FHIT_HUMAN
ID FHIT_HUMAN Reviewed; 147 AA.
AC P49789; A2IAS9; A2IAT0; A2IAT6; A8K1A9; Q45QG9; Q6IU12;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 23-JAN-2007, sequence version 3.
DT 03-AUG-2022, entry version 193.
DE RecName: Full=Bis(5'-adenosyl)-triphosphatase;
DE EC=3.6.1.29 {ECO:0000269|PubMed:12574506, ECO:0000269|PubMed:15182206, ECO:0000269|PubMed:8794732, ECO:0000269|PubMed:9323207, ECO:0000269|PubMed:9543008, ECO:0000269|PubMed:9576908};
DE AltName: Full=AP3A hydrolase;
DE Short=AP3Aase;
DE AltName: Full=Adenosine 5'-monophosphoramidase FHIT {ECO:0000305|PubMed:18694747};
DE EC=3.9.1.- {ECO:0000269|PubMed:18694747};
DE AltName: Full=Adenylylsulfatase;
DE EC=3.6.2.1 {ECO:0000269|PubMed:18694747};
DE AltName: Full=Adenylylsulfate-ammonia adenylyltransferase;
DE EC=2.7.7.51 {ECO:0000269|PubMed:26181368};
DE AltName: Full=Diadenosine 5',5'''-P1,P3-triphosphate hydrolase;
DE AltName: Full=Dinucleosidetriphosphatase;
DE AltName: Full=Fragile histidine triad protein;
GN Name=FHIT;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA].
RX PubMed=8598045; DOI=10.1016/s0092-8674(00)81034-x;
RA Ohta M., Inoue H., Cotticelli M.G., Kastury K., Baffa R., Palazzo J.,
RA Siprashvili Z., Mori M., McCue P., Druck T., Croce C.M., Huebner K.;
RT "The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal
RT carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract
RT cancers.";
RL Cell 84:587-597(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX PubMed=9012482;
RA Druck T., Hadaczek P., Fu T.B., Ohta M., Siprashvili Z., Baffa R.,
RA Negrini M., Kastury K., Veronese M.L., Rosen D., Rothstein J., McCue P.,
RA Cotticelli M.G., Inoue H., Croce C.M., Huebner K.;
RT "Structure and expression of the human FHIT gene in normal and tumor
RT cells.";
RL Cancer Res. 57:504-512(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RX PubMed=24722188; DOI=10.1038/ncomms4650;
RA Corominas R., Yang X., Lin G.N., Kang S., Shen Y., Ghamsari L., Broly M.,
RA Rodriguez M., Tam S., Wanamaker S.A., Fan C., Yi S., Tasan M., Lemmens I.,
RA Kuang X., Zhao N., Malhotra D., Michaelson J.J., Vacic V., Calderwood M.A.,
RA Roth F.P., Tavernier J., Horvath S., Salehi-Ashtiani K., Korkin D.,
RA Sebat J., Hill D.E., Hao T., Vidal M., Iakoucheva L.M.;
RT "Protein interaction network of alternatively spliced isoforms from brain
RT links genetic risk factors for autism.";
RL Nat. Commun. 5:3650-3650(2014).
RN [4]
RP NUCLEOTIDE SEQUENCE [MRNA], AND NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF
RP 94-146.
RA Naqvi S.R.A., Malik A., Kukreti H., Chaudhary A., Anand R., Deo S.S.,
RA Shukla N.K., Husain S.A., Pasha S.T.;
RT "Mutational analysis of FHIT gene.";
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Brain;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Colon;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [8]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF HIS-35; HIS-94; HIS-96 AND
RP HIS-98.
RX PubMed=8794732; DOI=10.1021/bi961415t;
RA Barnes L.D., Garrison P.N., Siprashvili Z., Guranowski A., Robinson A.K.,
RA Ingram S.W., Croce C.M., Ohta M., Huebner K.;
RT "Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5''-
RT P1,P3-triphosphate hydrolase.";
RL Biochemistry 35:11529-11535(1996).
RN [9]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=9543008; DOI=10.1093/protein/10.12.1461;
RA Brenner C., Pace H.C., Garrison P.N., Robinson A.K., Rosler A., Liu X.H.,
RA Blackburn G.M., Croce C.M., Huebner K., Barnes L.D.;
RT "Purification and crystallization of complexes modeling the active state of
RT the fragile histidine triad protein.";
RL Protein Eng. 10:1461-1463(1997).
