HEXA

Heksozaminidaza A (alfa polipeptid), znana i kao HEXA, jest enzim koji je kod ljudi kodiran genom HEXA, na hromosomu 15.^[5][6]

HEXA
Dostupne strukture PDB Pretraga ortologa: PDBe RCSB Spisak PDB ID kodova 2GJX, 2GK1
Identifikatori
Aliasi	HEXA
Vanjski ID-jevi	OMIM: 606869 MGI: 96073 HomoloGene: 20146 GeneCards: HEXA
Lokacija gena (čovjek) Hrom. Hromosom 15 (čovjek)[1] Bend 15q23 Početak 72,340,924 bp[1] Kraj 72,376,420 bp[1]
Lokacija gena (miš) Hrom. Hromosom 9 (miš)[2] Bend 9 B|9 32.02 cM Početak 59,446,823 bp[2] Kraj 59,472,392 bp[2]
Ontologija gena Molekularna funkcija • 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 • GO:0001948, GO:0016582 vezivanje za proteine Ćelijska komponenta • Egzosom • membrana • Lizozom • lysosomal lumen • azurophil granule Biološki proces • hyaluronan catabolic process • glycosaminoglycan biosynthetic process • metabolizam • glycosphingolipid metabolic process • chondroitin sulfate catabolic process • keratan sulfate catabolic process • carbohydrate metabolic process Izvori:Amigo / QuickGO
Ortolozi
Vrste	Čovjek	Miš
Entrez	3073	15211
Ensembl	ENSG00000213614	ENSMUSG00000025232
UniProt	P06865	P29416
RefSeq (mRNK)	NM_000520 NM_001318825	NM_010421
RefSeq (bjelančevina)	NP_000511 NP_001305754	NP_034551
Lokacija (UCSC)	Chr 15: 72.34 – 72.38 Mb	Chr 9: 59.45 – 59.47 Mb
PubMed pretraga	[3]	[4]
Wikipodaci
Pogledaj/uredi – čovjek Pogledaj/uredi – miš

Gen HEXA nalazi se na dugom (q) kraku hromosoma 15 na poziciji q24.1.

Heksaozaminidaza A i kofaktor G_M2 proteinski aktivator katalizirati razgradnju G_M2 gangliozida i drugih molekula koje sadrže terminalne N-acetil heksozamine.^[7] Heksozaminidaza A je heterodimer sastavljen od alfa podjedinice (ovaj protein) i beta podjedinice. Polipeptid alfa podjedinice kodiran je genom HEXA, dok je beta podjedinica kodirana genom HEXB . Genske mutacije u genu koji kodira beta podjedinicu (HEXB) često rezultiraju Sandhoffovom bolešću; budući da, mutacije u genu koji kodira alfa podjedinicu (HEXA, ovaj gen) smanjuju hidrolizu G_M2 gangliozida, što je glavni uzrok Tay–Sachsove bolesti.^[8]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 529 aminokiselina, a molekulska težina 60.703 Da.^[9].

10		20		30		40		50
MTSSRLWFSL		LLAAAFAGRA		TALWPWPQNF		QTSDQRYVLY		PNNFQFQYDV
SSAAQPGCSV		LDEAFQRYRD		LLFGSGSWPR		PYLTGKRHTL		EKNVLVVSVV
TPGCNQLPTL		ESVENYTLTI		NDDQCLLLSE		TVWGALRGLE		TFSQLVWKSA
EGTFFINKTE		IEDFPRFPHR		GLLLDTSRHY		LPLSSILDTL		DVMAYNKLNV
FHWHLVDDPS		FPYESFTFPE		LMRKGSYNPV		THIYTAQDVK		EVIEYARLRG
IRVLAEFDTP		GHTLSWGPGI		PGLLTPCYSG		SEPSGTFGPV		NPSLNNTYEF
MSTFFLEVSS		VFPDFYLHLG		GDEVDFTCWK		SNPEIQDFMR		KKGFGEDFKQ
LESFYIQTLL		DIVSSYGKGY		VVWQEVFDNK		VKIQPDTIIQ		VWREDIPVNY
MKELELVTKA		GFRALLSAPW		YLNRISYGPD		WKDFYIVEPL		AFEGTPEQKA
LVIGGEACMW		GEYVDNTNLV		PRLWPRAGAV		AERLWSNKLT		SDLTFAYERL
SHFRCELLRR		GVQAQPLNVG		FCEQEFEQT

