Lysosomal acid glucosylceramidase (GBA1) (GBA1 or GBA)

Glucosylceramidase beta (GBA1), also known as lysosomal acid glucosylceramidase, is a lysosomal housekeeping enzyme that catalyzes the breakdown of glucosylceramide (glucocerebroside) into glucose and ceramide through a retaining β-glucosidase mechanism.[7][9] The enzyme is maximally active at pH 5.5, the pH of the lysosomal compartment, and requires the activating protein Saposin C and negatively charged lipids for optimal catalytic activity.[5] GBA1 plays a critical role in sphingolipid metabolism, recycling membrane components when cells die so that the products can be reused in new cells.[9] Inherited deficiency of GBA1 causes Gaucher disease, a recessively inherited lysosomal storage disorder characterized by abnormal accumulation of glucosylceramide in bodily tissues, leading to weakened bones, liver damage, and spleen enlargement and dysfunction.[2][7] Beyond classic Gaucher disease, GBA1 mutations have also been identified as a genetic risk factor for Parkinson's disease and other neurodegenerative conditions.[7] As a well-characterized enzyme with established disease associations, GBA1 is a validated therapeutic target for lysosomal storage disorders, with both enzyme replacement therapies and substrate reduction therapies developed to address deficiency of this critical enzyme.

Other names

Glucocerebrosidase (GCase)Beta-glucocerebrosidaseAcid beta-glucosidaseGlucosylceramidase

Retaining β-glucosidase mechanism using double-displacement acid/base chemistry Requires activating protein Saposin C and negatively charged lipids for maximal catalytic activity Optimal activity at pH 5.5 (lysosomal pH) Catalyzes hydrolysis of the β-glycosidic linkage in glucosylceramide