HBB

HBB
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	6HBW, 1A00, 1A01, 1A0U, 1A0Z, 1A3N, 1A3O, 1ABW, 1ABY, 1AJ9, 1B86, 1BAB, 1BBB, 1BIJ, 1BUW, 1BZ0, 1BZ1, 1BZZ, 1C7B, 1C7C, 1C7D, 1CBL, 1CBM, 1CH4, 1CLS, 1CMY, 1COH, 1DKE, 1DXT, 1DXU, 1DXV, 1FN3, 1G9V, 1GBU, 1GBV, 1GLI, 1GZX, 1HAB, 1HAC, 1HBA, 1HBB, 1HBS, 1HCO, 1HDB, 1HGA, 1HGB, 1HGC, 1HHO, 1IRD, 1J3Y, 1J3Z, 1J40, 1J41, 1J7S, 1J7W, 1J7Y, 1JY7, 1K0Y, 1K1K, 1KD2, 1LFL, 1LFQ, 1LFT, 1LFV, 1LFY, 1LFZ, 1LJW, 1M9P, 1MKO, 1NEJ, 1NIH, 1NQP, 1O1I, 1O1J, 1O1K, 1O1L, 1O1M, 1O1N, 1O1O, 1O1P, 1QI8, 1QSH, 1QSI, 1QXD, 1QXE, 1R1X, 1R1Y, 1RPS, 1RQ3, 1RQ4, 1RQA, 1RVW, 1SDK, 1SDL, 1THB, 1UIW, 1VWT, 1XXT, 1XY0, 1XYE, 1XZ2, 1XZ4, 1XZ5, 1XZ7, 1XZU, 1XZV, 1Y09, 1Y0A, 1Y0C, 1Y0D, 1Y0T, 1Y0W, 1Y22, 1Y2Z, 1Y31, 1Y35, 1Y45, 1Y46, 1Y4B, 1Y4F, 1Y4G, 1Y4P, 1Y4Q, 1Y4R, 1Y4V, 1Y5F, 1Y5J, 1Y5K, 1Y7C, 1Y7D, 1Y7G, 1Y7Z, 1Y83, 1Y85, 1Y8W, 1YDZ, 1YE0, 1YE1, 1YE2, 1YEN, 1YEO, 1YEQ, 1YEU, 1YEV, 1YFF, 1YG5, 1YGD, 1YGF, 1YH9, 1YHE, 1YHR, 1YIE, 1YIH, 1YVQ, 1YVT, 1YZI, 2D5Z, 2D60, 2DN1, 2DN2, 2DN3, 2DXM, 2H35, 2HBC, 2HBD, 2HBE, 2HBF, 2HBS, 2HCO, 2HHD, 2HHE, 2M6Z, 2W6V, 2W72, 2YRS, 3B75, 3D17, 3D7O, 3DUT, 3HXN, 3IC0, 3IC2, 3KMF, 3NL7, 3NMM, 3ODQ, 3ONZ, 3OO4, 3OO5, 3P5Q, 3QJB, 3QJC, 3QJD, 3QJE, 3R5I, 3S65, 3S66, 3SZK, 3W4U, 3WCP, 3WHM, 4FC3, 4HHB, 4IJ2, 4L7Y, 4M4A, 4M4B, 4MQC, 4MQG, 4MQH, 4MQI, 4N7N, 4N7O, 4N7P, 4N8T, 4NI0, 4NI1, 4ROL, 4ROM, 4WJG, 4X0L, 4XS0, 5E29, 5E6E, 5EE4, 5HU6, 5JDO, 5KDQ, 5E83
Identifikatori
Aliasi	HBB
Vanjski ID-jevi	OMIM: 141900 MGI: 5474850 HomoloGene: 68066 GeneCards: HBB
Lokacija gena (čovjek)
Hrom.	Hromosom 11 (čovjek)
Kraj	5,229,395 bp
Lokacija gena (miš)
Hrom.	Hromosom 7 (miš)
Kraj	103,463,203 bp
Ontologija gena
Molekularna funkcija	• iron ion binding; • oxygen binding; • oxygen carrier activity; • peroxidase activity; • vezivanje iona metala; • hemoglobin binding; • GO:0001948, GO:0016582 vezivanje za proteine; • heme binding; • haptoglobin binding;
Ćelijska komponenta	• citosol; • endocytic vesicle lumen; • blood microparticle; • extracellular region; • hemoglobin complex; • Egzosom; • haptoglobin-hemoglobin complex; • tertiary granule lumen; • ficolin-1-rich granule lumen; • Vanćelijsko;
Biološki proces	• positive regulation of cell death; • protein heterooligomerization; • nitric oxide transport; • positive regulation of nitric oxide biosynthetic process; • oxygen transport; • Koagulacija (krv); • receptor-mediated endocytosis; • regulation of blood pressure; • bicarbonate transport; • hydrogen peroxide catabolic process; • platelet aggregation; • response to hydrogen peroxide; • renal absorption; • cellular oxidant detoxification; • neutrophil degranulation; • GO:0015915 transport;
	Izvori:Amigo / QuickGO
Ortolozi
	3043
	101488143
	ENSG00000244734
	ENSMUSG00000073940
	P68871
	P02088
	NM_000518
	NM_008220
	NP_000509
	NP_032246; NP_001188320; NP_001265090
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Hemoglobinska podjedinica beta, (beta globin, β-globin, hemoglobin beta) je globinski protein, koji je kodiran genom HBB. Zajedno sa alfa globinom (HBA), čini najčešći oblik hemoglobina kod odraslih ljudi, hemoglobin A (HbA).^[5] > Dug je 147 aminokiselina i ima molekulsku masu 15.867 Da. Normalni odrasli ljudski HbA je heterotetramer koji se sastoji od po dva alfa i beta lanca.

