UniProtKB - P49789 (FHIT_HUMAN)
Bis(5'-adenosyl)-triphosphatase
FHIT
Functioni
Possesses dinucleoside triphosphate hydrolase activity (PubMed:12574506, PubMed:15182206, PubMed:8794732, PubMed:9323207, PubMed:9576908, PubMed:9543008).
Cleaves P1-P3-bis(5'-adenosyl) triphosphate (Ap3A) to yield AMP and ADP (PubMed:12574506, PubMed:15182206, PubMed:8794732, PubMed:9323207, PubMed:9576908, PubMed:9543008).
Can also hydrolyze P1-P4-bis(5'-adenosyl) tetraphosphate (Ap4A), but has extremely low activity with ATP (PubMed:8794732).
Exhibits adenylylsulfatase activity, hydrolyzing adenosine 5'-phosphosulfate to yield AMP and sulfate (PubMed:18694747).
Exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates with a single phosphate group such as adenosine 5'monophosphoramidate (AMP-NH2) to yield AMP and NH2 (PubMed:18694747).
Exhibits adenylylsulfate-ammonia adenylyltransferase, catalyzing the ammonolysis of adenosine 5'-phosphosulfate resulting in the formation of adenosine 5'-phosphoramidate (PubMed:26181368).
Also catalyzes the ammonolysis of adenosine 5-phosphorofluoridate and diadenosine triphosphate (PubMed:26181368).
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 (PubMed:18077326).
Plays a role in the induction of apoptosis via SRC and AKT1 signaling pathways (PubMed:16407838).
Inhibits MDM2-mediated proteasomal degradation of p53/TP53 and thereby plays a role in p53/TP53-mediated apoptosis (PubMed:15313915).
Induction of apoptosis depends on the ability of FHIT to bind P1-P3-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 Ca2+ transporters, enhancing mitochondrial calcium uptake (PubMed:12574506, PubMed:19622739).
Functions as tumor suppressor (By similarity).
By similarity10 PublicationsCatalytic activityi
Kineticsi
- KM=1.9 µM for P1-P3-bis(5'-adenosyl) triphosphate1 Publication
- KM=3 µM for adenosine 5'-phosphoramidate (at pH 6.8)1 Publication
- KM=2.4 mM for adenosine 5'-phosphosulfate1 Publication
- KM=1.6 mM for adenosine-phosphorofluoridate1 Publication
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 8 | SubstrateCombined sources1 Publication | 1 | |
Binding sitei | 27 | SubstrateCombined sources1 Publication | 1 | |
Binding sitei | 83 | SubstrateCombined sources1 Publication | 1 | |
Active sitei | 96 | Tele-AMP-histidine intermediate2 Publications | 1 | |
Binding sitei | 98 | SubstrateCombined sources1 Publication | 1 | |
Sitei | 114 | Important for induction of apoptosis1 Publication | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 89 – 92 | SubstrateCombined sources1 Publication | 4 |
GO - Molecular functioni
- adenosine 5'-monophosphoramidase activity Source: UniProtKB
- adenylylsulfatase activity Source: UniProtKB
- adenylylsulfate-ammonia adenylyltransferase activity Source: UniProtKB
- bis(5'-adenosyl)-triphosphatase activity Source: UniProtKB
- identical protein binding Source: IntAct
- nucleotide binding Source: UniProtKB-KW
- ubiquitin protein ligase binding Source: UniProtKB
GO - Biological processi
- diadenosine triphosphate catabolic process Source: UniProtKB
- intrinsic apoptotic signaling pathway by p53 class mediator Source: UniProtKB
- negative regulation of proteasomal ubiquitin-dependent protein catabolic process Source: UniProtKB
- purine nucleotide metabolic process Source: UniProtKB
Keywordsi
Molecular function | Hydrolase, Transferase |
Biological process | Apoptosis, Transcription, Transcription regulation |
Ligand | Manganese, Nucleotide-binding |
Enzyme and pathway databases
BRENDAi | 3.6.1.29, 2681 |
PathwayCommonsi | P49789 |
SABIO-RKi | P49789 |
SignaLinki | P49789 |
SIGNORi | P49789 |
Names & Taxonomyi
Protein namesi | Recommended name: Bis(5'-adenosyl)-triphosphatase (EC:3.6.1.296 Publications)Alternative name(s): AP3A hydrolase Short name: AP3Aase Adenosine 5'-monophosphoramidase FHIT1 Publication (EC:3.9.1.-1 Publication) Adenylylsulfatase (EC:3.6.2.11 Publication) Adenylylsulfate-ammonia adenylyltransferase (EC:2.7.7.511 Publication) Diadenosine 5',5'''-P1,P3-triphosphate hydrolase Dinucleosidetriphosphatase Fragile histidine triad protein |
