ITPA

ITPA
Dostupne strukture
PDB	Pretraga ortologa: PDBe RCSB
Spisak PDB ID kodova
	2CAR, 2I5D, 2J4E, 4F95
Identifikatori
Aliasi	ITPA
Vanjski ID-jevi	OMIM: 147520 MGI: 96622 HomoloGene: 6289 GeneCards: ITPA
Lokacija gena (čovjek)
Hrom.	Hromosom 20 (čovjek)
Kraj	3,223,870 bp
Lokacija gena (miš)
Hrom.	Hromosom 2 (miš)
Kraj	130,523,534 bp
Obrazac RNK ekspresije
	Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija	• nucleotide binding; • dITP diphosphatase activity; • XTP diphosphatase activity; • ITP diphosphatase activity; • hydrolase activity; • vezivanje iona metala; • nucleotide diphosphatase activity; • NADH pyrophosphatase activity; • nucleoside-triphosphate diphosphatase activity; • vezivanje identičnih proteina;
Ćelijska komponenta	• citoplazma; • citosol;
Biološki proces	• ITP catabolic process; • nucleotide metabolic process; • GO:0051312, GO:0007083 chromosome organization; • nucleoside triphosphate catabolic process; • purine nucleotide catabolic process; • deoxyribonucleoside triphosphate catabolic process;
	Izvori:Amigo / QuickGO
Ortolozi
	3704
	16434
	ENSG00000125877
	ENSMUSG00000074797
	Q9BY32
	Q9D892
NM_001267623; NM_033453; NM_181493; NM_001324236; NM_001324237;
	NM_001324238; NM_001324240; NM_001351739
	NM_025922; NM_001362648
NP_001254552; NP_001311165; NP_001311166; NP_001311167; NP_001311169;
	NP_258412; NP_852470; NP_001338668
	NP_080198; NP_001349577
	Wikipodaci
Pogledaj/uredi – čovjek	Pogledaj/uredi – miš

Inozin-trifosfat pirofosfataza jest enzim koji je kod ljudi kodiran genom ITPA,^[5]^[6] gwenom rdgB kod bakterija E.coli^[7] i genom HAM1 kod kvasca S. cerevisiae.^[8] Za ovaj gen pronađene su dvije varijante transkripta koje kodiraju dvije različite izoforme. Također, identificirane su najmanje dvije druge varijante transkripta koje su vjerovatno regulatorni, a ne kodirajući proteini.

Funkcija

Protein kodiran ovim genom, hidrolizira inozin-trifosfat i deoksiinozin-trifosfat u monofosfat-nukleotid i difosfat.^[6] Enzim ima višestruku specifičnost za supstrat i djeluje na druge nukleotide, uključujući ksantozin-trifosfat i dezoksiksantozin-trifosfat.^[8] Kodirani protein, koji je član porodice HAM1 NTPaze, nalazi se u citoplazmi i djeluje kao homodimer.

Klinički značaj

Defekti kodiranog proteina mogu rezultirati nedostatkom inozin-trifosfat pirofosforilaze.^[6] Enzim ITPaza defosforilizira ribavirin-trifosfat in vitro u ribavirin-monofosfat, a ITPazna smanjena enzimska aktivnost prisutna kod 30% ljudi pojačava mutagenezu virusa za hepatitis C.^[9] Genske varijante koje predviđaju smanjenu aktivnost ITPaze povezane su sa smanjenim rizikom od anemije izazvane ribavirinom, povećanim rizikom od trombocitopenije, nižim koncentracijama ribavirina, kao i smanjenim rizikom relapsa sličnog ribavirinu, nakon terapije virusa hepatitisa C (HCV), zasnovane na interferonu infekcija v irisom genotipa 2 ili 3.^[10]