HBB je kodiran genom HBB na ljudskom hromozomu 11. Mutacije u genu proizvode nekoliko varijanti proteina koji su povezani s genetičkim poremećajima, kao što su bolest srpastih ćelija i beta talasemija, kao i korisne osobine poput genetička otpornost na malariju.^[6]^[7]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 147 aminokiselina, a molekulska težina 15.998 Da.^[8]

10	20	30	40	50
MVHLTPEEKS	AVTALWGKVN	VDEVGGEALG	RLLVVYPWTQ	RFFESFGDLS
TPDAVMGNPK	VKAHGKKVLG	AFSDGLAHLD	NLKGTFATLS	ELHCDKLHVD
PENFRLLGNV	LVCVLAHHFG	KEFTPPVQAA	YQKVVAGVAN	ALAHKYH

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

Genski lokus

HBB protein proizvodi gen HBB koji se nalazi u multigenskom β-globinskom lokusu na hromosomu 11, na položaj 15.4 kratkog kraka. Ekspresija beta globina i susjednih globina u lokusu β-globina kontrolira se jednim regija kontrole lokusa (LCR), najvažnijim regulatornim elementom u lokusu koji se nalazi uzvodno od globinskog gena.^[9] Normalna alelna varijanta duga je 1600 parova baza (bp) i sadrži tri egzona. Poredak gena u beta-globinskom klasteru je 5'-epsilon–gama-G–gama-A–delta–beta-3'.^[5]

Povezani genetički poremećaji

Beta talasemija

Beta talasemija je nasljedna genetička mutacija u jednom (beta talasemija minor) ili obje (beta talasemija major) alela beta-globina na hromosomu 11. Mutantni aleli podijeljeni su u dvije grupe: β0, u kojima nema funkcionalnih β proizvoda – globin i β , u kojem se proizvodi mala količina normalnog proteina β-globina. Beta talasemija minor javlja se kada osoba naslijedi jedan normalni B i jedan abnormalni beta alel (ili β0, ili β ). Beta talasemija minor dovodi do blage mikrocitne anemije koja je često asimptomska ili može uzrokovati umor i ili bljedilo kože. Beta talasemija se javlja kada osoba naslijedi dva abnormalna alela. To mogu biti ili dva β alela, dva β0 alela ili po jedan od svakog. Beta talasemija major je teško zdravstveno stanje. Ozbiljna anemija počinje se javljati u dobi od 6 mjeseci. Bez medicinskog tretmana smrt se često javlja prije 12. godine.^[10] Beta talasemija major može se liječiti doživotnim transfuzijama krvi ili transplantacijom koštane srži.^[11]^[12]

Prema nedavnoj studiji, stop gain mutacija Gln40stop u genu HBB čest je uzrok autosomno recesivne beta talasemije u sardinijskom narodu (gotovo isključivo na Sardiniji). Nositelji ove mutacije pokazuju povećan broj crvenih krvnih zrnaca. Zanimljivost je da je ista mutacija povezana i sa smanjenjem nivoa LDL u serumu kod nositelja, pa autori sugeriraju da je to zbog potrebe holesterola za regeneraciju ćelijskih membrana.^[13]

Bolest srpastih ćelija

Otkriveno je više od hiljadu prirodnih varijanti HBB. Najčešći je HbS koji uzrokuje bolest srpastih ćelija. HbS proizvodi tačkasta mutacija u HBB-u, u kojem je kodon GAG zamijenjen GTG -om. To rezultira zamjenom hidrofilne aminokiseline glutaminska kiselina hidrofobnom aminokiselinom valin na šestom mjestu eta lanca (β6Glu → Val). Ova zamjena stvara hidrofobnu pjegu na vanjskoj strani proteina koja se lijepi za hidrofobnu regiju susjednog beta lanca molekule hemoglobina. Ovo dalje uzrokuje skupljanje molekula HbS u kruta vlakna, uzrokujući "srpastost" cijelih crvenih krvnih zrnaca u homozigotnom stanju (HbS/HbS).^[14] Homozigotni alel postao je jedan od najsmrtonosnijih genetičkih faktora,^[15] budući da su heterozigoti za mutirani alel (HbS/HbA) otporni na malariju i razvijaju minimalne učinke anemije.^[16]

Hemoglobin C

Bolest srpastih ćelija blisko je povezana s drugim mutiranim hemoglobinom koji se naziva hemoglobin C (HbC), jer se mogu naslijediti zajedno.^[17] HbC mutacija je na istom položaju u HbS, ali je glutaminska kiselina zamijenjena lizinom (β6Glu → Lys). Mutacija je posebno rasprostranjena u populaciji zapadne Afrike. HbC pruža gotovo potpunu zaštitu od Plasmodium falciparum u homozigotnih (CC) jedinki i srednju zaštitu u heterozigotnih (AC) osoba.^[18] To ukazuje da HbC ima jači uticaj od HbS, te se predviđa da će zamijeniti HbS u regijama endemskim za malariju.^[19]

Hemoglobin E

Druga tačkasta mutacija u HBB, u kojoj je glutaminska kiselina zamijenjena lizinom na položaju 26 (β26Glu → Lys), dovodi do stvaranja hemoglobina E).^[20] HbE ima vrlo nestabilnu asocijaciju α- i β-globina. Iako sam nestabilni protein ima blagi učinak, naslijeđen sa obilježjima HbS i talasemije, pretvara se u životno opasan oblik β-talasemije. Mutacija je relativno novijeg porijekla, što sugerira da je rezultat selektivnog pritiska protiv teške malarije falciparum, jer heterozigotni alel sprečava razvoj malarije.^[21]

Interakcije

HBB je u interakciji s hemoglobinom alfa 1 (HBA1) stvara hemoglobin A, glavni hemoglobin u odraslih ljudi.^[22]^[23] Interakcija je dvostruka. Prvo, jedan HBB i jedan HBA1 se kombiniraju, nekovalentno, kako bi se formirao dimer. Drugo, dva dimera se spajaju i tvore četverolančani tetramer, koji postaje funkcionalni hemoglobin.^[24]