RN [10]
RP CHROMOSOMAL TRANSLOCATION WITH RNF139.
RX PubMed=9689122; DOI=10.1073/pnas.95.16.9572;
RA Gemmill R.M., West J.D., Boldog F., Tanaka N., Robinson L.J., Smith D.I.,
RA Li F., Drabkin H.A.;
RT "The hereditary renal cell carcinoma 3;8 translocation fuses FHIT to a
RT patched-related gene, TRC8.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:9572-9577(1998).
RN [11]
RP INTERACTION WITH UBE2I.
RX PubMed=11085938; DOI=10.1042/bj3520443;
RA Shi Y., Zou M., Farid N.R., Paterson M.C.;
RT "Association of FHIT (fragile histidine triad), a candidate tumour
RT suppressor gene, with the ubiquitin-conjugating enzyme hUBC9.";
RL Biochem. J. 352:443-448(2000).
RN [12]
RP FUNCTION, CATALYTIC ACTIVITY, AND MUTAGENESIS OF ILE-10; LEU-25 AND HIS-96.
RX PubMed=12574506; DOI=10.1073/pnas.0437915100;
RA Trapasso F., Krakowiak A., Cesari R., Arkles J., Yendamuri S., Ishii H.,
RA Vecchione A., Kuroki T., Bieganowski P., Pace H.C., Huebner K., Croce C.M.,
RA Brenner C.;
RT "Designed FHIT alleles establish that Fhit-induced apoptosis in cancer
RT cells is limited by substrate binding.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:1592-1597(2003).
RN [13]
RP ACTIVE SITE, CATALYTIC ACTIVITY, MUTAGENESIS OF HIS-96, AND FUNCTION.
RX PubMed=15182206; DOI=10.1021/bi049762n;
RA Huang K., Arabshahi A., Wei Y., Frey P.A.;
RT "The mechanism of action of the fragile histidine triad, Fhit: isolation of
RT a covalent adenylyl enzyme and chemical rescue of H96G-Fhit.";
RL Biochemistry 43:7637-7642(2004).
RN [14]
RP FUNCTION, SUBCELLULAR LOCATION, AND INTERACTION WITH MDM2.
RX PubMed=15313915; DOI=10.1158/0008-5472.can-04-0195;
RA Nishizaki M., Sasaki J., Fang B., Atkinson E.N., Minna J.D., Roth J.A.,
RA Ji L.;
RT "Synergistic tumor suppression by coexpression of FHIT and p53 coincides
RT with FHIT-mediated MDM2 inactivation and p53 stabilization in human non-
RT small cell lung cancer cells.";
RL Cancer Res. 64:5745-5752(2004).
RN [15]
RP PHOSPHORYLATION BY SRC, SUBUNIT, SUBCELLULAR LOCATION, MASS SPECTROMETRY,
RP DISEASE, PHOSPHORYLATION AT TYR-114 AND TYR-145, AND MUTAGENESIS OF TYR-114
RP AND TYR-145.
RX PubMed=15007172; DOI=10.1073/pnas.0400481101;
RA Pekarsky Y., Garrison P.N., Palamarchuk A., Zanesi N., Aqeilan R.I.,
RA Huebner K., Barnes L.D., Croce C.M.;
RT "Fhit is a physiological target of the protein kinase Src.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:3775-3779(2004).
RN [16]
RP MUTAGENESIS OF TYR-114, FUNCTION, AND SITE.
RX PubMed=16407838; DOI=10.1038/sj.onc.1209323;
RA Semba S., Trapasso F., Fabbri M., McCorkell K.A., Volinia S., Druck T.,
RA Iliopoulos D., Pekarsky Y., Ishii H., Garrison P.N., Barnes L.D.,
RA Croce C.M., Huebner K.;
RT "Fhit modulation of the Akt-survivin pathway in lung cancer cells: Fhit-
RT tyrosine 114 (Y114) is essential.";
RL Oncogene 25:2860-2872(2006).
RN [17]
RP INTERACTION WITH CTNNB1, IDENTIFICATION IN A COMPLEX WITH CTNNB1 AND LEF1,
RP AND FUNCTION.
