Faktor IX

F9
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	1CFH, 1CFI, 1EDM, 1IXA, 1MGX, 1NL0, 1RFN, 2WPH, 2WPI, 2WPJ, 2WPK, 2WPL, 2WPM, 3KCG, 3LC3, 3LC5, 4YZU, 4Z0K, 4ZAE, 4WM0, 4WMA, 4WMI, 4WMK, 4WN2, 4WNH, 5EGM, 5JBC, 5JB9, 5JBB, 5JB8, 5JBA
Identifikatori
Aliasi	F9
Vanjski ID-jevi	OMIM: 300746 MGI: 88384 HomoloGene: 106 GeneCards: F9
Lokacija gena (čovjek)
Hrom.	Hromosom X
Kraj	139,563,459 bp
Lokacija gena (miš)
Hrom.	Hromosom X (miš)
Kraj	59,076,119 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• endopeptidase activity; • vezivanje iona metala; • GO:0070122 peptidase activity; • serine-type peptidase activity; • hydrolase activity; • calcium ion binding; • serine-type endopeptidase activity; • GO:0001948, GO:0016582 vezivanje za proteine;
Ćelijska komponenta	• endoplasmic reticulum lumen; • ćelijska membrana; • Golgi lumen; • Egzosom; • extracellular region; • Vanćelijsko; • collagen-containing extracellular matrix;
Biološki proces	• Hemostaza; • blood coagulation, intrinsic pathway; • zymogen activation; • endoplasmic reticulum to Golgi vesicle-mediated transport; • signal peptide processing; • blood coagulation, extrinsic pathway; • peptidyl-glutamic acid carboxylation; • Proteoliza; • Koagulacija (krv);
	Izvori:Amigo / QuickGO
Ortolozi
	2158
	14071
	ENSG00000101981
	ENSMUSG00000031138
	P00740
	P16294
	NM_000133; NM_001313913
	NM_007979; NM_001305797
	NP_000124; NP_001300842
	NP_001292726; NP_032005
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Faktor IX ili Christmasov faktor (EC 3.4.21.22) je jedan od serinskih proteaza sistema koagulacije; pripada porodici peptidaza S1. Nedostatak ovog proteina uzrokuje hemofiliju B. Otkriven je 1952. godine nakon što je ustanovljeno da dječaku po imenu Stephen Christmas nedostaje pravilan ovaj faktor, što je dovelo do hemofilije.^[5]

Aminokiselinska sekvenca

Dužina polipeptidnog lanca je 461 aminokiselina, а molekulska masa — 51 778 Da.

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
MQRVNMIMAE	SPGLITICLL	GYLLSAECTV	FLDHENANKI	LNRPKRYNSG
KLEEFVQGNL	ERECMEEKCS	FEEAREVFEN	TERTTEFWKQ	YVDGDQCESN
PCLNGGSCKD	DINSYECWCP	FGFEGKNCEL	DVTCNIKNGR	CEQFCKNSAD
NKVVCSCTEG	YRLAENQKSC	EPAVPFPCGR	VSVSQTSKLT	RAETVFPDVD
YVNSTEAETI	LDNITQSTQS	FNDFTRVVGG	EDAKPGQFPW	QVVLNGKVDA
FCGGSIVNEK	WIVTAAHCVE	TGVKITVVAG	EHNIEETEHT	EQKRNVIRII
PHHNYNAAIN	KYNHDIALLE	LDEPLVLNSY	VTPICIADKE	YTNIFLKFGS
GYVSGWGRVF	HKGRSALVLQ	YLRVPLVDRA	TCLRSTKFTI	YNNMFCAGFH
EGGRDSCQGD	SGGPHVTEVE	GTSFLTGIIS	WGEECAMKGK	YGIYTKVSRY
VNWIKEKTKL	T

Fiziologija

Put zgrušavanja krvi i protein C

Faktor IX se proizvodi kao zimogen, neaktivni prekursor. Obrađuje se glikoziliran, da bi se uklonio signalni peptid , a zatim se cijepa pomoću faktora XIa (kontaktnog puta) ili faktora VIIa (put tkivnog faktora) za proizvodnju dvolančane forme, gdje su lanci povezani disulfidnim mostom.^[6]^[7] Kada se aktivira u faktor IXa, u prisustvu Ca²⁺, membranskih fosfolipida i kofaktora faktora VIII, hidrolizira jednu vezu arginin-izoleucin u faktoru X da formira faktor Xa.