Reference

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000125877 - Ensembl, maj 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000074797 - 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.
^ Lin S, McLennan AG, Ying K, Wang Z, Gu S, Jin H, Wu C, Liu W, Yuan Y, Tang R, Xie Y, Mao Y (maj 2001). "Cloning, expression, and characterization of a human inosine triphosphate pyrophosphatase encoded by the itpa gene". J Biol Chem. 276 (22): 18695–701. doi:10.1074/jbc.M011084200. PMID 11278832.
^ ^a ^b ^c "Entrez Gene: ITPA inosine triphosphatase (nucleoside triphosphate pyrophosphatase)".
^ Burgis NE, Cunningham RP (2007). "Substrate specificity of RdgB protein, a deoxyribonucleoside triphosphate pyrophosphohydrolase". J Biol Chem. 282 (8): 3531–8. doi:10.1074/jbc.M608708200. PMID 17090528.
^ ^a ^b Davies O, Mendes P, Smallbone K, Malys N (2012). "Characterisation of multiple substrate-specific (d)ITP/(d)XTPase and modelling of deaminated purine nucleotide metabolism". BMB Reports. 45 (4): 259–64. doi:10.5483/BMBRep.2012.45.4.259. PMID 22531138.
^ Nyström K, Wanrooij PH, Waldenström J, Adamek L, Brunet S, Said J, Nilsson S, Wind-Rotolo M, Hellstrand K, Norder H, Tang KW, Lagging M (oktobar 2018). "Inosine Triphosphate Pyrophosphatase Dephosphorylates Ribavirin Triphosphate and Reduced Enzymatic Activity Potentiates Mutagenesis in Hepatitis C Virus". Journal of Virology. 92 (19): 01087–18. doi:10.1002/hep.27009. PMC 6146798. PMID 30045981.
^ Rembeck K, Waldenstrom J, Hellstrand K, Nilsson S, Nyström K, Martner A, Lindh M, Norkrans G, Westin J, Pedersen C, Färkkil M, Langeland N, Rauning Buhl M, Morch K, Brehm Christensen P, and Lagging M (juni 2014). "Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3". Hepatology. 59 (6): 2131–2139. doi:10.1002/hep.27009. PMID 24519039.

Dopunska literatura

Holmes SL, Turner BM, Hirschhorn K (1979). "Human inosine triphosphatase: catalytic properties and population studies". Clin. Chim. Acta. 97 (2–3): 143–53. doi:10.1016/0009-8981(79)90410-8. PMID 487601.
Fraser JH; Meyers H; Henderson JF; et al. (1976). "Individual variation in inosine triphosphate accumulation in human erythrocytes". Clin. Biochem. 8 (6): 353–64. doi:10.1016/S0009-9120(75)93685-1. PMID 1204209.
Clawson GA; Song YL; Schwartz AM; et al. (1992). "Interaction of human immunodeficiency virus type I Rev protein with nuclear scaffold nucleoside triphosphatase activity". Cell Growth Differ. 2 (11): 575–82. PMID 1667585.
Deloukas P; Matthews LH; Ashurst J; et al. (2002). "The DNA sequence and comparative analysis of human chromosome 20". Nature. 414 (6866): 865–71. doi:10.1038/414865a. PMID 11780052.
Sumi S; Marinaki AM; Arenas M; et al. (2002). "Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency". Hum. Genet. 111 (4–5): 360–7. doi:10.1007/s00439-002-0798-z. PMID 12384777.
Cao H, Hegele RA (2003). "DNA polymorphisms in ITPA including basis of inosine triphosphatase deficiency". J. Hum. Genet. 47 (11): 620–2. doi:10.1007/s100380200095. PMID 12436200.
Strausberg RL; Feingold EA; Grouse LH; et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. doi:10.1073/pnas.242603899. PMC 139241. PMID 12477932.
Gerhard DS; Wagner L; Feingold EA; et al. (2004). "The Status, Quality, and Expansion of the NIH Full-Length cDNA Project: The Mammalian Gene Collection (MGC)". Genome Res. 14 (10B): 2121–7. doi:10.1101/gr.2596504. PMC 528928. PMID 15489334.
Marinaki AM; Duley JA; Arenas M; et al. (2005). "Mutation in the ITPA gene predicts intolerance to azathioprine". Nucleosides Nucleotides Nucleic Acids. 23 (8–9): 1393–7. doi:10.1081/NCN-200027639. PMID 15571265.
Marinaki AM; Sumi S; Arenas M; et al. (2005). "Allele frequency of inosine triphosphate pyrophosphatase gene polymorphisms in a Japanese population". Nucleosides Nucleotides Nucleic Acids. 23 (8–9): 1399–401. doi:10.1081/NCN-200027641. PMID 15571266.
Maeda T; Sumi S; Ueta A; et al. (2005). "Genetic basis of inosine triphosphate pyrophosphohydrolase deficiency in the Japanese population". Mol. Genet. Metab. 85 (4): 271–9. doi:10.1016/j.ymgme.2005.03.011. PMID 15946879.
Breen DP, Marinaki AM, Arenas M, Hayes PC (2005). "Pharmacogenetic association with adverse drug reactions to azathioprine immunosuppressive therapy following liver transplantation". Liver Transpl. 11 (7): 826–33. doi:10.1002/lt.20377. PMID 15973722.
Porta J; Kolar C; Kozmin SG; et al. (2006). "Structure of the orthorhombic form of human inosine triphosphate pyrophosphatase". Acta Crystallographica Section F. 62 (Pt 11): 1076–81. doi:10.1107/S1744309106041790. PMC 2225220. PMID 17077483.
Arenas M; Duley J; Sumi S; et al. (2007). "The ITPA c.94C>A and g.IVS2+21A>C sequence variants contribute to missplicing of the ITPA gene". Biochim. Biophys. Acta. 1772 (1): 96–102. doi:10.1016/j.bbadis.2006.10.006. PMID 17113761.
Stenmark P; Kursula P; Flodin S; et al. (2007). "Crystal structure of human inosine triphosphatase. Substrate binding and implication of the inosine triphosphatase deficiency mutation P32T". J. Biol. Chem. 282 (5): 3182–7. doi:10.1074/jbc.M609838200. PMID 17138556.
Atanasova S; Shipkova M; Svinarov D; et al. (2007). "Analysis of ITPA phenotype-genotype correlation in the Bulgarian population revealed a novel gene variant in exon 6". Therapeutic Drug Monitoring. 29 (1): 6–10. doi:10.1097/FTD.0b013e3180308554. PMID 17304144.