Gene namesi | Name:FHIT |
Organismi | Homo sapiens (Human) |
Taxonomic identifieri | 9606 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo |
Proteomesi |
|
Organism-specific databases
HGNCi | HGNC:3701, FHIT |
MIMi | 601153, gene |
neXtProti | NX_P49789 |
VEuPathDBi | HostDB:ENSG00000189283 |
Subcellular locationi
Nucleus
- Nucleus 1 Publication
Mitochondrion
- Mitochondrion 1 Publication
Cytoplasm and Cytosol
- Cytoplasm 2 Publications
Cytosol
- cytosol Source: UniProtKB
Mitochondrion
- mitochondrion Source: UniProtKB-SubCell
Nucleus
- fibrillar center Source: HPA
- nucleus Source: GO_Central
Plasma Membrane
- plasma membrane Source: HPA
Other locations
- cytoplasm Source: UniProtKB
Keywords - Cellular componenti
Cytoplasm, Mitochondrion, NucleusPathology & Biotechi
Involvement in diseasei
Mutagenesis
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Mutagenesisi | 10 | I → W: Strongly reduces affinity for substrates and impairs apoptosis; when associated with W-25. 1 Publication | 1 | |
Mutagenesisi | 25 | L → W: Reduces affinity for substrates and impairs apoptosis. Strongly reduces affinity for substrates and impairs apoptosis; when associated with W-10. 1 Publication | 1 | |
Mutagenesisi | 35 | H → N: 50% decrease in catalytic activity. No loss in substrate binding. 1 Publication | 1 | |
Mutagenesisi | 94 | H → N: 75% decrease in catalytic activity. No loss in substrate binding. 1 Publication | 1 | |
Mutagenesisi | 96 | H → D: Loss of catalytic activity. 4 Publications | 1 | |
Mutagenesisi | 96 | H → G: Total loss of catalytic activity. Rescuable with free imidazole. 4 Publications | 1 | |
Mutagenesisi | 96 | H → N: Total loss of catalytic activity. No loss in substrate binding. 4 Publications | 1 | |
Mutagenesisi | 98 | H → N: 98% decrease in catalytic activity. 1 Publication | 1 | |
Mutagenesisi | 114 | Y → A: Impairs induction of apoptosis. Strongly reduced affinity for substrates. 2 Publications | 1 | |
Mutagenesisi | 114 | Y → D: Impairs induction of apoptosis. Reduces affinity for substrates. 2 Publications | 1 | |
Mutagenesisi | 114 | Y → F: Loss of phosphorylation by SRC. Impairs induction of apoptosis. 2 Publications | 1 | |
Mutagenesisi | 145 | Y → F: No effect on phosphorylation by SRC. 1 Publication | 1 |
Keywords - Diseasei
Tumor suppressorOrganism-specific databases
DisGeNETi | 2272 |
MalaCardsi | FHIT |
OpenTargetsi | ENSG00000189283 |
Orphaneti | 422526, Hereditary clear cell renal cell carcinoma |
PharmGKBi | PA28140 |
Miscellaneous databases
Pharosi | P49789, Tchem |
Chemistry databases
ChEMBLi | CHEMBL1795151 |
DrugBanki | DB02373, Adenosine monotungstate DB04389, Ado-P-Ch2-P-Ps-Ado |
Genetic variation databases
BioMutai | FHIT |
DMDMi | 1706794 |
PTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000109789 | 1 – 147 | Bis(5'-adenosyl)-triphosphataseAdd BLAST | 147 |
Amino acid modifications
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Modified residuei | 114 | Phosphotyrosine; by SRC1 Publication | 1 | |
Modified residuei | 145 | Phosphotyrosine1 Publication | 1 |
Post-translational modificationi
Keywords - PTMi
PhosphoproteinProteomic databases
EPDi | P49789 |
jPOSTi | P49789 |
MassIVEi | P49789 |
PaxDbi | P49789 |
PeptideAtlasi | P49789 |
PRIDEi | P49789 |
ProteomicsDBi | 56119 |
PTM databases
iPTMneti | P49789 |
PhosphoSitePlusi | P49789 |
Expressioni
Tissue specificityi
Gene expression databases
Bgeei | ENSG00000189283, Expressed in pigmented layer of retina and 150 other tissues |
ExpressionAtlasi | P49789, baseline and differential |
Genevisiblei | P49789, HS |
Organism-specific databases
HPAi | ENSG00000189283, Tissue enhanced (choroid) |
Interactioni
Subunit structurei
Homodimer.
