HEXA

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Hexosaminidase A (alpha polypeptide)
Protein HEXA PDB 2gjx.png
PDB rendering based on 2gjx.
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols HEXA ; TSD
External IDs OMIM606869 MGI96073 HomoloGene20146 ChEMBL: 1250415 GeneCards: HEXA Gene
EC number 3.2.1.52
Orthologs
Species Human Mouse
Entrez 3073 15211
Ensembl ENSG00000213614 ENSMUSG00000025232
UniProt P06865 P29416
RefSeq (mRNA) NM_000520 NM_010421
RefSeq (protein) NP_000511 NP_034551
Location (UCSC) Chr 15:
72.64 – 72.67 Mb
Chr 9:
59.54 – 59.57 Mb
PubMed search [1] [2]

Hexosaminidase A (alpha polypeptide), also known as HEXA, is an enzyme that in humans is encoded by the HEXA gene, located on the 15th chromosome.[1][2]

Hexosaminidase A and the cofactor GM2 activator protein catalyze the degradation of the GM2 gangliosides and other molecules containing terminal N-acetyl hexosamines.[3] 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.[4]

Function[edit]

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.[5]

Gene mutations resulting in Tay–Sachs disease[edit]

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.[6]

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.[7]

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. There is no cure for Tay–Sachs disease.[6]

References[edit]

  1. ^ Korneluk RG, Mahuran DJ, Neote K, Klavins MH, O'Dowd BF, Tropak M, Willard HF, Anderson MJ, Lowden JA, Gravel RA (June 1986). "Isolation of cDNA clones coding for the alpha-subunit of human beta-hexosaminidase. Extensive homology between the alpha- and beta-subunits and studies on Tay-Sachs disease". J. Biol. Chem. 261 (18): 8407–13. PMID 3013851. 
  2. ^ Proia RL, Soravia E (April 1987). "Organization of the gene encoding the human beta-hexosaminidase alpha-chain". J. Biol. Chem. 262 (12): 5677–81. PMID 2952641. 
  3. ^ Knapp S, Vocadlo D, Gao Z, Kirk B, Lou J, Withers SG (1996). "NAG-thiazoline, an N-acetylbeta-hexosaminidase inhibitor that implicates acetamido participation". J. Am. Chem. Soc. 118 (28): 6804–6805. doi:10.1021/ja960826u. 
  4. ^ Mark BL, Mahuran DJ, Cherney MM, Zhao D, Knapp S, James MN (April 2003). "Crystal Structure of Human β-Hexosaminidase B: Understanding the Molecular Basis of Sandhoff and Tay–Sachs Disease". J. Mol. Biol. 327 (5): 1093–109. doi:10.1016/S0022-2836(03)00216-X. PMC 2910754. PMID 12662933. 
  5. ^ Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN (June 2006). "Crystallographic Structure of Human β-Hexosaminidase A: Interpretation of Tay-Sachs Mutations and Loss of GM2 Ganglioside Hydrolysis". J. Mol. Biol. 359 (4): 913–29. doi:10.1016/j.jmb.2006.04.004. PMC 2910082. PMID 16698036. 
  6. ^ a b Ozand PT, Nyhan WL, Barshop BA (2005). "Part Thirteen Lipid Storage Disorders: Tay-Sachs disease/hexosaminidase A deficiency". Atlas of metabolic diseases. London: Hodder Arnold. p. 539–546. ISBN 0-340-80970-1. 
  7. ^ Boles, Debra J. and Richard L. Proia (1995). "The molecular basis of HEXA mRNA deficiency caused by the most common Tay-Sachs disease mutation". Am. J. Hum. Genet. 56 (3): 716–724. PMC 1801160. PMID 7887427. 

Further reading[edit]

External links[edit]