HEXB

HEXB
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1NOU, 1NOW, 1NP0, 1O7A, 2GJX, 2GK1, 3LMY, 5BRO
Identifikatori
Aliasi	HEXB
Vanjski ID-jevi	OMIM: 606873 MGI: 96074 HomoloGene: 437 GeneCards: HEXB
Lokacija gena (čovjek)
Hrom.	Hromosom 5 (čovjek)
Kraj	74,722,647 bp
Lokacija gena (miš)
Hrom.	Hromosom 13 (miš)
Kraj	97,334,865 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• acetylglucosaminyltransferase activity; • hydrolase activity, hydrolyzing O-glycosyl compounds; • protein homodimerization activity; • hydrolase activity, acting on glycosyl bonds; • beta-N-acetylhexosaminidase activity; • protein heterodimerization activity; • hydrolase activity; • N-acetyl-beta-D-galactosaminidase activity; • GO:0001948, GO:0016582 vezivanje za proteine;
Ćelijska komponenta	• membrana; • azurophil granule; • Akrozom; • lysosomal lumen; • Lizozom; • Egzosom; • extracellular region; • Vanćelijsko; • azurophil granule lumen;
Biološki proces	• skeletal system development; • hyaluronan catabolic process; • spolno razmnožavanje; • glycosphingolipid metabolic process; • locomotory behavior; • neuromuscular process controlling balance; • astrocyte cell migration; • lipid storage; • cellular calcium ion homeostasis; • sluh; • regulation of cellular metabolic process; • single fertilization; • Ovogeneza; • neuromuscular process; • male courtship behavior; • keratan sulfate catabolic process; • regulation of cell shape; • phospholipid biosynthetic process; • chondroitin sulfate catabolic process; • myelination; • oligosaccharide catabolic process; • metabolizam; • lysosome organization; • penetration of zona pellucida; • ganglioside catabolic process; • GO:0003257, GO:0010735, GO:1901228, GO:1900622, GO:1904488 positive regulation of transcription by RNA polymerase II; • glycosaminoglycan metabolic process; • neutrophil degranulation; • carbohydrate metabolic process;
	Izvori:Amigo / QuickGO
Ortolozi
	3074
	15212
	ENSG00000049860
	ENSMUSG00000021665
	P07686
	P20060
	NM_001292004; NM_000521
	NM_010422
	NP_000512; NP_001278933
	NP_034552
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Podjedinica beta beta-heksozaminidaze jest enzim koji je kod ljudi kodiran genom HEXB sa hromosoma 5.^[5]^[6]^[7]

Heksosaminidaza B je beta podjedinica lizosomskog enzima beta-heksozaminidaze, koja zajedno s proteinom aktivatorom kofaktora GM2 katalizira razgradnju gangliozida GM2 i drugih molekula koje sadrže terminalne N-acetil heksozamine. Beta-heksozaminidaza sastoji se od dvije podjedinice, alfa i beta, koje su kodirane posebnim genima. I beta-heksozaminidaza alfa i beta podjedinice su članovi porodice 20 glikozil-hidrolaza. Mutacije u genima podjedinica alfa ili beta dovode do nakupljanja GM2 gangliozida u neuronima i neurodegenerativnih poremećaja koji se nazivaju GM2 gangliozidoze. Mutacije gena beta podjedinice dovode do Sandhoffove bolesti (GM2-gangliosidoza tip II).^[7]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 556 aminokiselina, а molekulska težina 63.111 Da.^[8]

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

10	20	30	40	50
MELCGLGLPR	PPMLLALLLA	TLLAAMLALL	TQVALVVQVA	EAARAPSVSA
KPGPALWPLP	LSVKMTPNLL	HLAPENFYIS	HSPNSTAGPS	CTLLEEAFRR
YHGYIFGFYK	WHHEPAEFQA	KTQVQQLLVS	ITLQSECDAF	PNISSDESYT
LLVKEPVAVL	KANRVWGALR	GLETFSQLVY	QDSYGTFTIN	ESTIIDSPRF
SHRGILIDTS	RHYLPVKIIL	KTLDAMAFNK	FNVLHWHIVD	DQSFPYQSIT
FPELSNKGSY	SLSHVYTPND	VRMVIEYARL	RGIRVLPEFD	TPGHTLSWGK
GQKDLLTPCY	SRQNKLDSFG	PINPTLNTTY	SFLTTFFKEI	SEVFPDQFIH
LGGDEVEFKC	WESNPKIQDF	MRQKGFGTDF	KKLESFYIQK	VLDIIATINK
GSIVWQEVFD	DKAKLAPGTI	VEVWKDSAYP	EELSRVTASG	FPVILSAPWY
LDLISYGQDW	RKYYKVEPLD	FGGTQKQKQL	FIGGEACLWG	EYVDATNLTP
RLWPRASAVG	ERLWSSKDVR	DMDDAYDRLT	RHRCRMVERG	IAAQPLYAGY
CNHENM

Struktura

Gen

Gen HEXB nalazi se na hromosomu 5, na lokaciji 5q13.3 i sastoji se od 15 egzona, u rasponu od 35–40 kb.