Interacts with UBE2I.
Interacts with MDM2.
Interacts with CTNNB1.
Identified in a complex with CTNNB1 and LEF1.
6 PublicationsBinary interactionsi
P49789
With | #Exp. | IntAct |
---|---|---|
CTNNB1 [P35222] | 4 | EBI-741760,EBI-491549 |
DDIT4L [Q96D03] | 3 | EBI-741760,EBI-742054 |
itself | 13 | EBI-741760,EBI-741760 |
LEF1 [Q9UJU2] | 2 | EBI-741760,EBI-926131 |
GO - Molecular functioni
- identical protein binding Source: IntAct
- ubiquitin protein ligase binding Source: UniProtKB
Protein-protein interaction databases
BioGRIDi | 108563, 22 interactors |
DIPi | DIP-29947N |
IntActi | P49789, 9 interactors |
STRINGi | 9606.ENSP00000417480 |
Chemistry databases
BindingDBi | P49789 |
Miscellaneous databases
RNActi | P49789, protein |
Structurei
Secondary structure
3D structure databases
AlphaFoldDBi | P49789 |
SMRi | P49789 |
ModBasei | Search... |
PDBe-KBi | Search... |
Miscellaneous databases
EvolutionaryTracei | P49789 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 2 – 109 | HITPROSITE-ProRule annotationAdd BLAST | 108 |
Motif
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Motifi | 94 – 98 | Histidine triad motifPROSITE-ProRule annotation | 5 |
Phylogenomic databases
eggNOGi | KOG3379, Eukaryota |
GeneTreei | ENSGT00510000047967 |
HOGENOMi | CLU_056776_7_1_1 |
OMAi | DAIYGMM |
OrthoDBi | 1198291at2759 |
PhylomeDBi | P49789 |
TreeFami | TF105432 |
Family and domain databases
CDDi | cd01275, FHIT, 1 hit |
Gene3Di | 3.30.428.10, 1 hit |
InterProi | View protein in InterPro IPR039383, FHIT IPR019808, Histidine_triad_CS IPR011146, HIT-like IPR036265, HIT-like_sf |
Pfami | View protein in Pfam PF01230, HIT, 1 hit |
SUPFAMi | SSF54197, SSF54197, 1 hit |
PROSITEi | View protein in PROSITE PS00892, HIT_1, 1 hit PS51084, HIT_2, 1 hit |
(1+)i Sequence
Sequence statusi: Complete.
