Hexosaminidase+A

__ Hexosaminidase A (Hex A, Beta-hexosamindase) __
Hexosaminidase A (Hex A) is a protein enzyme found in lysosomes that is capable of breaking down GM2 gangliosides. The enzyme is composed of two parts, called the Alpha and Beta subunits. Although both portions of the enzyme have cleaving properties, only the Alpha subunits is capable of hydrolyzing, or breaking down, gangliosides. The Alpha subunit contains the amino acid Arg--424, a residue that allows it to bind to the N-acetyl-neuramanic portion of the GM2 ganglioside structure. A loop structure on the Alpha subunit (which isabsent on the Beta subunit) containing the amino acids Gly-280, Ser-281, Glu-282, and Pro-283, gives the enzyme its hydrolysis capability.

The enzyme is activated by a cofactor, the GM2 activator protein. Although the Alpha subunit is the portion that hydrolyzes gangliosides, the Beta subunit serves as a binding site for the GM2 activator cofactor. This means that if any of these three components of GM2 ganglioside hydrolysis are not functioning, it will ultimately result in the build up gangliosides, causing death in a progression consistent with Tay-Sachs disease (Lemieux, MJ, et. al., 2006)..

At a genetic level, all the components of this system are not only coded by different genes, but on entirely different chromosomes. Up until the recent renaissance in genetic research and molecular biology, all GM2 gangliosidosis diseases were thought to be one the same disease, Tay-Sachs, but now, TSD exclusively refers to a genetic mutation in the HEXA gene, resulting in a deficient Alpha subunit. The HEXA gene is located on the 15th chromosome, with the most common mutation resulting in TSD being identified as a 4-bp insertion, TATC in exon 11 of the gene (Boles, D.J., & Proia, R.L., 1995). This mutation results in a complete loss of function of the enzyme. Sandhoff disease, a GM2 gangliosidosis, is only distinguishable from TSD by genetic testing, as it results from a mutation of the HEXB gene, resulting in a loss of function of the Beta subunit and its ability to bind the GM2 protein activator, resulting in total loss of function for the Hex A enzyme. AB-variant, a clinically similar disease, is caused by a mutation of yet another gene, the GM2A gene, which codes for the GM2 activating cofactor. A mutation on this gene does not cause a deficient Hex A enzyme, but results in inactivity as the cofactor loses its ability to activate the Hex A enzyme (Mahuran, D.J., 1999).

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HEXA Gene

HEXA Protein Interactions

HEXA Gene and Hexosaminidase A Protein--Phylogenetic Analysis

Tay-Sachs Symptoms

GM2 Gangliosides and Sphigolipidoses Pathway

Materials and Methods

References