Simboli

C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin

Funkcija

Iako alfa i beta podjedinice heksozaminidaze A mogu obje cijepiti ostatke GalNAc, samo alfa podjedinica je u stanju da hidrolizira G_M2 gangliozide. Alfa podjedinica sadrži ključni ostatak, Arg-424, što je neophodno za vezivanje N-acetil-neuraminskog ostatka G_M2 gangliozida. Alfa podjedinica može hidrolizirati G_M2 gangliozide jer sadrži strukturu petlje koja se sastoji od aminokiselina: Gly-280, Ser-281, Glu-282 i Pro-283. Beta podjedinica nema petlju, ali služi kao idealna struktura za vezivanje proteina aktivatora G_M2 (G_M2AP) u alfa podjedinici. Kombinacija Arg-424 i aminokiselina koje uzrokuju stvaranje petlje omogućavaju alfa podjedinici da hidrolizuje G_M2 gangliozide u G_M3 gangliozide, uklanjanjem N-acetilgalaktozaminskih (GalNAc) ostataka iz G_M2 gangliozida.^[10]

Genske mutacije koje uzrokuju Tay–Sachsovu bolest

Brojne su mutacije koje dovode do nedostatka heksosaminidaze A, uključujući delexciju gena, nonsens i misens mutacije. Tay–Sachsova bolest nastaje kada heksosaminidaza A izgubi sposobnost funkcioniranja. Osobe s Tay–Sachsovom bolešću nisu u stanju ukloniti ostatke GalNAc iz G_M2 gangliozida, a kao rezultat toga na kraju skladište 100 do 1.000 puta više gangzioda G_M2 u mozgu od normalne osobe. Preko 100 različitih mutacija otkriveno je samo u dojenačkim slučajevima samo Tay–Sachsove bolesti.^[11]

Najčešća mutacija, koja se javlja kod preko 80 % pacijenata sa Tay–Sachsovom bolešću, posljedica je dodavanja četiri para baza (TATC) u egzonu 11 gena Hex A. Ova insercija dovodi do ranog stop kodona, što uzrokuje nedostatak hex A.^[12]

Djeca rođena s Tay–Sachsvom bolešću obično umiru između dvije i šest godina, od aspiracije i upale pluća. Tay–Sachsova bolest uzrokuje cerebralnu degeneraciju i sljepoću. Pacijenti također imaju mlitave ekstremitete i napade. Još ne postoji lijek za ovu bolest.^[11]

Genske terapije za Tay-Sachsovu bolest

Gen HEXA je gen koji kodira protein za lizosomski enzim beta-heksosaminidazu. Ovaj enzim, u kombinaciji s GM2 proteinskim aktivatorom, odgovoran je za razgradnju gangliozida GM2 unutar lizosoma. Defekti gena HEXA, međutim, sprečavaju ovu degradaciju, što dovodi do nakupljanja toksina u ćelijama mozga i kičmene moždine. Ovaj fatalni genetički poremećaj naziva se Tay-Sachsova bolest. Budući da defekt odgovsrsjućrg gena uglavnom pogađa živčane ćelije, pacijent s mutacijom HEXA doživjet će brzo pogoršanje motorne i mentalne funkcije prije nego što umre oko treće ili četvrte godine života.

Model nokaut-miša, koji je genetički modificiran kako bi se promatrali efekti inaktivacije ili oštećenja određenih gena, otkrio je da su miševi kojima je primijenjen HEXA gen imali mnoge iste simptome Tay-Sachsove bolesti, uz jedan izuzetak: nakupljanje GM2 distribuirano je drugačije u mozgu miševa nego u mozgu tiskog ljudskog Tay-Sachsovog pacijenta. Ovaj model omogućio je istraživnje genske terapije za HEXA defekte. Jedna studija, rađena na miševima, uspješno je ponovo uspostavila nivo beta-heksoaminidaze i uklonila nakupljanje toksičnih ćelija, upotrebom nerepliciranog Herpes simplex vektora za kodiranje gena koji nedostaje.

