Beta-N-acetylhexosaminidases catalyze the removal of beta-1,4-linked N-acetyl-D-hexosamine residues from the non-reducing ends of N-acetyl-beta-D-hexosaminides including N-acetylglucosides and N-acetylgalactosides. The hexA and hexB genes encode the alpha- and beta-subunits of the two major beta-N-acetylhexosaminidase isoenzymes, N-acetyl-beta-D-hexosaminidase A (HexA) and beta-N-acetylhexosaminidase B (HexB). Both the alpha and the beta catalytic subunits have a TIM-barrel fold and belong to the glycosyl hydrolase family 20 (GH20). The HexA enzyme is a heterodimer containing one alpha and one beta subunit while the HexB enzyme is a homodimer containing two beta-subunits. Hexosaminidase mutations cause an inability to properly hydrolyze certain sphingolipids which accumulate in lysosomes within the brain, resulting in the lipid storage disorders Tay-Sachs and Sandhoff. Mutations in the alpha subunit cause in a deficiency in the HexA enzyme and result in Tay-Sachs, mutations in the beta-subunit cause in a deficiency in both HexA and HexB enzymes and result in Sandhoff disease. In both disorders GM(2) gangliosides accumulate in lysosomes. The GH20 hexosaminidases are thought to act via a catalytic mechanism in which the catalytic nucleophile is not provided by solvent or the enzyme, but by the substrate itself.
Structure:1NP0_A; Homo sapiens Lysosomal Beta-Hexosaminidase isoform B (HexB) beta subunit, binds an intermediate analog NAG-Thiazoline (N-acetyl-beta-D-glucosamine-thiazoline).
Structure:2GK1_A/B; Homo sapiens Lysosomal Beta-Hexosaminidase isoform A (HexA), alpha and beta subunits each bind an intermediate analog NAG-Thiazoline (N-acetyl-beta-D-glucosamine-thiazoline), contacts at 4 A.
Comment:there are two active sites in the HexA heterodimer, one in the alpha subunit, one in the beta subunit. A Tyr residue from the beta subunit is found in the active site of the alpha subunit and vice versa.
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