HEXA
![](http://upload.wikimedia.org/wikipedia/commons/thumb/b/b4/HEXA_location.png/220px-HEXA_location.png)
Heksozaminidaza A (alfa polipeptid), znana i kao HEXA, jest enzim koji je kod ljudi kodiran genom HEXA, na hromosomu 15.[5][6]
Heksaozaminidaza A i kofaktor GM2 proteinski aktivator katalizirati razgradnju GM2 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 GM2 gangliozida, što je glavni uzrok Tay–Sachsove bolesti.[8]
Aminokiselinska sekvenca
[uredi | uredi izvor]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
[uredi | uredi izvor]Iako alfa i beta podjedinice heksozaminidaze A mogu obje cijepiti ostatke GalNAc, samo alfa podjedinica je u stanju da hidrolizira GM2 gangliozide. Alfa podjedinica sadrži ključni ostatak, Arg-424, što je neophodno za vezivanje N-acetil-neuraminskog ostatka GM2 gangliozida. Alfa podjedinica može hidrolizirati GM2 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 GM2 (GM2AP) u alfa podjedinici. Kombinacija Arg-424 i aminokiselina koje uzrokuju stvaranje petlje omogućavaju alfa podjedinici da hidrolizuje GM2 gangliozide u GM3 gangliozide, uklanjanjem N-acetilgalaktozaminskih (GalNAc) ostataka iz GM2 gangliozida.[10]
Genske mutacije koje uzrokuju Tay–Sachsovu bolest
[uredi | uredi izvor]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 GM2 gangliozida, a kao rezultat toga na kraju skladište 100 do 1.000 puta više gangzioda GM2 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
[uredi | uredi izvor]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
[uredi | uredi izvor]- ^ a b c GRCh38: Ensembl release 89: ENSG00000213614 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000025232 - Ensembl, maj 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 (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.
- ^ 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.
- ^ 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.
- ^ "UniProt, P06865". Pristupljeno 14. 7. 2021.
- ^ 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.
- ^ 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. str. 539–546. ISBN 0-340-80970-1.
- ^ 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
[uredi | uredi izvor]- 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
[uredi | uredi izvor]- Hexosaminidase A na US National Library of Medicine Medical Subject Headings (MeSH)
- EC 3.2.1.52
- National Tay-Sach’s Disease Site