RX PubMed=18077326; DOI=10.1073/pnas.0703664105;
RA Weiske J., Albring K.F., Huber O.;
RT "The tumor suppressor Fhit acts as a repressor of beta-catenin
RT transcriptional activity.";
RL Proc. Natl. Acad. Sci. U.S.A. 104:20344-20349(2007).
RN [18]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=18694747; DOI=10.1016/j.febslet.2008.07.060;
RA Guranowski A., Wojdyla A.M., Pietrowska-Borek M., Bieganowski P.,
RA Khurs E.N., Cliff M.J., Blackburn G.M., Blaziak D., Stec W.J.;
RT "Fhit proteins can also recognize substrates other than dinucleoside
RT polyphosphates.";
RL FEBS Lett. 582:3152-3158(2008).
RN [19]
RP SUBCELLULAR LOCATION, AND FUNCTION IN APOPTOSIS.
RX PubMed=19622739; DOI=10.1073/pnas.0906484106;
RA Rimessi A., Marchi S., Fotino C., Romagnoli A., Huebner K., Croce C.M.,
RA Pinton P., Rizzuto R.;
RT "Intramitochondrial calcium regulation by the FHIT gene product sensitizes
RT to apoptosis.";
RL Proc. Natl. Acad. Sci. U.S.A. 106:12753-12758(2009).
RN [20]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [21]
RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=26181368; DOI=10.1042/bsr20150135;
RA Wojdyla-Mamon A.M., Guranowski A.;
RT "Adenylylsulfate-ammonia adenylyltransferase activity is another inherent
RT property of Fhit proteins.";
RL Biosci. Rep. 35:0-0(2015).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (1.85 ANGSTROMS).
RX PubMed=9261067; DOI=10.1016/s0969-2126(97)00231-1;
RA Lima C.D., D'Amico K.L., Naday I., Rosenbaum G., Westbrook E.M.,
RA Hendrickson W.A.;
RT "MAD analysis of FHIT, a putative human tumor suppressor from the HIT
RT protein family.";
RL Structure 5:763-774(1997).
RN [23]
RP X-RAY CRYSTALLOGRAPHY (2.3 ANGSTROMS) IN COMPLEXES WITH SUBSTRATES,
RP CATALYTIC ACTIVITY, FUNCTION, SUBUNIT, AND ACTIVE SITE.
RX PubMed=9323207; DOI=10.1126/science.278.5336.286;
RA Lima C.D., Klein M.G., Hendrickson W.A.;
RT "Structure-based analysis of catalysis and substrate definition in the HIT
RT protein family.";
RL Science 278:286-290(1997).
RN [24]
RP X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) IN COMPLEXES WITH SUBSTRATE ANALOGS,
RP SUBUNIT, CATALYTIC ACTIVITY, MUTAGENESIS OF HIS-96, AND FUNCTION.
RX PubMed=9576908; DOI=10.1073/pnas.95.10.5484;
RA Pace H.C., Garrison P.N., Robinson A.K., Barnes L.D., Draganescu A.,
RA Roesler A., Blackburn G.M., Siprashvili Z., Croce C.M., Huebner K.,
RA Brenner C.;
RT "Genetic, biochemical, and crystallographic characterization of Fhit-
RT substrate complexes as the active signaling form of Fhit.";
RL Proc. Natl. Acad. Sci. U.S.A. 95:5484-5489(1998).
CC -!- FUNCTION: Possesses dinucleoside triphosphate hydrolase activity
CC (PubMed:12574506, PubMed:15182206, PubMed:8794732, PubMed:9323207,
CC PubMed:9576908, PubMed:9543008). Cleaves P(1)-P(3)-bis(5'-adenosyl)
CC triphosphate (Ap3A) to yield AMP and ADP (PubMed:12574506,
CC PubMed:15182206, PubMed:8794732, PubMed:9323207, PubMed:9576908,
CC PubMed:9543008). Can also hydrolyze P(1)-P(4)-bis(5'-adenosyl)
CC tetraphosphate (Ap4A), but has extremely low activity with ATP
CC (PubMed:8794732). Exhibits adenylylsulfatase activity, hydrolyzing
CC adenosine 5'-phosphosulfate to yield AMP and sulfate (PubMed:18694747).