Faktor IX inhibira antitrombin.^[6]

Kod ljudi i miševa, ekspresija faktora IX povećava se sa godinama. U modelima miša, mutacije unutar promotorske regije faktora IX imaju fenotip ovisan o starosti.^[8]

Arhitektura domena

Faktori VII, IX i X svi imaju ključne uloge u koagulaciji krvi i također dijele zajedničku arhitekturu domena.^[9] Protein faktora IX sastoji se od četiri proteinska domena: Gla domen, dvije tandemske kopije EGF domen i C-terminalni tripsin peptidazni domen koji vrši katalitsko cijepanje.

Arhitektura proteinskog domena ljudskog faktora IX, gdje je svaki proteinski domen predstavljen obojenom kutijom

Pokazalo se da je N-terminalni EGF domen barem dijelom odgovoran za vezivanje tkivnog faktora.^[9] Wilkinson et al. conclude that residues 88 to 109 of the second EGF domain mediate binding to platelets and assembly of the factor X activating complex.^[10]

Strukture sva četiri domena su riješene. Za svinjski protein određena je struktura dva EGF domena i tripsinolikog domena.^[11] Struktura Gla domena, koji je odgovoran za vezanje fosfolipida ovisno o Ca(II), također je određena putem NMR.^[12] Nekoliko struktura 'super aktivnih' mutanata također je riješeno,^[13] a koje otkrivaju prirodu aktivacije faktora IX putem drugih proteina u kaskadi zgrušavanja.

Genetika

Kod ljudi, gen F9 nalazi se na hromosomu X, na poziciji q27.1.

Gen za faktor IX se nalazi na hromosomu X (Xq27.1-q27.2) i stoga je X-vezani recesivan: mutacije u ovom genu pogađaju muškarce mnogo češće nego žene. U ovom genu otkrivene su najmanje 534 mutacije koje izazivaju bolest.^[14] Gen F9 su prvi klonirali Kotoku Kurachi i Earl Davie, 1982. godine.^[15]

Polly, transgenu kloniranu Poll Dorset ovcu koja nosi gen za faktor IX, proizveo je dr Ian Wilmut na Roslin Institute, 1997.^[16]

Klinički značaj

Nedostatak faktora IX uzrokuje Christmasovu bolest (hemofilija B).^[5] Opisano je preko 3000 varijanti faktora IX, koje utiču na 73% od 461 ostatka;^[17] neki ne izazivaju simptome, ali mnogi dovode do značajnog poremećaja krvarenja. Originalna mutacija Christmasove bolesti identificirana je sekvenciranjem njegove DNK, otkrivajući mutaciju koja je promijenila cistein u serin.^[18] Za liječenje Christmasove bolesti koristi se rekombinantni faktor IX. Formulacije uključuju:

nonacog alfa (marka BeneFix)^[19]
albutrepenonacog alfa (marka Idelvion)^[20]
eftrenonacog alfa (marka Alprolix)^[21]
nonacog beta pegol (marka Refixia)^[22]

Neke rijetke mutacije faktora IX dovode do povišene aktivnosti zgrušavanja i mogu rezultirati bolestima zgrušavanja, kao što je duboka venska tromboza. Ova mutacija dobitka funkcije čini protein hiperfunkcionalnim i povezana je s porodičnom trombofilijom ranog početka.^[23]

Nedostatak faktora IX liječi se injekcijom pročišćenog faktora IX. proizvedenog kloniranjem u različitim životinjskim vektorima ili u životinjskim ćelijama. Traneksamijska kiselina može biti od koristi kod pacijenata koji su podvrgnuti operaciji koji imaju naslijeđeni nedostatak faktora IX, kako bi se smanjio perioperativni rizik od krvarenja.^[24]

Listu svih mutacija u faktoru IX sastavlja i održava EAHAD.^[25]

Faktor koagulacije IX nalazi se na Listi esencijalnih lijekova Svjetske zdravstvene organizacije.