Protein

HEXB se sastoji od 556 aminokiselinskih ostataka i teži 63.111 Da.

Funkcija

HEXB je jedna od dvije podjedinice koje tvore β-heksozaminidazu koja funkcionira kao glikozil-hidrolaza zauklanjamje [β-vezane nesreducirajuće-terminalnih GalNAc ili GlcNAc ostataka u lizosomu.^[9] Nemogućnost HEXB-a dovesti će do defekta beta-heksozaminidaze i rezultirati grupom recesivnih poremećaja zvanih GM2 gangliozidoza, koje karakterizira nakupljanje GM2 gangliozida.^[10]

Klinički značaj

Genetički nedostaci u HEXB mogu rezultirati nakupljanjem GM2 gangliozida u neuronskim tkivima i dvije od tri bolesti lizosomskog skladištenja zajedno poznate kao GM2 gangliozidoza, od kojih je Sandhoffova bolest (defekti u podjedinici β) najbolje proučavan.^[9] Pacijenti imaju neurosomatske manifestacije. Terapijski učinci transdukcije gena podjedinice Hex ispitani su na mišjim modelima Sandhoffove bolesti.^[11] Intracerebroventrikulomska primjena modificirane β-heksozaminidaze B miševima u Sandhoff načinu rada obnovila je aktivnost β-heksozaminidaze u mozgu i smanjila skladištenje gangliozida GM2 u parenhimu.^[12]

Interakcije

Utvrđeno je da HEXB stupa u interakciju sa HEXA^[13] i gangliozidima.^[11]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000049860 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000021665 - 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.
^ O'Dowd BF, Quan F, Willard HF, Lamhonwah AM, Korneluk RG, Lowden JA, Gravel RA, Mahuran DJ (februar 1985). "Isolation of cDNA clones coding for the beta subunit of human beta-hexosaminidase". Proceedings of the National Academy of Sciences of the United States of America. 82 (4): 1184–8. doi:10.1073/pnas.82.4.1184. PMC 397219. PMID 2579389.
^ 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. doi:10.1016/S0021-9258(19)83927-3. PMID 3013851.
^ ^a ^b "Entrez Gene: HEXB hexosaminidase B (beta polypeptide)".
^ "UniProt, P07686" (jezik: engleski). Pristupljeno 15. 10. 2021.
^ ^a ^b Bateman KS, Cherney MM, Mahuran DJ, Tropak M, James MN (mart 2011). "Crystal structure of β-hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone". Journal of Medicinal Chemistry. 54 (5): 1421–9. doi:10.1021/jm101443u. PMC 3201983. PMID 21265544.
^ Sonnino S, Chigorno V (septembar 2000). "Ganglioside molecular species containing C18- and C20-sphingosine in mammalian nervous tissues and neuronal cell cultures". Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes. 1469 (2): 63–77. doi:10.1016/s0005-2736(00)00210-8. PMID 10998569.
^ ^a ^b Itakura T, Kuroki A, Ishibashi Y, Tsuji D, Kawashita E, Higashine Y, Sakuraba H, Yamanaka S, Itoh K (august 2006). "Inefficiency in GM2 ganglioside elimination by human lysosomal beta-hexosaminidase beta-subunit gene transfer to fibroblastic cell line derived from Sandhoff disease model mice". Biological & Pharmaceutical Bulletin. 29 (8): 1564–9. doi:10.1248/bpb.29.1564. PMID 16880605.
^ Matsuoka K, Tamura T, Tsuji D, Dohzono Y, Kitakaze K, Ohno K, Saito S, Sakuraba H, Itoh K (juni 2011). "Therapeutic potential of intracerebroventricular replacement of modified human β-hexosaminidase B for GM2 gangliosidosis". Molecular Therapy. 19 (6): 1017–24. doi:10.1038/mt.2011.27. PMC 3129794. PMID 21487393.
^ Gort L, de Olano N, Macías-Vidal J, Coll MA (septembar 2012). "GM2 gangliosidoses in Spain: analysis of the HEXA and HEXB genes in 34 Tay–Sachs and 14 Sandhoff patients". Gene. 506 (1): 25–30. doi:10.1016/j.gene.2012.06.080. PMID 22789865.