This entry has 1 described isoform and 2 potential isoforms that are computationally mapped.Show allAlign All
10 20 30 40 50
MSFRFGQHLI KPSVVFLKTE LSFALVNRKP VVPGHVLVCP LRPVERFHDL
60 70 80 90 100
RPDEVADLFQ TTQRVGTVVE KHFHGTSLTF SMQDGPEAGQ TVKHVHVHVL
110 120 130 140
PRKAGDFHRN DSIYEELQKH DKEDFPASWR SEEEMAAEAA ALRVYFQ
Computationally mapped potential isoform sequencesi
There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basketE9PBZ0 | E9PBZ0_HUMAN | Bis(5'-adenosyl)-triphosphatase | FHIT | 78 | Annotation score: | ||
A0A0A0MRB0 | A0A0A0MRB0_HUMAN | Bis(5'-adenosyl)-triphosphatase | FHIT | 58 | Annotation score: |
Experimental Info
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Sequence conflicti | 146 | F → S in BAF82513 (PubMed:14702039).Curated | 1 |
Mass spectrometryi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U46922 mRNA Translation: AAA99013.1 U76271 , U76267, U76268, U76269, U76270 Genomic DNA Translation: AAB52539.1 KJ534835 mRNA Translation: AHW56475.1 AY625256 Genomic DNA Translation: AAT37530.1 DQ120721 mRNA Translation: AAZ23623.1 EF186677 Genomic DNA Translation: ABM65879.1 EF183457 Genomic DNA Translation: ABM66086.1 EF183458 Genomic DNA Translation: ABM66087.1 EF183459 Genomic DNA Translation: ABM66088.1 EF183461 Genomic DNA Translation: ABM66090.1 EF183464 Genomic DNA Translation: ABM66093.1 AK289824 mRNA Translation: BAF82513.1 CH471055 Genomic DNA Translation: EAW65393.1 BC032336 mRNA Translation: AAH32336.1 |
CCDSi | CCDS2894.1 |
PIRi | A58802 |
RefSeqi | NP_001159715.1, NM_001166243.2 NP_001307828.1, NM_001320899.1 NP_001307829.1, NM_001320900.1 NP_002003.1, NM_002012.3 |
Genome annotation databases
Ensembli | ENST00000468189.5; ENSP00000417480.1; ENSG00000189283.10 ENST00000476844.5; ENSP00000417557.1; ENSG00000189283.10 ENST00000492590.6; ENSP00000418582.1; ENSG00000189283.10 |
GeneIDi | 2272 |
KEGGi | hsa:2272 |
MANE-Selecti | ENST00000492590.6; ENSP00000418582.1; NM_002012.4; NP_002003.1 |
UCSCi | uc003dkx.5, human |
Keywords - Coding sequence diversityi
Chromosomal rearrangementSimilar proteinsi
Cross-referencesi
Web resourcesi
Atlas of Genetics and Cytogenetics in Oncology and Haematology |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | U46922 mRNA Translation: AAA99013.1 U76271 , U76267, U76268, U76269, U76270 Genomic DNA Translation: AAB52539.1 KJ534835 mRNA Translation: AHW56475.1 AY625256 Genomic DNA Translation: AAT37530.1 DQ120721 mRNA Translation: AAZ23623.1 EF186677 Genomic DNA Translation: ABM65879.1 EF183457 Genomic DNA Translation: ABM66086.1 EF183458 Genomic DNA Translation: ABM66087.1 EF183459 Genomic DNA Translation: ABM66088.1 EF183461 Genomic DNA Translation: ABM66090.1 EF183464 Genomic DNA Translation: ABM66093.1 AK289824 mRNA Translation: BAF82513.1 CH471055 Genomic DNA Translation: EAW65393.1 BC032336 mRNA Translation: AAH32336.1 |
CCDSi | CCDS2894.1 |
PIRi | A58802 |
RefSeqi | NP_001159715.1, NM_001166243.2 NP_001307828.1, NM_001320899.1 NP_001307829.1, NM_001320900.1 NP_002003.1, NM_002012.3 |
3D structure databases
Select the link destinations: PDBei RCSB PDBi PDBji Links Updated | PDB entry | Method | Resolution (Å) | Chain | Positions | PDBsum |
1FHI | X-ray | 3.10 | A | 1-147 | [»] | |
1FIT | X-ray | 1.85 | A | 1-147 | [»] | |
2FHI | X-ray | 2.60 | A | 1-147 | [»] | |
2FIT | X-ray | 1.90 | A | 1-147 | [»] | |
3FIT | X-ray | 2.40 | A | 1-147 | [»] | |
4FIT | X-ray | 2.50 | A | 1-147 | [»] | |
5FIT | X-ray | 2.30 | A | 1-147 | [»] | |
6FIT | X-ray | 2.60 | A | 1-147 | [»] | |
AlphaFoldDBi | P49789 | |||||
SMRi | P49789 | |||||