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000101981 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000031138 - 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 Biggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR (Dec 1952). "Christmas disease: a condition previously mistaken for haemophilia". British Medical Journal. 2 (4799): 1378–82. doi:10.1136/bmj.2.4799.1378. PMC 2022306. PMID 12997790.
^ ^a ^b Di Scipio RG, Kurachi K, Davie EW (Jun 1978). "Activation of human factor IX (Christmas factor)". The Journal of Clinical Investigation. 61 (6): 1528–38. doi:10.1172/JCI109073. PMC 372679. PMID 659613.
^ Taran LD (Jul 1997). "Factor IX of the blood coagulation system: a review". Biochemistry. Biokhimiia. 62 (7): 685–93. PMID 9331959.
^ Boland EJ, Liu YC, Walter CA, Herbert DC, Weaker FJ, Odom MW, Jagadeeswaran P (Sep 1995). "Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice". Blood. 86 (6): 2198–205. doi:10.1182/blood.V86.6.2198.bloodjournal8662198. PMID 7662969.
^ ^a ^b Zhong D, Bajaj MS, Schmidt AE, Bajaj SP (Feb 2002). "The N-terminal epidermal growth factor-like domain in factor IX and factor X represents an important recognition motif for binding to tissue factor". The Journal of Biological Chemistry. 277 (5): 3622–31. doi:10.1074/jbc.M111202200. PMID 11723140.
^ Wilkinson FH, Ahmad SS, Walsh PN (Feb 2002). "The factor IXa second epidermal growth factor (EGF2) domain mediates platelet binding and assembly of the factor X activating complex". The Journal of Biological Chemistry. 277 (8): 5734–41. doi:10.1074/jbc.M107753200. PMID 11714704.
^ Brandstetter H, Bauer M, Huber R, Lollar P, Bode W (Oct 1995). "X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B". Proceedings of the National Academy of Sciences of the United States of America. 92 (21): 9796–800. Bibcode:1995PNAS...92.9796B. doi:10.1073/pnas.92.21.9796. PMC 40889. PMID 7568220.
^ Freedman SJ, Furie BC, Furie B, Baleja JD (Sep 1995). "Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX". Biochemistry. 34 (38): 12126–37. doi:10.1021/bi00038a005. PMID 7547952.
^ Zögg T, Brandstetter H (Dec 2009). "Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa". Structure. 17 (12): 1669–78. doi:10.1016/j.str.2009.10.011. PMID 20004170.
^ Šimčíková D, Heneberg P (decembar 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.
^ Kurachi K, Davie EW (Nov 1982). "Isolation and characterization of a cDNA coding for human factor IX". Proceedings of the National Academy of Sciences of the United States of America. 79 (21): 6461–4. Bibcode:1982PNAS...79.6461K. doi:10.1073/pnas.79.21.6461. PMC 347146. PMID 6959130.
^ Nicholl D. (2002). An Introduction to Genetic Engineering Second Edition. Cambridge University Press. str. 257.
^ Goodeve, A. C. (2015). "Hemophilia B: Molecular pathogenesis and mutation analysis". Journal of Thrombosis and Haemostasis. 13 (7): 1184–1195. doi:10.1111/jth.12958. PMC 4496316. PMID 25851415.
^ Taylor SA, Duffin J, Cameron C, Teitel J, Garvey B, Lillicrap DP (Jan 1992). "Characterization of the original Christmas disease mutation (cysteine 206----serine): from clinical recognition to molecular pathogenesis". Thrombosis and Haemostasis. 67 (1): 63–5. doi:10.1055/s-0038-1648381. PMID 1615485.
^ "BeneFIX EPAR". European Medicines Agency (EMA). Pristupljeno 17. 6. 2020.
^ "Idelvion EPAR". European Medicines Agency (EMA). 17. 9. 2018. Pristupljeno 17. 6. 2020.
^ "Alprolix EPAR". European Medicines Agency (EMA). Pristupljeno 17. 6. 2020.
^ "Refixia EPAR". European Medicines Agency (EMA). Pristupljeno 17. 6. 2020.
^ Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR (Oct 2009). "X-linked thrombophilia with a mutant factor IX (factor IX Padua)". The New England Journal of Medicine. 361 (17): 1671–5. doi:10.1056/NEJMoa0904377. PMID 19846852.
^ Rossi M, Jayaram R, Sayeed R (Sep 2011). "Do patients with haemophilia undergoing cardiac surgery have good surgical outcomes?". Interactive Cardiovascular and Thoracic Surgery. 13 (3): 320–31. doi:10.1510/icvts.2011.272401. PMID 21712351.
^ "Home: EAHAD Factor 9 Gene Variant Database".