CC Exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine
CC nucleotide phosphoramidates with a single phosphate group such as
CC adenosine 5'monophosphoramidate (AMP-NH2) to yield AMP and NH2
CC (PubMed:18694747). Exhibits adenylylsulfate-ammonia
CC adenylyltransferase, catalyzing the ammonolysis of adenosine 5'-
CC phosphosulfate resulting in the formation of adenosine 5'-
CC phosphoramidate (PubMed:26181368). Also catalyzes the ammonolysis of
CC adenosine 5-phosphorofluoridate and diadenosine triphosphate
CC (PubMed:26181368). Modulates transcriptional activation by CTNNB1 and
CC thereby contributes to regulate the expression of genes essential for
CC cell proliferation and survival, such as CCND1 and BIRC5
CC (PubMed:18077326). Plays a role in the induction of apoptosis via SRC
CC and AKT1 signaling pathways (PubMed:16407838). Inhibits MDM2-mediated
CC proteasomal degradation of p53/TP53 and thereby plays a role in
CC p53/TP53-mediated apoptosis (PubMed:15313915). Induction of apoptosis
CC depends on the ability of FHIT to bind P(1)-P(3)-bis(5'-adenosyl)
CC triphosphate or related compounds, but does not require its catalytic
CC activity, it may in part come from the mitochondrial form, which
CC sensitizes the low-affinity Ca(2+) transporters, enhancing
CC mitochondrial calcium uptake (PubMed:12574506, PubMed:19622739).
CC Functions as tumor suppressor (By similarity).
CC {ECO:0000250|UniProtKB:O89106, ECO:0000269|PubMed:12574506,
CC ECO:0000269|PubMed:15313915, ECO:0000269|PubMed:16407838,
CC ECO:0000269|PubMed:18077326, ECO:0000269|PubMed:18694747,
CC ECO:0000269|PubMed:19622739, ECO:0000269|PubMed:26181368,
CC ECO:0000269|PubMed:8794732, ECO:0000269|PubMed:9323207,
CC ECO:0000269|PubMed:9543008}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H2O + P(1),P(3)-bis(5'-adenosyl) triphosphate = ADP + AMP + 2
CC H(+); Xref=Rhea:RHEA:13893, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:58529, ChEBI:CHEBI:456215, ChEBI:CHEBI:456216;
CC EC=3.6.1.29; Evidence={ECO:0000269|PubMed:12574506,
CC ECO:0000269|PubMed:15182206, ECO:0000269|PubMed:8794732,
CC ECO:0000269|PubMed:9323207, ECO:0000269|PubMed:9543008,
CC ECO:0000269|PubMed:9576908};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=adenosine 5'-phosphosulfate + H2O = AMP + 2 H(+) + sulfate;
CC Xref=Rhea:RHEA:17041, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16189, ChEBI:CHEBI:58243, ChEBI:CHEBI:456215; EC=3.6.2.1;
CC Evidence={ECO:0000269|PubMed:18694747};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=adenosine 5'-phosphosulfate + NH4(+) = adenosine 5'-
CC phosphoramidate + 2 H(+) + sulfate; Xref=Rhea:RHEA:19197,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16189, ChEBI:CHEBI:28938,
CC ChEBI:CHEBI:57890, ChEBI:CHEBI:58243; EC=2.7.7.51;
CC Evidence={ECO:0000269|PubMed:26181368};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=adenosine 5'-phosphoramidate + H2O = AMP + NH4(+);
CC Xref=Rhea:RHEA:67916, ChEBI:CHEBI:15377, ChEBI:CHEBI:28938,
CC ChEBI:CHEBI:57890, ChEBI:CHEBI:456215;
CC Evidence={ECO:0000269|PubMed:18694747};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=1.9 uM for P(1)-P(3)-bis(5'-adenosyl) triphosphate
CC {ECO:0000269|PubMed:9543008};
CC KM=3 uM for adenosine 5'-phosphoramidate (at pH 6.8)
CC {ECO:0000269|PubMed:18694747};
CC KM=2.4 mM for adenosine 5'-phosphosulfate
CC {ECO:0000269|PubMed:26181368};
CC KM=1.6 mM for adenosine-phosphorofluoridate
CC {ECO:0000269|PubMed:26181368};
CC -!- SUBUNIT: Homodimer. Interacts with UBE2I. Interacts with MDM2.