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000125877 - Ensembl, maj 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000074797 - 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.

[pmid11278832-5] Lin S, McLennan AG, Ying K, Wang Z, Gu S, Jin H, Wu C, Liu W, Yuan Y, Tang R, Xie Y, Mao Y (maj 2001). "Cloning, expression, and characterization of a human inosine triphosphate pyrophosphatase encoded by the itpa gene". J Biol Chem. 276 (22): 18695–701. doi:10.1074/jbc.M011084200. PMID 11278832.

[entrez-6] "Entrez Gene: ITPA inosine triphosphatase (nucleoside triphosphate pyrophosphatase)".

[pmid_17090528-7] Burgis NE, Cunningham RP (2007). "Substrate specificity of RdgB protein, a deoxyribonucleoside triphosphate pyrophosphohydrolase". J Biol Chem. 282 (8): 3531–8. doi:10.1074/jbc.M608708200. PMID 17090528.

[pmid_22531138-8] Davies O, Mendes P, Smallbone K, Malys N (2012). "Characterisation of multiple substrate-specific (d)ITP/(d)XTPase and modelling of deaminated purine nucleotide metabolism". BMB Reports. 45 (4): 259–64. doi:10.5483/BMBRep.2012.45.4.259. PMID 22531138.

[9] Nyström K, Wanrooij PH, Waldenström J, Adamek L, Brunet S, Said J, Nilsson S, Wind-Rotolo M, Hellstrand K, Norder H, Tang KW, Lagging M (oktobar 2018). "Inosine Triphosphate Pyrophosphatase Dephosphorylates Ribavirin Triphosphate and Reduced Enzymatic Activity Potentiates Mutagenesis in Hepatitis C Virus". Journal of Virology. 92 (19): 01087–18. doi:10.1002/hep.27009. PMC 6146798. PMID 30045981.

[10] Rembeck K, Waldenstrom J, Hellstrand K, Nilsson S, Nyström K, Martner A, Lindh M, Norkrans G, Westin J, Pedersen C, Färkkil M, Langeland N, Rauning Buhl M, Morch K, Brehm Christensen P, and Lagging M (juni 2014). "Variants of the inosine triphosphate pyrophosphatase gene are associated with reduced relapse risk following treatment for HCV genotype 2/3". Hepatology. 59 (6): 2131–2139. doi:10.1002/hep.27009. PMID 24519039.

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