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Hexosaminidase
| Catalog | Product Name | EC No. | CAS No. | Source | Price |
|---|---|---|---|---|---|
| NATE-0343 | Native Jack Bean β-(1-2,3,4,6) Hexosaminidase, Sequencing-grade | Jack Bean | Inquiry |
Related Reading
Introductions
Hexosaminidase is an enzyme involved in the hydrolysis of terminal N-acetyl-D-hexosamine residues in N-acetyl-β-D-hexosaminides. Elevated levels of hexosaminidase in blood and urine have been proposed as a biomarker of relapse in the treatment of alcoholism. The genetic inability to form functional hexosaminidase is responsible for lipid storage disorders Ty-Sachs disease and Sandhoff's disease.
HEXA
Hexosaminidase A, also known as HEXA, is an enzyme that in humans is encoded by the HEXA gene located on chromosome. HEXA and the cofactor GM2 activator protein catalyze the degradation of GM2 gangliosides and other molecules containing terminal N-acetylhexosamines. HEXA is a heterodimer consisting of an α-subunit (the protein) and aβ-subunit. α-subunit polypeptides are encoded by the HEXA gene, while β-subunit polypeptides are encoded by the HEXB gene.
Function
Even though the alpha and beta subunits of hexosaminidase A can both cleave GalNAc residues, only the alpha subunit is able to hydrolyze GM2 gangliosides. The alpha subunit contains a key residue, Arg-424, which is essential for binding the N-acetyl-neuramanic residue of GM2 gangliosides. The alpha subunit can hydrolyze GM2 gangliosides because it contains a loop structure consisting of the amino acids: Gly-280, Ser-281, Glu-282, and Pro-283. The loop is absent in the beta subunit, but it serves as an ideal structure for the binding of the GM2 activator protein (GM2AP) in the alpha subunit. A combination of Arg-424 and the amino acids that cause the formation of the loop allow the alpha subunit to hydrolyze GM2 gangliosides into GM3 gangliosides by removing the N-acetylgalactosamine (GalNAc) residue from GM2 gangliosides.
Mechanism
The Michaelis complex consisting of a glutamate residue, a GalNAc residue on the GM2 ganglioside and an aspartate residue leads to the formation of an oxazoline ion intermediate. A glutamate residue (alpha Glu-323/beta Glu-355) functions as an acid by donating its hydrogen to the glycosidic oxygen atom on the GalNAc residue. An aspartate residue (alpha Asp-322/beta Asp-354) positions the C2-acetamido group so that it can be attacked by a nucleophile (the N-acetamido oxygen atom on substrate carbon 1). The aspartic acid residue stabilizes the positive charge on the nitrogen atom of the oxazolinium ion intermediate. Glutamate acts as a base to deprotonate water, leading to the formation of product complexes and GM3 gangliosides.
Gene mutations
There are many mutations that cause aminohexosidase A deficiency, including gene deletions, nonsense mutations, and missense mutations. Tay-Sachs disease occurs when aminohexosidase A loses its function. patients with Tay-Sachs disease are unable to remove GalNAc residues from GM2 gangliosides, so they end up with 100 to 1,000 times more GM2 gangliosides stored in the brain than normal individuals. More than 100 different mutations common to infant cases of Tay-Sachs disease alone have been identified, they occur in more than 80% of Tay-Sachs patients and are caused by a four-base pair addition (TATC) in exon 11 of the Hex A gene. This insertion leads to an early termination codon, resulting in a Hex A deficiency. Children with Tay-Sachs usually die from aspiration and pneumonia between the ages of 2 and 6. Tay-Sachs causes brain degeneration and blindness. Patients also experience limb flaccidity and seizures.