CC Interacts with CTNNB1. Identified in a complex with CTNNB1 and LEF1.
CC {ECO:0000269|PubMed:11085938, ECO:0000269|PubMed:15007172,
CC ECO:0000269|PubMed:15313915, ECO:0000269|PubMed:18077326,
CC ECO:0000269|PubMed:9323207, ECO:0000269|PubMed:9576908}.
CC -!- INTERACTION:
CC P49789; P35222: CTNNB1; NbExp=4; IntAct=EBI-741760, EBI-491549;
CC P49789; Q96D03: DDIT4L; NbExp=3; IntAct=EBI-741760, EBI-742054;
CC P49789; P49789: FHIT; NbExp=13; IntAct=EBI-741760, EBI-741760;
CC P49789; Q9UJU2: LEF1; NbExp=2; IntAct=EBI-741760, EBI-926131;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:15007172,
CC ECO:0000269|PubMed:15313915}. Mitochondrion
CC {ECO:0000269|PubMed:19622739}. Nucleus {ECO:0000269|PubMed:15313915}.
CC -!- TISSUE SPECIFICITY: Low levels expressed in all tissues tested.
CC Phospho-FHIT observed in liver and kidney, but not in brain and lung.
CC Phospho-FHIT undetected in all tested human tumor cell lines.
CC -!- PTM: Phosphorylation at Tyr-114 by SRC is required for induction of
CC apoptosis. {ECO:0000269|PubMed:15007172}.
CC -!- MASS SPECTROMETRY: Mass=16733; Method=MALDI;
CC Evidence={ECO:0000269|PubMed:15007172};
CC -!- DISEASE: Note=A chromosomal aberration involving FHIT has been found in
CC a lymphoblastoid cell line established from a family with renal cell
CC carcinoma and thyroid carcinoma. Translocation t(3;8)(p14.2;q24.1) with
CC RNF139. Although the 3p14.2 breakpoint has been shown to interrupt FHIT
CC in its 5-prime non-coding region, it is unlikely that FHIT is causally
CC related to renal or other malignancies. {ECO:0000269|PubMed:15007172}.
CC -!- DISEASE: Note=Associated with digestive tract cancers. Numerous tumor
CC types are found to have aberrant forms of FHIT protein due to deletions
CC in a coding region of chromosome 3p14.2 including the fragile site
CC locus FRA3B. {ECO:0000269|PubMed:15007172}.
CC -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC Haematology;
CC URL="http://atlasgeneticsoncology.org/Genes/FHITID192ch3p14.html";
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DR EMBL; U46922; AAA99013.1; -; mRNA.
DR EMBL; U76271; AAB52539.1; -; Genomic_DNA.
DR EMBL; U76267; AAB52539.1; JOINED; Genomic_DNA.
DR EMBL; U76268; AAB52539.1; JOINED; Genomic_DNA.
DR EMBL; U76269; AAB52539.1; JOINED; Genomic_DNA.
DR EMBL; U76270; AAB52539.1; JOINED; Genomic_DNA.
DR EMBL; KJ534835; AHW56475.1; -; mRNA.
DR EMBL; AY625256; AAT37530.1; -; Genomic_DNA.
DR EMBL; DQ120721; AAZ23623.1; -; mRNA.
DR EMBL; EF186677; ABM65879.1; -; Genomic_DNA.
DR EMBL; EF183457; ABM66086.1; -; Genomic_DNA.
DR EMBL; EF183458; ABM66087.1; -; Genomic_DNA.
DR EMBL; EF183459; ABM66088.1; -; Genomic_DNA.
DR EMBL; EF183461; ABM66090.1; -; Genomic_DNA.
DR EMBL; EF183464; ABM66093.1; -; Genomic_DNA.
DR EMBL; AK289824; BAF82513.1; -; mRNA.
DR EMBL; CH471055; EAW65393.1; -; Genomic_DNA.
DR EMBL; BC032336; AAH32336.1; -; mRNA.
DR CCDS; CCDS2894.1; -.
DR PIR; A58802; A58802.
