Beta-Hexosaminidase

'''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.<ref>PMID:16698036</ref> The structure reveals an <scene name='Beta-Hexosaminidase/Subunits/4'>αβ-heterodimer</scene>, with each subunit having a functional active site. Only the <scene name='Beta-Hexosaminidase/Alpha/2'>α-subunit</scene> active site can hydrolyze GM2 gangliosides due to <scene name='Beta-Hexosaminidase/Gsep/6'>a flexible loop</scene> α₂₈₀GSEP₂₈₃ structure that is removed post-translationaly from β, and to the presence of <scene name='Beta-Hexosaminidase/4234/5'>α-Asn 423 and α-Arg 424</scene>. The <scene name='Beta-Hexosaminidase/Gsep_out/3'>loop structure</scene> is involved in binding the GM2 activator protein, while <scene name='Beta-Hexosaminidase/424_b/1'>α-Arg424</scene> is critical for binding the carboxylate group of the N-acetyl-neuraminic acid residue of GM2. <scene name='Beta-Hexosaminidase/2_active/1'>Two active sites</scene> are present in the HexA dimer; one comprising residues from <scene name='Beta-Hexosaminidase/Active_alpha/1'>the α-subunit</scene> (R178 D207 H262 E323 D322 W373 W392 W460 Y421 R424 N423 E462) and a second one from residues of the <scene name='Beta-Hexosaminidase/Active_beta/1'>β-subunit</scene> (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 <scene name='Beta-Hexosaminidase/Glyco/1'>undergoes glycosylation</scene> 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. <scene name='Beta-Hexosaminidase/Opening/8'>Mutations</scene> in the α-subunit are associated with TS disease and with Late Onset Tay Sachs disease (LOTS) (<b><font color='#0865F1'>Chronic</font></b> & <b><font color='#F90D19'>Acute</font></b> clinical phenotype). Interestingly, <scene name='Beta-Hexosaminidase/Mut_2/2'>α-G269S</scene> is the most common mutation associated with LOTS disease. See also [[Hexosaminidase (Hebrew)]].