HEXA Knowpia

HEXA
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	2GJX, 2GK1
Identifiers
Aliases	HEXA, TSD, hexosaminidase subunit alpha
External IDs	OMIM: 606869 MGI: 96073 HomoloGene: 20146 GeneCards: HEXA
Gene location (Human)
Chr.	Chromosome 15 (human)
End	72,376,420 bp
Gene location (Mouse)
Chr.	Chromosome 9 (mouse)
End	59,472,392 bp
RNA expression pattern
	Top expressed in
	gallbladder; ; stromal cell of endometrium; ; left lobe of thyroid gland; ; right coronary artery; ; right lobe of thyroid gland; ; left adrenal gland; ; right uterine tube; ; right lung; ; rectum; ; upper lobe of left lung;
	Top expressed in
	calvaria; ; body of femur; ; iris; ; aortic valve; ; crypt of lieberkuhn of small intestine; ; ascending aorta; ; ciliary body; ; islet of Langerhans; ; Paneth cell; ; utricle;
	More reference expression data
	n/a
Gene ontology
Molecular function	acetylglucosaminyltransferase activity; protein heterodimerization activity; hydrolase activity, hydrolyzing O-glycosyl compounds; hydrolase activity; hydrolase activity, acting on glycosyl bonds; beta-N-acetylhexosaminidase activity; N-acetyl-beta-D-galactosaminidase activity; protein binding;
Cellular component	extracellular exosome; membrane; lysosome; lysosomal lumen; azurophil granule;
Biological process	hyaluronan catabolic process; glycosaminoglycan biosynthetic process; metabolism; glycosphingolipid metabolic process; chondroitin sulfate catabolic process; keratan sulfate catabolic process; carbohydrate metabolic process;
	Sources:Amigo / QuickGO
Orthologs
	3073
	15211
	ENSG00000213614
	ENSMUSG00000025232
	P06865
	P29416
	NM_000520; NM_001318825
	NM_010421
	NP_000511; NP_001305754
	NP_034551
	Wikidata
View/Edit Human	View/Edit Mouse

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.^[5]^[6]

Hexosaminidase A and the cofactor G_M2 activator protein catalyze the degradation of the G_M2 gangliosides and other molecules containing terminal N-acetyl hexosamines.^[7] 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 G_M2 gangliosides, which is the main cause of Tay–Sachs disease.^[8]

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 G_M2 gangliosides. The alpha subunit contains a key residue, Arg-424, which is essential for binding the N-acetyl-neuraminic residue of G_M2 gangliosides. The alpha subunit can hydrolyze G_M2 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 G_M2 activator protein (G_M2AP) 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 G_M2 gangliosides into G_M3 gangliosides by removing the N-acetylgalactosamine (GalNAc) residue from G_M2 gangliosides.^[9]

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 G_M2 ganglioside, and as a result, they end up storing 100 to 1000 times more G_M2 gangliosides in the brain than the normal person. Over 100 different mutations have been discovered just in infantile cases of Tay–Sachs disease alone.^[10]

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.^[11]

Children born with Tay–Sachs usually die between two and 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.^[10]

Gene therapies for Tay-Sachs edit

The HEXA gene is a protein encoding gene that codes for the lysosomal enzyme beta-hexosaminidase. This enzyme, combined with the GM2 activator protein, is responsible for the breakdown of ganglioside GM2 within the lysosome. Defects in the HEXA gene, however, prevent this degradation, leading to a buildup of toxins in brain and spinal cord cells. This fatal genetic disorder is called Tay-Sachs disease. Because the Tay-Sachs gene defect mainly affects neural cells, a patient with the HEXA mutation will experience a quick deterioration of motor and mental function before dying around the age of three or four.^{[citation needed]}

A “knockout” model, which is a mouse that has been genetically modified to observe the effects of inactivation of or damage to certain genes, found that the mice that were administered the HEXA gene experienced many of the same symptoms of Tay-Sachs, with one exception: GM2 buildup was distributed differently in the brains of the mice than in those of a typical human Tay-Sachs patient. ^{[citation needed]} This model has allowed scientists to research gene therapies for HEXA defects. One study, done on mice, successfully reestablished beta-hexoaminidase levels and removed the toxic cell buildup by using a non-replicated Herpes simplex vector to code for the missing gene.^{[citation needed]}

References edit

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000213614 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000025232 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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". The Journal of Biological Chemistry. 261 (18): 8407–13. doi:10.1016/S0021-9258(19)83927-3. PMID 3013851.
^ Proia RL, Soravia E (April 1987). "Organization of the gene encoding the human beta-hexosaminidase alpha-chain". The Journal of Biological Chemistry. 262 (12): 5677–81. doi:10.1016/S0021-9258(18)45628-1. PMID 2952641.
^ 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.
^ Mark BL, Mahuran DJ, Cherney MM, Zhao D, Knapp S, James MN (April 2003). "Crystal structure of human beta-hexosaminidase B: understanding the molecular basis of Sandhoff and Tay-Sachs disease". Journal of Molecular Biology. 327 (5): 1093–109. doi:10.1016/S0022-2836(03)00216-X. PMC 2910754. PMID 12662933.
^ Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN (June 2006). "Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis". Journal of Molecular Biology. 359 (4): 913–29. doi:10.1016/j.jmb.2006.04.004. PMC 2910082. PMID 16698036.
^ ^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. pp. 539–546. ISBN 0-340-80970-1.
^ Boles DJ, Proia RL (March 1995). "The molecular basis of HEXA mRNA deficiency caused by the most common Tay-Sachs disease mutation". American Journal of Human Genetics. 56 (3): 716–24. PMC 1801160. PMID 7887427.