ModBasei | Search... | |||||
PDBe-KBi | Search... |
Protein-protein interaction databases
BioGRIDi | 108563, 22 interactors |
DIPi | DIP-29947N |
IntActi | P49789, 9 interactors |
STRINGi | 9606.ENSP00000417480 |
Chemistry databases
BindingDBi | P49789 |
ChEMBLi | CHEMBL1795151 |
DrugBanki | DB02373, Adenosine monotungstate DB04389, Ado-P-Ch2-P-Ps-Ado |
PTM databases
iPTMneti | P49789 |
PhosphoSitePlusi | P49789 |
Genetic variation databases
BioMutai | FHIT |
DMDMi | 1706794 |
Proteomic databases
EPDi | P49789 |
jPOSTi | P49789 |
MassIVEi | P49789 |
PaxDbi | P49789 |
PeptideAtlasi | P49789 |
PRIDEi | P49789 |
ProteomicsDBi | 56119 |
Protocols and materials databases
Antibodypediai | 3636, 630 antibodies from 39 providers |
DNASUi | 2272 |
Genome annotation databases
Ensembli | ENST00000468189.5; ENSP00000417480.1; ENSG00000189283.10 ENST00000476844.5; ENSP00000417557.1; ENSG00000189283.10 ENST00000492590.6; ENSP00000418582.1; ENSG00000189283.10 |
GeneIDi | 2272 |
KEGGi | hsa:2272 |
MANE-Selecti | ENST00000492590.6; ENSP00000418582.1; NM_002012.4; NP_002003.1 |
UCSCi | uc003dkx.5, human |
Organism-specific databases
CTDi | 2272 |
DisGeNETi | 2272 |
GeneCardsi | FHIT |
HGNCi | HGNC:3701, FHIT |
HPAi | ENSG00000189283, Tissue enhanced (choroid) |
MalaCardsi | FHIT |
MIMi | 601153, gene |
neXtProti | NX_P49789 |
OpenTargetsi | ENSG00000189283 |
Orphaneti | 422526, Hereditary clear cell renal cell carcinoma |
PharmGKBi | PA28140 |
VEuPathDBi | HostDB:ENSG00000189283 |
GenAtlasi | Search... |
Phylogenomic databases
eggNOGi | KOG3379, Eukaryota |
GeneTreei | ENSGT00510000047967 |
HOGENOMi | CLU_056776_7_1_1 |
OMAi | DAIYGMM |
OrthoDBi | 1198291at2759 |
PhylomeDBi | P49789 |
TreeFami | TF105432 |
Enzyme and pathway databases
BRENDAi | 3.6.1.29, 2681 |
PathwayCommonsi | P49789 |
SABIO-RKi | P49789 |
SignaLinki | P49789 |
SIGNORi | P49789 |
Miscellaneous databases
BioGRID-ORCSi | 2272, 10 hits in 1075 CRISPR screens |
ChiTaRSi | FHIT, human |
EvolutionaryTracei | P49789 |
GeneWikii | FHIT |
GenomeRNAii | 2272 |
Pharosi | P49789, Tchem |
PROi | PR:P49789 |
RNActi | P49789, protein |
SOURCEi | Search... |
Gene expression databases
Bgeei | ENSG00000189283, Expressed in pigmented layer of retina and 150 other tissues |
ExpressionAtlasi | P49789, baseline and differential |
Genevisiblei | P49789, HS |
Family and domain databases
CDDi | cd01275, FHIT, 1 hit |
Gene3Di | 3.30.428.10, 1 hit |
InterProi | View protein in InterPro IPR039383, FHIT IPR019808, Histidine_triad_CS IPR011146, HIT-like IPR036265, HIT-like_sf |
Pfami | View protein in Pfam PF01230, HIT, 1 hit |
SUPFAMi | SSF54197, SSF54197, 1 hit |
PROSITEi | View protein in PROSITE PS00892, HIT_1, 1 hit PS51084, HIT_2, 1 hit |
MobiDBi | Search... |
Entry informationi
Entry namei | FHIT_HUMAN | |
Accessioni | P49789Primary (citable) accession number: P49789 Secondary accession number(s): A2IAS9 Q6IU12 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | October 1, 1996 |
Last sequence update: | January 23, 2007 | |
Last modified: | May 25, 2022 | |
This is version 192 of the entry and version 3 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program | |
Disclaimer | Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care. |
Miscellaneousi
Keywords - Technical termi
3D-structure, Reference proteomeDocuments
- Human chromosome 3
Human chromosome 3: entries, gene names and cross-references to MIM - MIM cross-references
Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot - PDB cross-references
Index of Protein Data Bank (PDB) cross-references