DB code: S00268

CATH domain 3.30.428.10 : HIT family, subunit A Catalytic domain
E.C. 3.6.1.29
CSA 5fit
M-CSA 5fit
MACiE M0101

CATH domain Related DB codes (homologues)

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
P49789 Bis(5''-adenosyl)-triphosphatase
EC 3.6.1.29
Diadenosine 5'',5''''''-P1,P3-triphosphate hydrolase
Dinucleosidetriphosphatase
AP3A hydrolase
AP3Aase
Fragile histidine triad protein
NP_001159715.1 (Protein)
NM_001166243.1 (DNA/RNA sequence)
NP_002003.1 (Protein)
NM_002012.2 (DNA/RNA sequence)
PF01230 (HIT)
[Graphical View]

KEGG enzyme name
bis(5'-adenosyl)-triphosphatase
dinucleosidetriphosphatase
diadenosine 5,5-P1,P3-triphosphatase
1-P,3-P-bis(5'-adenosyl)-triphosphate adenylohydrolase

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
P49789 FHIT_HUMAN P(1)-P(3)-bis(5''-adenosyl) triphosphate + H(2)O = ADP + AMP. Homodimer. Cytoplasm. Divalent cations. Magnesium, but manganese and to a lesser extent calcium or cobalt can be substituted, but not zinc, cadmium or nickel.

KEGG Pathways
Map code Pathways E.C.
MAP00230 Purine metabolism

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00572 C06197 C00001 C00008 C00020
E.C. (Enzyme-AMP complex formation)
Compound Divalent cation P1,P3-Bis(5'-adenosyl) triphosphate H2O ADP AMP Transition-state Enzyme-AMP intermediate
Type divalent metal (Ca2+, Mg2+) amine group,nucleotide H2O amine group,nucleotide amine group,nucleotide
ChEBI 27775
 27775
 		15377
 15377
 		16761
 16761
 		16027
 16027
PubChem 165381
 165381
 		22247451
 962
 22247451
 962
 		6022
 6022
 		6083
 6083
1fhiA Unbound Analogue:IB2 Unbound Unbound Unbound Unbound
1fitA Unbound Unbound Unbound Analogue:SO4 Unbound Unbound
2fhiA Unbound Analogue:IB2 Unbound Unbound Unbound Unbound
2fitA Unbound Unbound Unbound Analogue:SO4 Unbound Unbound
3fitA Unbound Unbound Unbound Analogue:__A-SO4_300 Unbound Unbound
4fitA Unbound Unbound Unbound Unbound Unbound Unbound
5fitA Unbound Unbound Unbound Analogue:AP2 Unbound Unbound
6fitA Unbound Unbound Unbound Unbound Transition-state-analogue:AMW Unbound

Reference for Active-site residues
resource references E.C.
PDB;6fit, literature [15]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
1fhiA HIS 35;GLN 83;HIS 96;HIS 98 THR 91;HIS 94
1fitA HIS 35;GLN 83;HIS 96;HIS 98 THR 91;HIS 94
2fhiA HIS 35;GLN 83; ;HIS 98 THR 91;HIS 94 mutant H96N
2fitA HIS 35;GLN 83;HIS 96;HIS 98 THR 91;HIS 94
3fitA HIS 35;GLN 83;HIS 96;HIS 98 THR 91;HIS 94
4fitA HIS 35;GLN 83;HIS 96;HIS 98 THR 91;HIS 94
5fitA HIS 35;GLN 83;HIS 96;HIS 98 THR 91;HIS 94
6fitA HIS 35;GLN 83;HIS 96;HIS 98 THR 91;HIS 94

References for Catalytic Mechanism
References Sections No. 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]
Resource
Comments
Medline ID
PubMed ID 8286347
Journal Biochemistry
Year 1994
Volume 33
Pages 235-40
Authors Guranowski A, Brown P, Ashton PA, Blackburn GM
Title Regiospecificity of the hydrolysis of diadenosine polyphosphates catalyzed by three specific pyrophosphohydrolases.
Related PDB
Related UniProtKB
[2]
Resource
Comments FUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND MUTAGENESIS OF HIS-35; HIS-94; HIS-96 AND HIS-98.
Medline ID
PubMed ID 8794732
Journal Biochemistry
Year 1996
Volume 35
Pages 11529-35
Authors Barnes LD, Garrison PN, Siprashvili Z, Guranowski A, Robinson AK, Ingram SW, