Bis(5'-adenosyl)-triphosphatase

Details

Name
Bis(5'-adenosyl)-triphosphatase
Synonyms
  • 3.6.1.29
  • AP3A hydrolase
  • AP3Aase
  • Diadenosine 5',5'''-P1,P3-triphosphate hydrolase
  • Dinucleosidetriphosphatase
  • Fragile histidine triad protein
Gene Name
FHIT
Organism
Humans
Amino acid sequence
>lcl|BSEQ0020560|Bis(5'-adenosyl)-triphosphatase
MSFRFGQHLIKPSVVFLKTELSFALVNRKPVVPGHVLVCPLRPVERFHDLRPDEVADLFQ
TTQRVGTVVEKHFHGTSLTFSMQDGPEAGQTVKHVHVHVLPRKAGDFHRNDSIYEELQKH
DKEDFPASWRSEEEMAAEAAALRVYFQ
Number of residues
147
Molecular Weight
16858.11
Theoretical pI
7.09
GO Classification
Functions
bis(5'-adenosyl)-triphosphatase activity / catalytic activity / hydrolase activity / identical protein binding / nucleotide binding / ubiquitin protein ligase binding
Processes
DNA replication / intrinsic apoptotic signaling pathway by p53 class mediator / negative regulation of proteasomal ubiquitin-dependent protein catabolic process / nucleotide metabolic process / purine nucleotide metabolic process / regulation of transcription, DNA-templated / transcription, DNA-templated
Components
cytoplasm / cytosol / extracellular exosome / mitochondrion / nucleus
General Function
Ubiquitin protein ligase binding
Specific Function
Cleaves P(1)-P(3)-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP. Can also hydrolyze P(1)-P(4)-bis(5'-adenosyl) tetraphosphate (Ap4A), but has extremely low activity with ATP. Modulates transcriptional activation by CTNNB1 and thereby contributes to regulate the expression of genes essential for cell proliferation and survival, such as CCND1 and BIRC5. Plays a role in the induction of apoptosis via SRC and AKT1 signaling pathways. Inhibits MDM2-mediated proteasomal degradation of p53/TP53 and thereby plays a role in p53/TP53-mediated apoptosis. Induction of apoptosis depends on the ability of FHIT to bind P(1)-P(3)-bis(5'-adenosyl) triphosphate or related compounds, but does not require its catalytic activity, it may in part come from the mitochondrial form, which sensitizes the low-affinity Ca(2+) transporters, enhancing mitochondrial calcium uptake. Functions as tumor suppressor.
Pfam Domain Function
Transmembrane Regions
Not Available
Cellular Location
Cytoplasm
Gene sequence
>lcl|BSEQ0020561|Bis(5'-adenosyl)-triphosphatase (FHIT)
ATGTCGTTCAGATTTGGCCAACATCTCATCAAGCCCTCTGTAGTGTTTCTCAAAACAGAA
CTGTCCTTCGCTCTTGTGAATAGGAAACCTGTGGTACCAGGACATGTCCTTGTGTGCCCG
CTGCGGCCAGTGGAGCGCTTCCATGACCTGCGTCCTGATGAAGTGGCCGATTTGTTTCAG
ACGACCCAGAGAGTCGGGACAGTGGTGGAAAAACATTTCCATGGGACCTCTCTCACCTTT
TCCATGCAGGATGGCCCCGAAGCCGGACAGACTGTGAAGCACGTTCACGTCCATGTTCTT
CCCAGGAAGGCTGGAGACTTTCACAGGAATGACAGCATCTATGAGGAGCTCCAGAAACAT
GACAAGGAGGACTTTCCTGCCTCTTGGAGATCAGAGGAGGAAATGGCAGCAGAAGCCGCA
GCTCTGCGGGTCTACTTTCAGTGA
Chromosome Location
3
Locus
3p14.2
External Identifiers
ResourceLink
UniProtKB IDP49789
UniProtKB Entry NameFHIT_HUMAN
GenBank Protein ID1203836
GenBank Gene IDU46922
GenAtlas IDFHIT
HGNC IDHGNC:3701
General References
  1. Ohta M, Inoue H, Cotticelli MG, Kastury K, Baffa R, Palazzo J, Siprashvili Z, Mori M, McCue P, Druck T, Croce CM, Huebner K: The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers. Cell. 1996 Feb 23;84(4):587-97. [PubMed:8598045]
  2. Druck T, Hadaczek P, Fu TB, Ohta M, Siprashvili Z, Baffa R, Negrini M, Kastury K, Veronese ML, Rosen D, Rothstein J, McCue P, Cotticelli MG, Inoue H, Croce CM, Huebner K: Structure and expression of the human FHIT gene in normal and tumor cells. Cancer Res. 1997 Feb 1;57(3):504-12. [PubMed:9012482]