Dopunska literatura

Davie EW, Fujikawa K (1975). "Basic mechanisms in blood coagulation". Annual Review of Biochemistry. 44: 799–829. doi:10.1146/annurev.bi.44.070175.004055. PMID 237463.
Sommer SS (Jul 1992). "Assessing the underlying pattern of human germline mutations: lessons from the factor IX gene". FASEB Journal. 6 (10): 2767–74. doi:10.1096/fasebj.6.10.1634040. PMID 1634040. S2CID 15211597.
Lenting PJ, van Mourik JA, Mertens K (Dec 1998). "The life cycle of coagulation factor VIII in view of its structure and function". Blood. 92 (11): 3983–96. doi:10.1182/blood.V92.11.3983. PMID 9834200.
Lowe GD (Dec 2001). "Factor IX and thrombosis" (PDF). British Journal of Haematology. 115 (3): 507–13. doi:10.1046/j.1365-2141.2001.03186.x. PMID 11736930. S2CID 44650866.
O'Connell NM (Jun 2003). "Factor XI deficiency--from molecular genetics to clinical management". Blood Coagulation & Fibrinolysis. 14 Suppl 1: S59-64. doi:10.1097/00001721-200306001-00014. PMID 14567539.
Du X (maj 2007). "Signaling and regulation of the platelet glycoprotein Ib-IX-V complex". Current Opinion in Hematology. 14 (3): 262–9. doi:10.1097/MOH.0b013e3280dce51a. PMID 17414217. S2CID 39904506.

Vanjski linkovi

"Coagulation Factor IX (Recombinant), Fc Fusion Protein". Drug Information Portal. U.S. National Library of Medicine.
"Eftrenonacog alfa". Drug Information Portal. U.S. National Library of Medicine.
"Nonacog alfa". Drug Information Portal. U.S. National Library of Medicine.
"Albutrepenonacog alfa". Drug Information Portal. U.S. National Library of Medicine.
"Nonacog beta pegol". Drug Information Portal. U.S. National Library of Medicine.
P00740
GeneReviews/NCBI/NIH/UW entry on Hemophilia B
The MEROPS online database for peptidases and their inhibitors: S01.214 Arhivirano 5. 5. 2005. na Wayback Machine

	Portal Biologija
	Portal Medicina

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000101981 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000031138 - 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.

[PMD12997790-5] Biggs R, Douglas AS, Macfarlane RG, Dacie JV, Pitney WR (Dec 1952). "Christmas disease: a condition previously mistaken for haemophilia". British Medical Journal. 2 (4799): 1378–82. doi:10.1136/bmj.2.4799.1378. PMC 2022306. PMID 12997790.

[pmid659613-6] Di Scipio RG, Kurachi K, Davie EW (Jun 1978). "Activation of human factor IX (Christmas factor)". The Journal of Clinical Investigation. 61 (6): 1528–38. doi:10.1172/JCI109073. PMC 372679. PMID 659613.

[pmid9331959-7] Taran LD (Jul 1997). "Factor IX of the blood coagulation system: a review". Biochemistry. Biokhimiia. 62 (7): 685–93. PMID 9331959.

[pmid7662969-8] Boland EJ, Liu YC, Walter CA, Herbert DC, Weaker FJ, Odom MW, Jagadeeswaran P (Sep 1995). "Age-specific regulation of clotting factor IX gene expression in normal and transgenic mice". Blood. 86 (6): 2198–205. doi:10.1182/blood.V86.6.2198.bloodjournal8662198. PMID 7662969.