Dopunska literatura

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.
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.
McInnes B, Potier M, Wakamatsu N, Melancon SB, Klavins MH, Tsuji S, Mahuran DJ (august 1992). "An unusual splicing mutation in the HEXB gene is associated with dramatically different phenotypes in patients from different racial backgrounds". The Journal of Clinical Investigation. 90 (2): 306–14. doi:10.1172/JCI115863. PMC 443103. PMID 1386607.
Bolhuis PA, Bikker H (novembar 1992). "Deletion of the 5'-region in one or two alleles of HEXB in 15 out of 30 patients with Sandhoff disease". Human Genetics. 90 (3): 328–9. doi:10.1007/bf00220096. PMID 1487253. S2CID 219692.
Wakamatsu N, Kobayashi H, Miyatake T, Tsuji S (februar 1992). "A novel exon mutation in the human beta-hexosaminidase beta subunit gene affects 3' splice site selection". The Journal of Biological Chemistry. 267 (4): 2406–13. doi:10.1016/S0021-9258(18)45894-2. PMID 1531140.
Banerjee P, Siciliano L, Oliveri D, McCabe NR, Boyers MJ, Horwitz AL, Li SC, Dawson G (novembar 1991). "Molecular basis of an adult form of beta-hexosaminidase B deficiency with motor neuron disease". Biochemical and Biophysical Research Communications. 181 (1): 108–15. doi:10.1016/S0006-291X(05)81388-9. PMID 1720305.
Boose JA, Tifft CJ, Proia RL, Myerowitz R (novembar 1990). "Synthesis of a human lysosomal enzyme, beta-hexosaminidase B, using the baculovirus expression system". Protein Expression and Purification. 1 (2): 111–20. doi:10.1016/1046-5928(90)90003-H. PMID 1967020.
Mahuran DJ (april 1990). "Characterization of human placental beta-hexosaminidase I2. Proteolytic processing intermediates of hexosaminidase A". The Journal of Biological Chemistry. 265 (12): 6794–9. doi:10.1016/S0021-9258(19)39219-1. PMID 2139028.
Neote K, McInnes B, Mahuran DJ, Gravel RA (novembar 1990). "Structure and distribution of an Alu-type deletion mutation in Sandhoff disease". The Journal of Clinical Investigation. 86 (5): 1524–31. doi:10.1172/JCI114871. PMC 296899. PMID 2147027.
Neote K, Brown CA, Mahuran DJ, Gravel RA (decembar 1990). "Translation initiation in the HEXB gene encoding the beta-subunit of human beta-hexosaminidase". The Journal of Biological Chemistry. 265 (34): 20799–806. doi:10.1016/S0021-9258(17)45286-0. PMID 2147427.
Dlott B, d'Azzo A, Quon DV, Neufeld EF (oktobar 1990). "Two mutations produce intron insertion in mRNA and elongated beta-subunit of human beta-hexosaminidase". The Journal of Biological Chemistry. 265 (29): 17921–7. doi:10.1016/S0021-9258(18)38251-6. PMID 2170400.
Nakano T, Suzuki K (mart 1989). "Genetic cause of a juvenile form of Sandhoff disease. Abnormal splicing of beta-hexosaminidase beta chain gene transcript due to a point mutation within intron 12". The Journal of Biological Chemistry. 264 (9): 5155–8. doi:10.1016/S0021-9258(18)83712-7. PMID 2522450.
Hubbes M, Callahan J, Gravel R, Mahuran D (juni 1989). "The amino-terminal sequences in the pro-alpha and -beta polypeptides of human lysosomal beta-hexosaminidase A and B are retained in the mature isozymes". FEBS Letters. 249 (2): 316–20. doi:10.1016/0014-5793(89)80649-0. PMID 2525487. S2CID 83872800.
Bikker H, van den Berg FM, Wolterman RA, de Vijlder JJ, Bolhuis PA (februar 1989). "Demonstration of a Sandhoff disease-associated autosomal 50-kb deletion by field inversion gel electrophoresis". Human Genetics. 81 (3): 287–8. doi:10.1007/BF00279006. PMID 2921040. S2CID 39411971.
Bolhuis PA, Oonk JG, Kamp PE, Ris AJ, Michalski JC, Overdijk B, Reuser AJ (januar 1987). "Ganglioside storage, hexosaminidase lability, and urinary oligosaccharides in adult Sandhoff's disease". Neurology. 37 (1): 75–81. doi:10.1212/wnl.37.1.75. PMID 2948136. S2CID 20622020.
Proia RL (mart 1988). "Gene encoding the human beta-hexosaminidase beta chain: extensive homology of intron placement in the alpha- and beta-chain genes". Proceedings of the National Academy of Sciences of the United States of America. 85 (6): 1883–7. doi:10.1073/pnas.85.6.1883. PMC 279885. PMID 2964638.
Mahuran DJ, Neote K, Klavins MH, Leung A, Gravel RA (april 1988). "Proteolytic processing of pro-alpha and pro-beta precursors from human beta-hexosaminidase. Generation of the mature alpha and beta a beta b subunits". The Journal of Biological Chemistry. 263 (10): 4612–8. doi:10.1016/S0021-9258(18)68826-X. PMID 2965147.