DR RefSeq; NP_001159715.1; NM_001166243.2.
DR RefSeq; NP_001307828.1; NM_001320899.1.
DR RefSeq; NP_001307829.1; NM_001320900.1.
DR RefSeq; NP_002003.1; NM_002012.3.
DR PDB; 1FHI; X-ray; 3.10 A; A=1-147.
DR PDB; 1FIT; X-ray; 1.85 A; A=1-147.
DR PDB; 2FHI; X-ray; 2.60 A; A=1-147.
DR PDB; 2FIT; X-ray; 1.90 A; A=1-147.
DR PDB; 3FIT; X-ray; 2.40 A; A=1-147.
DR PDB; 4FIT; X-ray; 2.50 A; A=1-147.
DR PDB; 5FIT; X-ray; 2.30 A; A=1-147.
DR PDB; 6FIT; X-ray; 2.60 A; A=1-147.
DR PDBsum; 1FHI; -.
DR PDBsum; 1FIT; -.
DR PDBsum; 2FHI; -.
DR PDBsum; 2FIT; -.
DR PDBsum; 3FIT; -.
DR PDBsum; 4FIT; -.
DR PDBsum; 5FIT; -.
DR PDBsum; 6FIT; -.
DR AlphaFoldDB; P49789; -.
DR SMR; P49789; -.
DR BioGRID; 108563; 22.
DR DIP; DIP-29947N; -.
DR IntAct; P49789; 9.
DR STRING; 9606.ENSP00000417480; -.
DR BindingDB; P49789; -.
DR ChEMBL; CHEMBL1795151; -.
DR DrugBank; DB02373; Adenosine monotungstate.
DR DrugBank; DB04389; Ado-P-Ch2-P-Ps-Ado.
DR iPTMnet; P49789; -.
DR PhosphoSitePlus; P49789; -.
DR BioMuta; FHIT; -.
DR DMDM; 1706794; -.
DR EPD; P49789; -.
DR jPOST; P49789; -.
DR MassIVE; P49789; -.
DR PaxDb; P49789; -.
DR PeptideAtlas; P49789; -.
DR PRIDE; P49789; -.
DR ProteomicsDB; 56119; -.
DR Antibodypedia; 3636; 646 antibodies from 39 providers.
DR DNASU; 2272; -.
DR Ensembl; ENST00000468189.5; ENSP00000417480.1; ENSG00000189283.10.
DR Ensembl; ENST00000476844.5; ENSP00000417557.1; ENSG00000189283.10.
DR Ensembl; ENST00000492590.6; ENSP00000418582.1; ENSG00000189283.10.
DR GeneID; 2272; -.
DR KEGG; hsa:2272; -.
DR MANE-Select; ENST00000492590.6; ENSP00000418582.1; NM_002012.4; NP_002003.1.
DR UCSC; uc003dkx.5; human.
DR CTD; 2272; -.
DR DisGeNET; 2272; -.
DR GeneCards; FHIT; -.
DR HGNC; HGNC:3701; FHIT.
DR HPA; ENSG00000189283; Tissue enhanced (choroid).
DR MalaCards; FHIT; -.
DR MIM; 601153; gene.
DR neXtProt; NX_P49789; -.
DR OpenTargets; ENSG00000189283; -.
DR Orphanet; 422526; Hereditary clear cell renal cell carcinoma.
DR PharmGKB; PA28140; -.
DR VEuPathDB; HostDB:ENSG00000189283; -.
DR eggNOG; KOG3379; Eukaryota.
DR GeneTree; ENSGT00510000047967; -.
DR HOGENOM; CLU_056776_7_1_1; -.
DR OMA; DAIYGMM; -.
DR OrthoDB; 1198291at2759; -.
DR PhylomeDB; P49789; -.
DR TreeFam; TF105432; -.
DR BRENDA; 3.6.1.29; 2681.
DR PathwayCommons; P49789; -.
DR SABIO-RK; P49789; -.
DR SignaLink; P49789; -.
DR SIGNOR; P49789; -.
DR BioGRID-ORCS; 2272; 10 hits in 1075 CRISPR screens.
DR ChiTaRS; FHIT; human.
DR EvolutionaryTrace; P49789; -.
DR GeneWiki; FHIT; -.
DR GenomeRNAi; 2272; -.
