Lysosomal A, B, and S isoenzymes Functional
lysosomal β-hexosaminidase enzymes are dimeric in structure. Three isoenzymes are produced through the combination of α and β subunits to form any one of three active dimers: The α and β subunits are encoded by separate genes,
HEXA and
HEXB respectively. β-Hexosaminidase and the cofactor
GM2 activator protein catalyze the degradation of the GM2
gangliosides and other molecules containing terminal
N-acetyl hexosamines. Gene mutations in
HEXB often result in
Sandhoff disease; whereas,
mutations in
HEXA decrease the
hydrolysis of GM2 gangliosides, which is the main cause of
Tay–Sachs disease.
Function Even though the α and β subunits of lysosomal hexosaminidase can both cleave GalNAc residues, only the α subunit is able to hydrolyze GM2 gangliosides because of a key residue,
Arg-424, and a loop structure that forms from the amino acid sequence in the alpha subunit. The loop in the α subunit, consisting of
Gly-280,
Ser-281,
Glu-282, and
Pro-283 which is absent in the β subunit, serves as an ideal structure for the binding of the GM2 activator protein (GM2AP), and arginine is essential for binding the
N-acetyl-neuraminic acid residue of GM2 gangliosides. The GM2 activator protein transports GM2 gangliosides and presents the
lipids to hexosaminidase, so a functional hexosaminidase enzyme is able to hydrolyze GM2 gangliosides into GM3 gangliosides by removing the
N-acetylgalactosamine (GalNAc) residue from GM2 gangliosides. The most common mutation, which occurs in over 80 percent of Tay–Sachs patients, results from a four base pair addition (TATC) in exon 11 of the Hex A gene. This insertion leads to an early stop
codon, which causes the Hex A deficiency. Children born with Tay–Sachs usually die between two and four years of age from aspiration and
pneumonia. Tay–Sachs causes cerebral degeneration and blindness. Patients also experience flaccid extremities and seizures. At present there has been no cure or effective treatment of Tay–Sachs disease. The two subunits of hexosaminidase A are shown below:
Cytosolic C and D isozymes The bifunctional protein NCOAT (
nuclear
cytoplasmic
O-GlcNAcase and
acetyl
transferase) that is encoded by the
MGEA5 gene possesses both hexosaminidase and
histone acetyltransferase activities. NCOAT is also known as hexosaminidase C and has distinct substrate specificities compared to lysosomal hexosaminidase A. A
single-nucleotide polymorphism in the human O-GlcNAcase gene is linked to
diabetes mellitus type 2. A fourth mammalian hexosaminidase polypeptide which has been designated hexosaminidase D (
HEXDC) has recently been identified. == References ==