Vanjski linkovi

Šablon:Proteases Šablon:Carbon-nitrogen non-peptide hydrolases Šablon:Acid anhydride hydrolases Šablon:Carbon-carbon hydrolases

Šablon:Enzimi glikolipidnog/sfingolipidnog metabolizma

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000049860 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000021665 - 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.

[pmid2579389-5] O'Dowd BF, Quan F, Willard HF, Lamhonwah AM, Korneluk RG, Lowden JA, Gravel RA, Mahuran DJ (februar 1985). "Isolation of cDNA clones coding for the beta subunit of human beta-hexosaminidase". Proceedings of the National Academy of Sciences of the United States of America. 82 (4): 1184–8. doi:10.1073/pnas.82.4.1184. PMC 397219. PMID 2579389.

[pmid3013851-6] 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. doi:10.1016/S0021-9258(19)83927-3. PMID 3013851.

[entrez-7] "Entrez Gene: HEXB hexosaminidase B (beta polypeptide)".

[UniProt-8] "UniProt, P07686" (jezik: engleski). Pristupljeno 15. 10. 2021.

[Bateman_2011-9] Bateman KS, Cherney MM, Mahuran DJ, Tropak M, James MN (mart 2011). "Crystal structure of β-hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone". Journal of Medicinal Chemistry. 54 (5): 1421–9. doi:10.1021/jm101443u. PMC 3201983. PMID 21265544.

[10] Sonnino S, Chigorno V (septembar 2000). "Ganglioside molecular species containing C18- and C20-sphingosine in mammalian nervous tissues and neuronal cell cultures". Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes. 1469 (2): 63–77. doi:10.1016/s0005-2736(00)00210-8. PMID 10998569.

[Itakura_2006-11] Itakura T, Kuroki A, Ishibashi Y, Tsuji D, Kawashita E, Higashine Y, Sakuraba H, Yamanaka S, Itoh K (august 2006). "Inefficiency in GM2 ganglioside elimination by human lysosomal beta-hexosaminidase beta-subunit gene transfer to fibroblastic cell line derived from Sandhoff disease model mice". Biological & Pharmaceutical Bulletin. 29 (8): 1564–9. doi:10.1248/bpb.29.1564. PMID 16880605.

[12] Matsuoka K, Tamura T, Tsuji D, Dohzono Y, Kitakaze K, Ohno K, Saito S, Sakuraba H, Itoh K (juni 2011). "Therapeutic potential of intracerebroventricular replacement of modified human β-hexosaminidase B for GM2 gangliosidosis". Molecular Therapy. 19 (6): 1017–24. doi:10.1038/mt.2011.27. PMC 3129794. PMID 21487393.

[13] Gort L, de Olano N, Macías-Vidal J, Coll MA (septembar 2012). "GM2 gangliosidoses in Spain: analysis of the HEXA and HEXB genes in 34 Tay–Sachs and 14 Sandhoff patients". Gene. 506 (1): 25–30. doi:10.1016/j.gene.2012.06.080. PMID 22789865.

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p r u Hydrolases: ether bond (EC 3.3)
3.3.1	Adenosylhomocysteinase
3.3.2	Epoxide hydrolase Leukotriene-A4 hydrolase

p r u Enzimi
Teme	Aktivno mjesto Alosterna regulacija Difuzijski limitirani enzim EC broj Enzimska kataliza Inhibicija enzimskih reakcija Kinetika enzima Koenzim Kooperativnost Lineweaver–Burkov dijagram Michaelis–Mentenova kinetika Mjesto vezanja Spisak enzima
Tipovi	EC1 Oksidoreduktaze/spisak EC2 Transferaze/spisak EC3 Hidrolaze/spisak EC4 Lijaze/spisak EC5 Izomeraze/spisak EC6 Ligaze/spisak