Evolucija čovjeka

Malarija uzrokovana protozoom Plasmodium falciparum glavni je selektivni faktor u evoluciji čovjeka.^[7]^[25] U različitom je stupnju uticao na mutacije u HBB -u što je rezultiralo postojanjem brojnih varijanti HBB-a. Neke od ovih mutacija nisu izravno smrtonosne i umjesto toga daju otpor malariji, posebno u Africi gdje je malarija epidemijska.^[26] Ljudi afričkog porijekla evoluirali su tako da imaju veće stope mutiranog HBB-a jer heterozigotne osobe imaju pogrešno oblikovana crvena krvna zrnca, koja sprečavaju napade malarijskih parazita. Stoga su HBB mutanti izvori pozitivne selekcije u ovim regijama i važni su za njihov dugoročni opstanak.^[6]^[27] Takvi selekcijski markeri važni su za praćenje ljudskog porijekla i diverzifikacije iz Afrike.^[28]

Također pogledajte

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000244734 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000073940 - 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.
^ ^a ^b "Entrez Gene: HBB hemoglobin, beta".
^ ^a ^b Sabeti, Pardis C (2008). "Natural selection: uncovering mechanisms of evolutionary adaptation to infectious disease". Nature Education. 1 (1): 13.
^ ^a ^b Kwiatkowski DP (2005). "How malaria has affected the human genome and what human genetics can teach us about malaria". The American Journal of Human Genetics. 77 (2): 171–192. doi:10.1086/432519. PMC 1224522. PMID 16001361.
^ "UniProt, P68871". Pristupljeno 22. 8. 2021.
^ Levings PP, Bungert J (2002). "The human beta-globin locus control region". Eur. J. Biochem. 269 (6): 1589–99. doi:10.1046/j.1432-1327.2002.02797.x. PMID 11895428.
^ H. Franklin Bunn; Vijay G. Sankaran (2017). "8". Pathology of blood disorders. str. 927–933.
^ Muncie HL, Campbell J (2009). "Alpha and beta thalassemia". American Family Physician. 80 (4): 339–44. PMID 19678601.
^ "Beta thalassemia". Genetics Home Reference. U.S. National Library of Medicine. 11. 11. 2014. Pristupljeno 18. 11. 2014.
^ Sidore, C.; et al. (2015). "Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers". Nature Genetics. 47 (11): 1272–1281. doi:10.1038/ng.3368. PMC 4627508. PMID 26366554.
^ Thom CS, Dickson CF, Gell DA, Weiss MJ (2013). "Hemoglobin variants: biochemical properties and clinical correlates". Cold Spring Harb Perspect Med. 3 (3): a011858. doi:10.1101/cshperspect.a011858. PMC 3579210. PMID 23388674.
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^ Luzzatto L (2012). "Sickle cell anaemia and malaria". Mediterr J Hematol Infect Dis. 4 (1): e2012065. doi:10.4084/MJHID.2012.065. PMC 3499995. PMID 23170194.
^ Piel FB, Howes RE, Patil AP, Nyangiri OA, Gething PW, Bhatt S, Williams TN, Weatherall DJ, Hay SI (2013). "The distribution of haemoglobin C and its prevalence in newborns in Africa". Scientific Reports. 3 (1671): 1671. Bibcode:2013NatSR...3E1671P. doi:10.1038/srep01671. PMC 3628164. PMID 23591685.
^ Modiano D, Luoni G, Sirima BS, Simporé J, Verra F, Konaté A, Rastrelli E, Olivieri A, Calissano C, Paganotti GM, D'Urbano L, Sanou I, Sawadogo A, Modiano G, Coluzzi M (2001). "Haemoglobin C protects against clinical Plasmodium falciparum malaria". Nature. 414 (6861): 305–308. Bibcode:2001Natur.414..305M. doi:10.1038/35104556. PMID 11713529. S2CID 4360808.
^ Verra F, Bancone G, Avellino P, Blot I, Simporé J, Modiano D (2007). "Haemoglobin C and S in natural selection against Plasmodium falciparum malaria: a plethora or a single shared adaptive mechanism?". Parassitologia. 49 (4): 209–13. PMID 18689228.
^ Olivieri NF, Pakbaz Z, Vichinsky E (2011). "Hb E/beta-thalassaemia: a common & clinically diverse disorder". The Indian Journal of Medical Research. 134 (4): 522–531. PMC 3237252. PMID 22089616.
^ Chotivanich K, Udomsangpetch R, Pattanapanyasat K, Chierakul W, Simpson J, Looareesuwan S, White N (2002). "Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria". Blood. 100 (4): 1172–1176. doi:10.1182/blood.V100.4.1172.h81602001172_1172_1176. PMID 12149194.
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Dopunska literatura

