosidase (GCase)

Lysosomal acid β-glucosidase (GCase) is a membrane-associated lysosomal enzyme responsible for hydrolyzing the β-glycosidic bond of glucocerebroside, yielding glucose and ceramide as products[1][2][4][5]. It is a member of the glycoside hydrolase family 30, with a multidomain structure consisting of a catalytic TIM barrel (harboring active site residues Glu 235 and Glu 340), an Ig-like domain, and an N-terminal β-sheet domain[1][4][5]. GCase requires Saposin C as an activator and functions optimally at acidic pH typical of lysosomes[4][1]. Deficiency or mutation in the GBA1 gene encoding GCase results in the accumulation of glucocerebroside in macrophages, leading to Gaucher disease, the most common lysosomal storage disorder[2][4][5]. Mutations in this enzyme are also recognized as genetic risk factors for Parkinson's disease. Therapeutic strategies include enzyme replacement and substrate reduction, but challenges such as immunogenicity and incomplete CNS penetration remain[4][5].

Other names

Glucocerebrosidaseacid β-glucosidaseD-glucosyl-N-acylsphingosine glucohydrolaseGBA1 productGlcCerase

Enzyme replacement therapy: recombinant or modified human GCase replaces deficient enzyme (e.g., imiglucerase, velaglucerase alfa, taliglucerase alfa)[4] Substrate reduction therapy: inhibits substrate (glucosylceramide) synthesis (e.g., eliglustat, miglustat) Irreversible enzyme inhibition: covalently binds active site, permanently inactivating enzyme (Conduritol B epoxide)[1]