[pmid11723140-9] Zhong D, Bajaj MS, Schmidt AE, Bajaj SP (Feb 2002). "The N-terminal epidermal growth factor-like domain in factor IX and factor X represents an important recognition motif for binding to tissue factor". The Journal of Biological Chemistry. 277 (5): 3622–31. doi:10.1074/jbc.M111202200. PMID 11723140.

[pmid11714704-10] Wilkinson FH, Ahmad SS, Walsh PN (Feb 2002). "The factor IXa second epidermal growth factor (EGF2) domain mediates platelet binding and assembly of the factor X activating complex". The Journal of Biological Chemistry. 277 (8): 5734–41. doi:10.1074/jbc.M107753200. PMID 11714704.

[pmid7568220-11] Brandstetter H, Bauer M, Huber R, Lollar P, Bode W (Oct 1995). "X-ray structure of clotting factor IXa: active site and module structure related to Xase activity and hemophilia B". Proceedings of the National Academy of Sciences of the United States of America. 92 (21): 9796–800. Bibcode:1995PNAS...92.9796B. doi:10.1073/pnas.92.21.9796. PMC 40889. PMID 7568220.

[pmid7547952-12] Freedman SJ, Furie BC, Furie B, Baleja JD (Sep 1995). "Structure of the calcium ion-bound gamma-carboxyglutamic acid-rich domain of factor IX". Biochemistry. 34 (38): 12126–37. doi:10.1021/bi00038a005. PMID 7547952.

[pmid20004170-13] Zögg T, Brandstetter H (Dec 2009). "Structural basis of the cofactor- and substrate-assisted activation of human coagulation factor IXa". Structure. 17 (12): 1669–78. doi:10.1016/j.str.2009.10.011. PMID 20004170.

[Šimčíková_2019_-_supplementary_table_S7-14] Šimčíková D, Heneberg P (decembar 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.

[15] Kurachi K, Davie EW (Nov 1982). "Isolation and characterization of a cDNA coding for human factor IX". Proceedings of the National Academy of Sciences of the United States of America. 79 (21): 6461–4. Bibcode:1982PNAS...79.6461K. doi:10.1073/pnas.79.21.6461. PMC 347146. PMID 6959130.

[16] Nicholl D. (2002). An Introduction to Genetic Engineering Second Edition. Cambridge University Press. str. 257.

[17] Goodeve, A. C. (2015). "Hemophilia B: Molecular pathogenesis and mutation analysis". Journal of Thrombosis and Haemostasis. 13 (7): 1184–1195. doi:10.1111/jth.12958. PMC 4496316. PMID 25851415.

[18] Taylor SA, Duffin J, Cameron C, Teitel J, Garvey B, Lillicrap DP (Jan 1992). "Characterization of the original Christmas disease mutation (cysteine 206----serine): from clinical recognition to molecular pathogenesis". Thrombosis and Haemostasis. 67 (1): 63–5. doi:10.1055/s-0038-1648381. PMID 1615485.

[19] "BeneFIX EPAR". European Medicines Agency (EMA). Pristupljeno 17. 6. 2020.

[20] "Idelvion EPAR". European Medicines Agency (EMA). 17. 9. 2018. Pristupljeno 17. 6. 2020.

[21] "Alprolix EPAR". European Medicines Agency (EMA). Pristupljeno 17. 6. 2020.

[22] "Refixia EPAR". European Medicines Agency (EMA). Pristupljeno 17. 6. 2020.

[pmid19846852-23] Simioni P, Tormene D, Tognin G, Gavasso S, Bulato C, Iacobelli NP, Finn JD, Spiezia L, Radu C, Arruda VR (Oct 2009). "X-linked thrombophilia with a mutant factor IX (factor IX Padua)". The New England Journal of Medicine. 361 (17): 1671–5. doi:10.1056/NEJMoa0904377. PMID 19846852.

[pmid21712351-24] Rossi M, Jayaram R, Sayeed R (Sep 2011). "Do patients with haemophilia undergoing cardiac surgery have good surgical outcomes?". Interactive Cardiovascular and Thoracic Surgery. 13 (3): 320–31. doi:10.1510/icvts.2011.272401. PMID 21712351.

[urlHome:_EAHAD_Factor_9_Gene_Variant_Database-25] "Home: EAHAD Factor 9 Gene Variant Database".

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