EzCatDB: S00268
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DB codeS00268
CATH domainDomain 13.30.428.10 : HIT family, subunit ACatalytic domain
E.C.3.6.1.29
CSA5fit
MACiEM0101


Enzyme Name
UniProtKBKEGG

P49789
Protein nameBis(5''-adenosyl)-triphosphatasebis(5'-adenosyl)-triphosphatase
dinucleosidetriphosphatase
diadenosine 5,5-P1,P3-triphosphatase
1-P,3-P-bis(5'-adenosyl)-triphosphate adenylohydrolase
SynonymsEC 3.6.1.29
Diadenosine 5'',5''''''-P1,P3-triphosphate hydrolase
Dinucleosidetriphosphatase
AP3A hydrolase
AP3Aase
Fragile histidine triad protein
RefSeqNP_001159715.1 (Protein)
NM_001166243.1 (DNA/RNA sequence)
NP_002003.1 (Protein)
NM_002012.2 (DNA/RNA sequence)
PfamPF01230 (HIT)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00230Purine metabolism

UniProtKB:Accession NumberP49789
Entry nameFHIT_HUMAN
ActivityP(1)-P(3)-bis(5''-adenosyl) triphosphate + H(2)O = ADP + AMP.
SubunitHomodimer.
Subcellular locationCytoplasm.
CofactorDivalent cations. Magnesium, but manganese and to a lesser extent calcium or cobalt can be substituted, but not zinc, cadmium or nickel.

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProductsintermediates
KEGG-idC00572C06197C00001C00008C00020

CompoundDivalent cationP1,P3-Bis(5'-adenosyl) triphosphateH2OADPAMPTransition-state Enzyme-AMP intermediate
Typedivalent metal (Ca2+, Mg2+)amine group,nucleotideH2Oamine group,nucleotideamine group,nucleotide

ChEBI
27775
15377
16761
16027


PubChem
165381
962
22247451
6022
6083


               
1fhiAUnboundAnalogue:IB2 UnboundUnboundUnboundUnbound
1fitAUnboundUnbound UnboundAnalogue:SO4UnboundUnbound
2fhiAUnboundAnalogue:IB2 UnboundUnboundUnboundUnbound
2fitAUnboundUnbound UnboundAnalogue:SO4UnboundUnbound
3fitAUnboundUnbound UnboundAnalogue:__A-SO4 300UnboundUnbound
4fitAUnboundUnbound UnboundUnboundUnboundUnbound
5fitAUnboundUnbound UnboundAnalogue:AP2UnboundUnbound
6fitAUnboundUnbound UnboundUnboundTransition-state-analogue:AMWUnbound

Active-site residues
resource
PDB;6fit, literature [15]
pdbCatalytic residuesMain-chain involved in catalysiscomment
           
1fhiAHIS 35;GLN 83;HIS 96;HIS 98
THR 91;HIS 94
 
1fitAHIS 35;GLN 83;HIS 96;HIS 98
THR 91;HIS 94
 
2fhiAHIS 35;GLN 83;      ;HIS 98
THR 91;HIS 94
mutant H96N
2fitAHIS 35;GLN 83;HIS 96;HIS 98
THR 91;HIS 94
 
3fitAHIS 35;GLN 83;HIS 96;HIS 98
THR 91;HIS 94
 
4fitAHIS 35;GLN 83;HIS 96;HIS 98
THR 91;HIS 94
 
5fitAHIS 35;GLN 83;HIS 96;HIS 98
THR 91;HIS 94
 
6fitAHIS 35;GLN 83;HIS 96;HIS 98
THR 91;HIS 94
 

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[3]p.236-237
[5]Fig.5, p.287-289
[6]p.771-772
[9]Fig.7, p.3674-3675
[15]Fig.4, p.9011-9012
[17]Fig.1