DR Pharos; P49789; Tchem.
DR PRO; PR:P49789; -.
DR Proteomes; UP000005640; Chromosome 3.
DR RNAct; P49789; protein.
DR Bgee; ENSG00000189283; Expressed in right adrenal gland and 109 other tissues.
DR ExpressionAtlas; P49789; baseline and differential.
DR Genevisible; P49789; HS.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0001650; C:fibrillar center; IDA:HPA.
DR GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:HPA.
DR GO; GO:0043530; F:adenosine 5'-monophosphoramidase activity; IDA:UniProtKB.
DR GO; GO:0047627; F:adenylylsulfatase activity; IDA:UniProtKB.
DR GO; GO:0047352; F:adenylylsulfate-ammonia adenylyltransferase activity; IDA:UniProtKB.
DR GO; GO:0047710; F:bis(5'-adenosyl)-triphosphatase activity; IDA:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IPI:IntAct.
DR GO; GO:0000166; F:nucleotide binding; IEA:UniProtKB-KW.
DR GO; GO:0031625; F:ubiquitin protein ligase binding; IPI:UniProtKB.
DR GO; GO:0015964; P:diadenosine triphosphate catabolic process; IDA:UniProtKB.
DR GO; GO:0072332; P:intrinsic apoptotic signaling pathway by p53 class mediator; IMP:UniProtKB.
DR GO; GO:0032435; P:negative regulation of proteasomal ubiquitin-dependent protein catabolic process; IMP:UniProtKB.
DR GO; GO:0006163; P:purine nucleotide metabolic process; IDA:UniProtKB.
DR CDD; cd01275; FHIT; 1.
DR Gene3D; 3.30.428.10; -; 1.
DR InterPro; IPR039383; FHIT.
DR InterPro; IPR019808; Histidine_triad_CS.
DR InterPro; IPR011146; HIT-like.
DR InterPro; IPR036265; HIT-like_sf.
DR Pfam; PF01230; HIT; 1.
DR SUPFAM; SSF54197; SSF54197; 1.
DR PROSITE; PS00892; HIT_1; 1.
DR PROSITE; PS51084; HIT_2; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Apoptosis; Chromosomal rearrangement; Cytoplasm; Hydrolase;
KW Manganese; Mitochondrion; Nucleotide-binding; Nucleus; Phosphoprotein;
KW Reference proteome; Transcription; Transcription regulation; Transferase;
KW Tumor suppressor.
FT CHAIN 1..147
FT /note="Bis(5'-adenosyl)-triphosphatase"
FT /id="PRO_0000109789"
FT DOMAIN 2..109
FT /note="HIT"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00464"
FT MOTIF 94..98
FT /note="Histidine triad motif"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00464"
FT ACT_SITE 96
FT /note="Tele-AMP-histidine intermediate"
FT /evidence="ECO:0000269|PubMed:15182206,
FT ECO:0000269|PubMed:9323207"
FT BINDING 8
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:9261067,
FT ECO:0007744|PDB:3FIT"
FT BINDING 27
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:9323207,
FT ECO:0007744|PDB:5FIT"
FT BINDING 83
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:9323207,
FT ECO:0007744|PDB:5FIT"
FT BINDING 89..92
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:9323207,
FT ECO:0007744|PDB:5FIT"
FT BINDING 98
FT /ligand="substrate"
FT /evidence="ECO:0000269|PubMed:9323207,
FT ECO:0007744|PDB:5FIT"
FT SITE 114
FT /note="Important for induction of apoptosis"
FT /evidence="ECO:0000269|PubMed:16407838"
FT MOD_RES 114
FT /note="Phosphotyrosine; by SRC"
FT /evidence="ECO:0000269|PubMed:15007172"
FT MOD_RES 145
FT /note="Phosphotyrosine"
FT /evidence="ECO:0000269|PubMed:15007172"
FT MUTAGEN 10
FT /note="I->W: Strongly reduces affinity for substrates and
FT impairs apoptosis; when associated with W-25."
FT /evidence="ECO:0000269|PubMed:12574506"
FT MUTAGEN 25
FT /note="L->W: Reduces affinity for substrates and impairs
FT apoptosis. Strongly reduces affinity for substrates and
FT impairs apoptosis; when associated with W-10."