Reference

1. GRCh38: Ensembl release 89: ENSG00000213614 - Ensembl, maj 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000025232 - Ensembl, maj 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. Korneluk RG, Mahuran DJ, Neote K, Klavins MH, O'Dowd BF, Tropak M, Willard HF, Anderson MJ, Lowden JA, Gravel RA (juni 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. PMID 3013851.
6. 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. PMID 2952641.
7. 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.
8. 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.
9. "UniProt, P06865". Pristupljeno 14. 7. 2021.
10. Lemieux MJ, Mark BL, Cherney MM, Withers SG, Mahuran DJ, James MN (juni 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.
11. 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. str. 539–546. ISBN 0-340-80970-1.
12. Boles DJ, Proia RL (mart 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.

Dopunska literatura

• Taniike, Masako; Yamanaka, Shoji; Proia, Richard L.; Langaman, Clarita; Bone-Turrentine, Teresa; Suzuki, Kinuko (1995). "Neuropathology of mice with targeted disruption of Hexa gene, a model of Tay-Sachs disease". Acta Neuropathologica. 89 (4): 296–304. doi:10.1007/s004010050250. PMID 7610760.
• Martino S, Marconi P, Tancini B, Dolcetta D, De Angelis MG, Montanucci P, Bregola G, Sandhoff K, Bordignon C, Emiliani C, Manservigi R, Orlacchio A (august 2005). "A direct gene transfer strategy via brain internal capsule reverses the biochemical defect in Tay-Sachs disease". Human Molecular Genetics. 14 (15): 2113–23. doi:10.1093/hmg/ddi216. PMID 15961412.
• Mahuran DJ (februar 1991). "The biochemistry of HEXA and HEXB gene mutations causing GM2 gangliosidosis". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1096 (2): 87–94. doi:10.1016/0925-4439(91)90044-A. PMID 1825792.
• Myerowitz R (1997). "Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene". Human Mutation. 9 (3): 195–208. doi:10.1002/(SICI)1098-1004(1997)9:3<195::AID-HUMU1>3.0.CO;2-7. PMID 9090523.
• Mahuran DJ (oktobar 1999). "Biochemical consequences of mutations causing the GM2 gangliosidoses". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1455 (2–3): 105–38. doi:10.1016/S0925-4439(99)00074-5. PMID 10571007.
• Gilbert F, Kucherlapati R, Creagan RP, Murnane MJ, Darlington GJ, Ruddle FH (januar 1975). "Tay-Sachs' and Sandhoff's diseases: the assignment of genes for hexosaminidase A and B to individual human chromosomes". Proceedings of the National Academy of Sciences of the United States of America. 72 (1): 263–7. doi:10.1073/pnas.72.1.263. PMC 432284. PMID 1054503.
• Trop I, Kaplan F, Brown C, Mahuran D, Hechtman P (1993). "A glycine250--> aspartate substitution in the alpha-subunit of hexosaminidase A causes juvenile-onset Tay-Sachs disease in a Lebanese-Canadian family". Human Mutation. 1 (1): 35–9. doi:10.1002/humu.1380010106. PMID 1301189.
• Akalin N, Shi HP, Vavougios G, Hechtman P, Lo W, Scriver CR, Mahuran D, Kaplan F (1993). "Novel Tay-Sachs disease mutations from China". Human Mutation. 1 (1): 40–6. doi:10.1002/humu.1380010107. PMID 1301190.
• Akerman BR, Zielenski J, Triggs-Raine BL, Prence EM, Natowicz MR, Lim-Steele JS, Kaback MM, Mules EH, Thomas GH, Clarke JT (1993). "A mutation common in non-Jewish Tay-Sachs disease: frequency and RNA studies". Human Mutation. 1 (4): 303–9. doi:10.1002/humu.1380010407. PMID 1301938.
