HEXA
Encyclopedia
Hexosaminidase A, also known as HEXA, is an enzyme
that in humans is encoded by the HEXA gene
.
Hexosaminidase A and the cofactor GM2 activator protein
catalyze the degradation of the GM2 gangliosides and other molecules containing terminal N-acetyl hexosamines. Hexosaminidase A is a heterodimer composed of an alpha subunit (this protein) and a beta
subunit. The alpha subunit polypeptide is encoded by the HEXA gene while the beta subunit is encoded by the HEXB
gene. Gene mutations in the gene encoding the beta subunit (HEXB) often result in Sandhoff disease
; whereas, mutations in the gene encoding the alpha subunit (HEXA, this gene) decrease the hydrolysis
of GM2 gangliosides, which is the main cause of Tay-Sachs disease
.
-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.
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 to six years of age from aspiration and pneumonia
. Tay-Sachs causes cerebral degeneration and blindness. Patients also experience flaccid extremities and seizures. At this point in time, there has been no cure for Tay-Sachs disease, but there is a treatment through an injection of a molecular chaperone.
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the HEXA gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Hexosaminidase A and the cofactor GM2 activator protein
GM2A
GM2 ganglioside activator also known as GM2A is a protein which in humans is encoded by the GM2A gene.- Function :The protein encoded by this gene is a small glycolipid transport protein which acts as a substrate specific co-factor for the lysosomal enzyme β-hexosaminidase A...
catalyze the degradation of the GM2 gangliosides and other molecules containing terminal N-acetyl hexosamines. Hexosaminidase A is a heterodimer composed of an alpha subunit (this protein) and a beta
HEXB
Beta-hexosaminidase subunit beta is an enzyme that in humans is encoded by the HEXB gene.-Further reading:...
subunit. The alpha subunit polypeptide is encoded by the HEXA gene while the beta subunit is encoded by the HEXB
HEXB
Beta-hexosaminidase subunit beta is an enzyme that in humans is encoded by the HEXB gene.-Further reading:...
gene. Gene mutations in the gene encoding the beta subunit (HEXB) often result in Sandhoff disease
Sandhoff disease
Sandhoff disease, also known as Sandhoff-Jatzkewitz disease, variant 0 of GM2-Gangliosidosis or Hexosaminidase A and B deficiency, is a lysosomal genetic, lipid storage disorder caused by the inherited deficiency to create functional beta-hexosaminidases A and B...
; whereas, mutations in the gene encoding the alpha subunit (HEXA, this gene) decrease the hydrolysis
Hydrolysis
Hydrolysis is a chemical reaction during which molecules of water are split into hydrogen cations and hydroxide anions in the process of a chemical mechanism. It is the type of reaction that is used to break down certain polymers, especially those made by condensation polymerization...
of GM2 gangliosides, which is the main cause of Tay-Sachs disease
Tay-Sachs disease
Tay–Sachs disease is an autosomal recessive genetic disorder...
.
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, ArgArginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
-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
Glycine
Glycine is an organic compound with the formula NH2CH2COOH. Having a hydrogen substituent as its 'side chain', glycine is the smallest of the 20 amino acids commonly found in proteins. Its codons are GGU, GGC, GGA, GGG cf. the genetic code.Glycine is a colourless, sweet-tasting crystalline solid...
-280, Ser
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
-281, Glu
Glutamic acid
Glutamic acid is one of the 20 proteinogenic amino acids, and its codons are GAA and GAG. It is a non-essential amino acid. The carboxylate anions and salts of glutamic acid are known as glutamates...
-282, and Pro
Proline
Proline is an α-amino acid, one of the twenty DNA-encoded amino acids. Its codons are CCU, CCC, CCA, and CCG. It is not an essential amino acid, which means that the human body can synthesize it. It is unique among the 20 protein-forming amino acids in that the α-amino group is secondary...
-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.
Gene mutations resulting in Tay-Sachs Disease
There are numerous mutations that lead to hexosaminidase A deficiency including gene deletions, nonsense mutations, and missense mutations. Tay-Sachs disease occurs when hexosaminidase A loses its ability to function. People with Tay-Sachs disease are unable to remove the GalNAc residue from the GM2 ganglioside, and as a result, they end up storing 100 to 1000 times more GM2 gangliosides in the brain than the normal person. Over 100 different mutations have been discovered just in infantile cases of Tay-Sachs disease alone.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 to six years of age from aspiration and pneumonia
Pneumonia
Pneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
. Tay-Sachs causes cerebral degeneration and blindness. Patients also experience flaccid extremities and seizures. At this point in time, there has been no cure for Tay-Sachs disease, but there is a treatment through an injection of a molecular chaperone.