Beta-N-acetylhexosaminidase (HEX) (HEX)

Beta-N-acetylhexosaminidase (HEX) is a critical lysosomal enzyme responsible for the degradation of GM2 gangliosides and other glycoconjugates by cleaving terminal N-acetylgalactosamine or N-acetylglucosamine residues (UniProt P06865). It exists in two major isoforms: Hexosaminidase A, which is a heterodimer of alpha and beta subunits, and Hexosaminidase B, a homodimer of beta subunits. Genetic mutations in the alpha subunit (encoded by HEXA) or the beta subunit (encoded by HEXB) result in Tay-Sachs and Sandhoff diseases, respectively, which are characterized by progressive neurodegeneration due to the toxic accumulation of GM2 gangliosides in neurons (PubMed: 30503573). As a therapeutic target, efforts focus on restoring enzyme activity through gene therapy, enzyme replacement, or pharmacological chaperones like pyrimethamine, which helps stabilize misfolded mutant proteins (PubMed: 21248210). A major challenge in targeting this enzyme is the requirement for therapeutic agents to cross the blood-brain barrier to reach affected neuronal tissues in the central nervous system.

Other names

HexosaminidaseN-acetyl-beta-glucosaminidaseBeta-hexosaminidaseN-acetyl-beta-D-hexosaminidaseEC 3.2.1.52

Pharmacological chaperoning to stabilize misfolded enzymes, enzyme replacement therapy to restore catalytic activity, and gene therapy to provide functional copies of the HEXA or HEXB genes.