  3. Corominas R, Yang X, Lin GN, Kang S, Shen Y, Ghamsari L, Broly M, Rodriguez M, Tam S, Trigg SA, Fan C, Yi S, Tasan M, Lemmens I, Kuang X, Zhao N, Malhotra D, Michaelson JJ, Vacic V, Calderwood MA, Roth FP, Tavernier J, Horvath S, Salehi-Ashtiani K, Korkin D, Sebat J, Hill DE, Hao T, Vidal M, Iakoucheva LM: Protein interaction network of alternatively spliced isoforms from brain links genetic risk factors for autism. Nat Commun. 2014 Apr 11;5:3650. doi: 10.1038/ncomms4650. [PubMed:24722188]
  4. Ota T, Suzuki Y, Nishikawa T, Otsuki T, Sugiyama T, Irie R, Wakamatsu A, Hayashi K, Sato H, Nagai K, Kimura K, Makita H, Sekine M, Obayashi M, Nishi T, Shibahara T, Tanaka T, Ishii S, Yamamoto J, Saito K, Kawai Y, Isono Y, Nakamura Y, Nagahari K, Murakami K, Yasuda T, Iwayanagi T, Wagatsuma M, Shiratori A, Sudo H, Hosoiri T, Kaku Y, Kodaira H, Kondo H, Sugawara M, Takahashi M, Kanda K, Yokoi T, Furuya T, Kikkawa E, Omura Y, Abe K, Kamihara K, Katsuta N, Sato K, Tanikawa M, Yamazaki M, Ninomiya K, Ishibashi T, Yamashita H, Murakawa K, Fujimori K, Tanai H, Kimata M, Watanabe M, Hiraoka S, Chiba Y, Ishida S, Ono Y, Takiguchi S, Watanabe S, Yosida M, Hotuta T, Kusano J, Kanehori K, Takahashi-Fujii A, Hara H, Tanase TO, Nomura Y, Togiya S, Komai F, Hara R, Takeuchi K, Arita M, Imose N, Musashino K, Yuuki H, Oshima A, Sasaki N, Aotsuka S, Yoshikawa Y, Matsunawa H, Ichihara T, Shiohata N, Sano S, Moriya S, Momiyama H, Satoh N, Takami S, Terashima Y, Suzuki O, Nakagawa S, Senoh A, Mizoguchi H, Goto Y, Shimizu F, Wakebe H, Hishigaki H, Watanabe T, Sugiyama A, Takemoto M, Kawakami B, Yamazaki M, Watanabe K, Kumagai A, Itakura S, Fukuzumi Y, Fujimori Y, Komiyama M, Tashiro H, Tanigami A, Fujiwara T, Ono T, Yamada K, Fujii Y, Ozaki K, Hirao M, Ohmori Y, Kawabata A, Hikiji T, Kobatake N, Inagaki H, Ikema Y, Okamoto S, Okitani R, Kawakami T, Noguchi S, Itoh T, Shigeta K, Senba T, Matsumura K, Nakajima Y, Mizuno T, Morinaga M, Sasaki M, Togashi T, Oyama M, Hata H, Watanabe M, Komatsu T, Mizushima-Sugano J, Satoh T, Shirai Y, Takahashi Y, Nakagawa K, Okumura K, Nagase T, Nomura N, Kikuchi H, Masuho Y, Yamashita R, Nakai K, Yada T, Nakamura Y, Ohara O, Isogai T, Sugano S: Complete sequencing and characterization of 21,243 full-length human cDNAs. Nat Genet. 2004 Jan;36(1):40-5. Epub 2003 Dec 21. [PubMed:14702039]
  5. Gerhard DS, Wagner L, Feingold EA, Shenmen CM, Grouse LH, Schuler G, Klein SL, Old S, Rasooly R, Good P, Guyer M, Peck AM, Derge JG, Lipman D, Collins FS, Jang W, Sherry S, Feolo M, Misquitta L, Lee E, Rotmistrovsky K, Greenhut SF, Schaefer CF, Buetow K, Bonner TI, Haussler D, Kent J, Kiekhaus M, Furey T, Brent M, Prange C, Schreiber K, Shapiro N, Bhat NK, Hopkins RF, Hsie F, Driscoll T, Soares MB, Casavant TL, Scheetz TE, Brown-stein MJ, Usdin TB, Toshiyuki S, Carninci P, Piao Y, Dudekula DB, Ko MS, Kawakami K, Suzuki Y, Sugano S, Gruber CE, Smith MR, Simmons B, Moore T, Waterman R, Johnson SL, Ruan Y, Wei CL, Mathavan S, Gunaratne PH, Wu J, Garcia AM, Hulyk SW, Fuh E, Yuan Y, Sneed A, Kowis C, Hodgson A, Muzny DM, McPherson J, Gibbs RA, Fahey J, Helton E, Ketteman M, Madan A, Rodrigues S, Sanchez A, Whiting M, Madari A, Young AC, Wetherby KD, Granite SJ, Kwong PN, Brinkley CP, Pearson RL, Bouffard GG, Blakesly RW, Green ED, Dickson MC, Rodriguez AC, Grimwood J, Schmutz J, Myers RM, Butterfield YS, Griffith M, Griffith OL, Krzywinski MI, Liao N, Morin R, Palmquist D, Petrescu AS, Skalska U, Smailus DE, Stott JM, Schnerch A, Schein JE, Jones SJ, Holt RA, Baross A, Marra MA, Clifton S, Makowski KA, Bosak S, Malek J: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. 2004 Oct;14(10B):2121-7. [PubMed:15489334]
  6. Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M, Huebner K: Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5"'-P1,P3-triphosphate hydrolase. Biochemistry. 1996 Sep 10;35(36):11529-35. [PubMed:8794732]
  7. Gemmill RM, West JD, Boldog F, Tanaka N, Robinson LJ, Smith DI, Li F, Drabkin HA: The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a patched-related gene, TRC8. Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9572-7. [PubMed:9689122]
  8. Shi Y, Zou M, Farid NR, Paterson MC: Association of FHIT (fragile histidine triad), a candidate tumour suppressor gene, with the ubiquitin-conjugating enzyme hUBC9. Biochem J. 2000 Dec 1;352 Pt 2:443-8. [PubMed:11085938]
  9. Trapasso F, Krakowiak A, Cesari R, Arkles J, Yendamuri S, Ishii H, Vecchione A, Kuroki T, Bieganowski P, Pace HC, Huebner K, Croce CM, Brenner C: Designed FHIT alleles establish that Fhit-induced apoptosis in cancer cells is limited by substrate binding. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):1592-7. Epub 2003 Feb 6. [PubMed:12574506]
  10. Huang K, Arabshahi A, Wei Y, Frey PA: The mechanism of action of the fragile histidine triad, Fhit: isolation of a covalent adenylyl enzyme and chemical rescue of H96G-Fhit. Biochemistry. 2004 Jun 15;43(23):7637-42. [PubMed:15182206]
  11. Nishizaki M, Sasaki J, Fang B, Atkinson EN, Minna JD, Roth JA, Ji L: Synergistic tumor suppression by coexpression of FHIT and p53 coincides with FHIT-mediated MDM2 inactivation and p53 stabilization in human non-small cell lung cancer cells. Cancer Res. 2004 Aug 15;64(16):5745-52. [PubMed:15313915]
  12. Pekarsky Y, Garrison PN, Palamarchuk A, Zanesi N, Aqeilan RI, Huebner K, Barnes LD, Croce CM: Fhit is a physiological target of the protein kinase Src. Proc Natl Acad Sci U S A. 2004 Mar 16;101(11):3775-9. Epub 2004 Mar 8. [PubMed:15007172]
  13. Semba S, Trapasso F, Fabbri M, McCorkell KA, Volinia S, Druck T, Iliopoulos D, Pekarsky Y, Ishii H, Garrison PN, Barnes LD, Croce CM, Huebner K: Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-tyrosine 114 (Y114) is essential. Oncogene. 2006 May 11;25(20):2860-72. [PubMed:16407838]
  14. Weiske J, Albring KF, Huber O: The tumor suppressor Fhit acts as a repressor of beta-catenin transcriptional activity. Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20344-9. Epub 2007 Dec 10. [PubMed:18077326]
  15. Rimessi A, Marchi S, Fotino C, Romagnoli A, Huebner K, Croce CM, Pinton P, Rizzuto R: Intramitochondrial calcium regulation by the FHIT gene product sensitizes to apoptosis. Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):12753-8. doi: 10.1073/pnas.0906484106. Epub 2009 Jul 21. [PubMed:19622739]
  16. Burkard TR, Planyavsky M, Kaupe I, Breitwieser FP, Burckstummer T, Bennett KL, Superti-Furga G, Colinge J: Initial characterization of the human central proteome. BMC Syst Biol. 2011 Jan 26;5:17. doi: 10.1186/1752-0509-5-17. [PubMed:21269460]
  17. Lima CD, D'Amico KL, Naday I, Rosenbaum G, Westbrook EM, Hendrickson WA: MAD analysis of FHIT, a putative human tumor suppressor from the HIT protein family. Structure. 1997 Jun 15;5(6):763-74. [PubMed:9261067]
  18. Lima CD, Klein MG, Hendrickson WA: Structure-based analysis of catalysis and substrate definition in the HIT protein family. Science. 1997 Oct 10;278(5336):286-90. [PubMed:9323207]
  19. Pace HC, Garrison PN, Robinson AK, Barnes LD, Draganescu A, Rosler A, Blackburn GM, Siprashvili Z, Croce CM, Huebner K, Brenner C: Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit. Proc Natl Acad Sci U S A. 1998 May 12;95(10):5484-9. [PubMed:9576908]

Drug Relations

Drug Relations
DrugBank IDNameDrug groupPharmacological action?ActionsDetails
DB02373Adenosine monotungstateexperimentalunknownDetails
DB04389Ado-P-Ch2-P-Ps-AdoexperimentalunknownDetails