Higgs DR, Vickers MA, Wilkie AO, Pretorius IM, Jarman AP, Weatherall DJ (1989). "A review of the molecular genetics of the human alpha-globin gene cluster". Blood. 73 (5): 1081–104. doi:10.1182/blood.V73.5.1081.1081. PMID 2649166.
Giardina B, Messana I, Scatena R, Castagnola M (1995). "The multiple functions of hemoglobin". Crit. Rev. Biochem. Mol. Biol. 30 (3): 165–96. doi:10.3109/10409239509085142. PMID 7555018.
Salzano AM, Carbone V, Pagano L, Buffardi S, De RC, Pucci P (2002). "Hb Vila Real [beta36(C2)Pro-->His] in Italy: characterization of the amino acid substitution and the DNA mutation". Hemoglobin. 26 (1): 21–31. doi:10.1081/HEM-120002937. PMID 11939509. S2CID 40757080.
Frischknecht H, Dutly F (2007). "A 65 bp duplication/insertion in exon II of the beta globin gene causing beta0-thalassemia". Haematologica. 92 (3): 423–4. doi:10.3324/haematol.10785. PMID 17339197.

Vanjski linkovi

Commons logo

Commons ima datoteke na temu: HBB

Šablon:Hemoproteini

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000244734 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000073940 - 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.

[entrez-5] "Entrez Gene: HBB hemoglobin, beta".

[sabeti-6] Sabeti, Pardis C (2008). "Natural selection: uncovering mechanisms of evolutionary adaptation to infectious disease". Nature Education. 1 (1): 13.

[kwiat-7] Kwiatkowski DP (2005). "How malaria has affected the human genome and what human genetics can teach us about malaria". The American Journal of Human Genetics. 77 (2): 171–192. doi:10.1086/432519. PMC 1224522. PMID 16001361.

[UniProt-8] "UniProt, P68871". Pristupljeno 22. 8. 2021.

[pmid11895428-9] Levings PP, Bungert J (2002). "The human beta-globin locus control region". Eur. J. Biochem. 269 (6): 1589–99. doi:10.1046/j.1432-1327.2002.02797.x. PMID 11895428.

[10] H. Franklin Bunn; Vijay G. Sankaran (2017). "8". Pathology of blood disorders. str. 927–933.

[11] Muncie HL, Campbell J (2009). "Alpha and beta thalassemia". American Family Physician. 80 (4): 339–44. PMID 19678601.

[12] "Beta thalassemia". Genetics Home Reference. U.S. National Library of Medicine. 11. 11. 2014. Pristupljeno 18. 11. 2014.

[13] Sidore, C.; et al. (2015). "Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers". Nature Genetics. 47 (11): 1272–1281. doi:10.1038/ng.3368. PMC 4627508. PMID 26366554.

[14] Thom CS, Dickson CF, Gell DA, Weiss MJ (2013). "Hemoglobin variants: biochemical properties and clinical correlates". Cold Spring Harb Perspect Med. 3 (3): a011858. doi:10.1101/cshperspect.a011858. PMC 3579210. PMID 23388674.

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