Beta-hexosaminidase subunit beta (HEXB) (HEXB)

Beta-hexosaminidase subunit beta (HEXB) is a vital lysosomal enzyme involved in the breakdown of GM2 gangliosides and other molecules containing terminal N-acetylhexosamines (UniProt P07686). It serves as a subunit for two functional enzymes: Hexosaminidase A (a heterodimer of alpha and beta subunits) and Hexosaminidase B (a homodimer of two beta subunits) (PubMed: 2195850). Mutations in the HEXB gene lead to Sandhoff disease, a severe lysosomal storage disorder characterized by the accumulation of GM2 gangliosides in the central nervous system, resulting in progressive neurodegeneration (NIH: GARD). As a therapeutic target, HEXB is the focus of pharmacological chaperone research, such as the use of pyrimethamine to stabilize mutant enzymes and improve their trafficking to the lysosome (PubMed: 20811621). Additionally, experimental approaches including enzyme replacement therapy and gene therapy aim to restore functional HEXB activity to mitigate substrate accumulation and disease progression (PubMed: 30531910). These therapies face significant hurdles, particularly the challenge of delivering large molecules or viral vectors across the blood-brain barrier to reach affected neurons (PubMed: 30531910). Monitoring treatment efficacy often involves measuring enzymatic activity levels and tracking the reduction of accumulated gangliosides in patient tissues (StatPearls: Sandhoff Disease).

Other names

Beta-N-acetylhexosaminidase subunit betaHexosaminidase subunit BCervical cancer proto-oncogene 4 proteinHCC-4N-acetyl-beta-glucosaminidase subunit beta

Pharmacological chaperones like pyrimethamine bind to the enzyme to stabilize its folding, preventing endoplasmic reticulum-associated degradation and increasing the amount of functional enzyme reaching the lysosome (PubMed: 20811621). Enzyme replacement therapy (ERT) and gene therapy aim to provide a functional version of the HEXB protein to restore the metabolic pathway for GM2 ganglioside degradation (PubMed: 30531910).