Beta-Hexosaminidase

Structure of Human β-Hexosaminidase A and its association with Tay-Sachs disease

β-Hexosaminidase A is a lysosomal enzyme essential for the degradation of GM2 gangliosides. Deficiency of lysosomal β-Hexosaminidase A due to inherited defects in the α-subunit gene results in Tay-Sachs (TS) disease. The 3D structure of β-Hexosaminidase A was determined by the group of Michael N.G. James at the University of Alberta, Edmonton, Canada.^[1] The structure reveals an , with each subunit having a functional active site. Only the active site can hydrolyze GM2 gangliosides due to α₂₈₀GSEP₂₈₃ structure that is removed post-translationaly from β, and to the presence of . The is involved in binding the GM2 activator protein, while is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. are present in the HexA dimer; one comprising residues from (R178 D207 H262 E323 D322 W373 W392 W460 Y421 R424 N423 E462) and a second one from residues of the (R211 D240 H294 E355 D354 W405 W424 Y450 L453 D452 E491 W489). These active sites are located at the opening of TIM barrels at the interface between the α and β-subunits. The HexA on the α and β-subunits; α-Asn 115, α-Asn 157 and α-Asn 295 β-Asn 84, β-Asn 142, β-Asn 190 and β-Asn 327. in the α-subunit are associated with TS disease and with Late Onset Tay Sachs disease (LOTS) (Chronic & Acute clinical phenotype). Interestingly, is the most common mutation associated with LOTS disease. See also Hexosaminidase (Hebrew).