• Fernandes M, Kaplan F, Natowicz M, Prence E, Kolodny E, Kaback M, Hechtman P (decembar 1992). "A new Tay-Sachs disease B1 allele in exon 7 in two compound heterozygotes each with a second novel mutation". Human Molecular Genetics. 1 (9): 759–61. doi:10.1093/hmg/1.9.759. PMID 1302612.
• McDowell GA, Mules EH, Fabacher P, Shapira E, Blitzer MG (novembar 1992). "The presence of two different infantile Tay-Sachs disease mutations in a Cajun population". American Journal of Human Genetics. 51 (5): 1071–7. PMC 1682822. PMID 1307230.
• Whitley CB, Anderson RA, McIvor RS (april 1992). "Heterozygosity for the "DN allele" (G533-greater than A) of the beta-hexosaminidase alpha subunit gene identified by direct DNA sequencing in a family with the B1 variant of GM2-gangliosidosis". Neuropediatrics. 23 (2): 96–101. doi:10.1055/s-2008-1071320. PMID 1318511.
• Triggs-Raine BL, Mules EH, Kaback MM, Lim-Steele JS, Dowling CE, Akerman BR, Natowicz MR, Grebner EE, Navon R, Welch JP (oktobar 1992). "A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: implications for carrier screening". American Journal of Human Genetics. 51 (4): 793–801. PMC 1682803. PMID 1384323.
• Hechtman P, Boulay B, De Braekeleer M, Andermann E, Melançon S, Larochelle J, Prevost C, Kaplan F (decembar 1992). "The intron 7 donor splice site transition: a second Tay-Sachs disease mutation in French Canada". Human Genetics. 90 (4): 402–6. doi:10.1007/bf00220467. PMID 1483696.
• Mules EH, Hayflick S, Miller CS, Reynolds LW, Thomas GH (april 1992). "Six novel deleterious and three neutral mutations in the gene encoding the alpha-subunit of hexosaminidase A in non-Jewish individuals". American Journal of Human Genetics. 50 (4): 834–41. PMC 1682641. PMID 1532289.
• Weitz G, Proia RL (maj 1992). "Analysis of the glycosylation and phosphorylation of the alpha-subunit of the lysosomal enzyme, beta-hexosaminidase A, by site-directed mutagenesis". The Journal of Biological Chemistry. 267 (14): 10039–44. PMID 1533633.
• Navon R, Proia RL (februar 1991). "Tay-Sachs disease in Moroccan Jews: deletion of a phenylalanine in the alpha-subunit of beta-hexosaminidase". American Journal of Human Genetics. 48 (2): 412–9. PMC 1683003. PMID 1825014.
• Mules EH, Dowling CE, Petersen MB, Kazazian HH, Thomas GH (juni 1991). "A novel mutation in the invariant AG of the acceptor splice site of intron 4 of the beta-hexosaminidase alpha-subunit gene in two unrelated American black GM2-gangliosidosis (Tay-Sachs disease) patients". American Journal of Human Genetics. 48 (6): 1181–5. PMC 1683116. PMID 1827945.
• Nakai H, Byers MG, Nowak NJ, Shows TB (1991). "Assignment of beta-hexosaminidase A alpha-subunit to human chromosomal region 15q23----q24". Cytogenetics and Cell Genetics. 56 (3–4): 164. doi:10.1159/000133077. PMID 1829032.
• Nishimoto J, Tanaka A, Nanba E, Suzuki K (august 1991). "Expression of the beta-hexosaminidase alpha subunit gene with the four-base insertion of infantile Jewish Tay-Sachs disease". The Journal of Biological Chemistry. 266 (22): 14306–9. PMID 1830584.
• dos Santos MR, Tanaka A, sá Miranda MC, Ribeiro MG, Maia M, Suzuki K (oktobar 1991). "GM2-gangliosidosis B1 variant: analysis of beta-hexosaminidase alpha gene mutations in 11 patients from a defined region in Portugal". American Journal of Human Genetics. 49 (4): 886–90. PMC 1683169. PMID 1832817.

Vanjski linkovi

• Hexosaminidase A na US National Library of Medicine Medical Subject Headings (MeSH)
• EC 3.2.1.52
• National Tay-Sach’s Disease Site