references
[1]
PubMed ID8286347
JournalBiochemistry
Year1994
Volume33
Pages235-40
AuthorsGuranowski A, Brown P, Ashton PA, Blackburn GM
TitleRegiospecificity of the hydrolysis of diadenosine polyphosphates catalyzed by three specific pyrophosphohydrolases.
[2]
CommentsFUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND MUTAGENESIS OF HIS-35; HIS-94; HIS-96 AND HIS-98.
PubMed ID8794732
JournalBiochemistry
Year1996
Volume35
Pages11529-35
AuthorsBarnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M, Huebner K
TitleFhit, a putative tumor suppressor in humans, is a dinucleoside 5',5"'-P1,P3-triphosphate hydrolase.
Related UniProtKBP49789
[3]
PubMed ID9164465
JournalNat Struct Biol
Year1997
Volume4
Pages231-8
AuthorsBrenner C, Garrison P, Gilmour J, Peisach D, Ringe D, Petsko GA, Lowenstein JM
TitleCrystal structures of HINT demonstrate that histidine triad proteins are GalT-related nucleotide-binding proteins.
[4]
PubMed ID9543008
JournalProtein Eng
Year1997
Volume10
Pages1461-3
AuthorsBrenner C, Pace HC, Garrison PN, Robinson AK, Rosler A, Liu XH, Blackburn GM, Croce CM, Huebner K, Barnes LD
TitlePurification and crystallization of complexes modeling the active state of the fragile histidine triad protein.
[5]
CommentsX-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
Medline ID97465981
PubMed ID9323207
JournalScience
Year1997
Volume278
Pages286-90
AuthorsLima CD, Klein MG, Hendrickson WA
TitleStructure-based analysis of catalysis and substrate definition in the HIT protein family.
Related PDB4fit,5fit,6fit
Related UniProtKBP49789
[6]
CommentsX-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
Medline ID97410386
PubMed ID9261067
JournalStructure
Year1997
Volume5
Pages763-74
AuthorsLima CD, D'Amico KL, Naday I, Rosenbaum G, Westbrook EM, Hendrickson WA
TitleMAD analysis of FHIT, a putative human tumor suppressor from the HIT protein family.
Related PDB1fit,2fit,3fit
Related UniProtKBP49789
[7]
PubMed ID9708352
JournalNucleosides Nucleotides
Year1998
Volume17
Pages301-8
AuthorsBlackburn GM, Liu X, Rosler A, Brenner C
TitleTwo hydrolase resistant analogues of diadenosine 5',5"'-P1,P3-triphosphate for studies with Fhit, the human fragile histidine triad protein.
[8]
CommentsX-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
Medline ID98245105
PubMed ID9576908
JournalProc Natl Acad Sci U S A
Year1998
Volume95
Pages5484-9
AuthorsPace HC, Garrison PN, Robinson AK, Barnes LD, Draganescu A, Rosler A, Blackburn GM, Siprashvili Z, Croce CM, Huebner K, Brenner C
TitleGenetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit.
Related PDB1fhi,2fhi
Related UniProtKBP49789
[9]
PubMed ID10090754
JournalBiochemistry
Year1999
Volume38
Pages3668-76
AuthorsAbend A, Garrison PN, Barnes LD, Frey PA
TitleStereochemical retention of the configuration in the action of Fhit on phosphorus-chiral substrates.
[10]
PubMed ID10497298
JournalJ Cell Physiol
Year1999
Volume181
Pages179-87
AuthorsBrenner C, Bieganowski P, Pace HC, Huebner K
TitleThe histidine triad superfamily of nucleotide-binding proteins.
[11]
PubMed ID10959838
JournalCurr Biol
Year2000
Volume10
Pages907-17
AuthorsPace HC, Hodawadekar SC, Draganescu A, Huang J, Bieganowski P, Pekarsky Y, Croce CM, Brenner C
TitleCrystal structure of the worm NitFhit Rosetta Stone protein reveals a Nit tetramer binding two Fhit dimers.
[12]
PubMed ID10671479
JournalJ Biol Chem
Year2000
Volume275
Pages4555-60
AuthorsDraganescu A, Hodawadekar SC, Gee KR, Brenner C
TitleFhit-nucleotide specificity probed with novel fluorescent and fluorogenic substrates.
[13]
PubMed ID10733886
JournalProtein Expr Purif
Year2000
Volume18
Pages320-6
AuthorsPawelczyk T, Kowara R, Golebiowski F, Matecki A
TitleExpression in Escherichia coli and simple purification of human Fhit protein.
[14]
PubMed ID11902576
JournalNat Rev Cancer
Year2001
Volume1
Pages214-21
AuthorsHuebner K, Croce CM
TitleFRA3B and other common fragile sites: the weakest links.
[15]
PubMed ID12119013
JournalBiochemistry
Year2002
Volume41
Pages9003-14
AuthorsBrenner C
TitleHint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases.
[16]
PubMed ID11896678
JournalChem Res Toxicol
Year2002
Volume15
Pages319-25
AuthorsKowara R, Karaczyn AA, Fivash MJ Jr, Kasprzak KS
TitleIn vitro inhibition of the enzymatic activity of tumor suppressor FHIT gene product by carcinogenic transition metals.
[17]
PubMed ID15182206
JournalBiochemistry
Year2004
Volume43
Pages7637-42
AuthorsHuang K, Arabshahi A, Wei Y, Frey PA
TitleThe mechanism of action of the fragile histidine triad, Fhit: isolation of a covalent adenylyl enzyme and chemical rescue of H96G-Fhit.
[18]
PubMed ID16359767
JournalBiochimie
Year2006
Volume88
Pages461-71
AuthorsAsensio AC, Rodriguez-Ferrer CR, Oaknin S, Rotllan P
TitleBiochemical and immunochemical characterisation of human diadenosine triphosphatase provides evidence for its identification with the tumour suppressor Fhit protein.

comments
Although divalent cation seems to be used as cofactor in this enzyme, it is not involved in catalysis.

createdupdated
2004-07-092009-02-26


Copyright: Nozomi Nagano, JST & CBRC-AIST
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Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2006)
Funded by Grant-in-Aid for Scientific Research (B)/Japan Society for the Promotion of Science (JSPS) (April 2005 - March 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (September 2005 - September 2008)
Funded by BIRD/Japan Science and Technology Corporation (JST) (October 2007 - September 2010)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2011 - March 2012)
Funded by Grant-in-Aid for Publication of Scientific Research Results/Japan Society for the Promotion of Science (JSPS) (April 2012 - March 2013)
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