FT /evidence="ECO:0000269|PubMed:12574506"
FT MUTAGEN 35
FT /note="H->N: 50% decrease in catalytic activity. No loss in
FT substrate binding."
FT /evidence="ECO:0000269|PubMed:8794732"
FT MUTAGEN 94
FT /note="H->N: 75% decrease in catalytic activity. No loss in
FT substrate binding."
FT /evidence="ECO:0000269|PubMed:8794732"
FT MUTAGEN 96
FT /note="H->D: Loss of catalytic activity."
FT /evidence="ECO:0000269|PubMed:12574506,
FT ECO:0000269|PubMed:15182206, ECO:0000269|PubMed:8794732,
FT ECO:0000269|PubMed:9576908"
FT MUTAGEN 96
FT /note="H->G: Total loss of catalytic activity. Rescuable
FT with free imidazole."
FT /evidence="ECO:0000269|PubMed:12574506,
FT ECO:0000269|PubMed:15182206, ECO:0000269|PubMed:8794732,
FT ECO:0000269|PubMed:9576908"
FT MUTAGEN 96
FT /note="H->N: Total loss of catalytic activity. No loss in
FT substrate binding."
FT /evidence="ECO:0000269|PubMed:12574506,
FT ECO:0000269|PubMed:15182206, ECO:0000269|PubMed:8794732,
FT ECO:0000269|PubMed:9576908"
FT MUTAGEN 98
FT /note="H->N: 98% decrease in catalytic activity."
FT /evidence="ECO:0000269|PubMed:8794732"
FT MUTAGEN 114
FT /note="Y->A: Impairs induction of apoptosis. Strongly
FT reduced affinity for substrates."
FT /evidence="ECO:0000269|PubMed:15007172,
FT ECO:0000269|PubMed:16407838"
FT MUTAGEN 114
FT /note="Y->D: Impairs induction of apoptosis. Reduces
FT affinity for substrates."
FT /evidence="ECO:0000269|PubMed:15007172,
FT ECO:0000269|PubMed:16407838"
FT MUTAGEN 114
FT /note="Y->F: Loss of phosphorylation by SRC. Impairs
FT induction of apoptosis."
FT /evidence="ECO:0000269|PubMed:15007172,
FT ECO:0000269|PubMed:16407838"
FT MUTAGEN 145
FT /note="Y->F: No effect on phosphorylation by SRC."
FT /evidence="ECO:0000269|PubMed:15007172"
FT CONFLICT 146
FT /note="F -> S (in Ref. 5; BAF82513)"
FT /evidence="ECO:0000305"
FT STRAND 3..5
FT /evidence="ECO:0007829|PDB:1FIT"
FT STRAND 8..10
FT /evidence="ECO:0007829|PDB:1FIT"
FT HELIX 12..14
FT /evidence="ECO:0007829|PDB:1FIT"
FT STRAND 15..18
FT /evidence="ECO:0007829|PDB:1FIT"
FT STRAND 20..26
FT /evidence="ECO:0007829|PDB:1FIT"
FT STRAND 36..42
FT /evidence="ECO:0007829|PDB:1FIT"
FT HELIX 47..49
FT /evidence="ECO:0007829|PDB:1FIT"
FT HELIX 52..72
FT /evidence="ECO:0007829|PDB:1FIT"
FT STRAND 76..82
FT /evidence="ECO:0007829|PDB:1FIT"
FT HELIX 86..88
FT /evidence="ECO:0007829|PDB:1FIT"
FT STRAND 92..94
FT /evidence="ECO:0007829|PDB:1FIT"
FT STRAND 97..102
FT /evidence="ECO:0007829|PDB:1FIT"
FT HELIX 132..144
FT /evidence="ECO:0007829|PDB:1FIT"
SQ SEQUENCE 147 AA; 16858 MW; 14D85961A19ECF3E CRC64;
MSFRFGQHLI KPSVVFLKTE LSFALVNRKP VVPGHVLVCP LRPVERFHDL RPDEVADLFQ
TTQRVGTVVE KHFHGTSLTF SMQDGPEAGQ TVKHVHVHVL PRKAGDFHRN DSIYEELQKH
DKEDFPASWR SEEEMAAEAA ALRVYFQ
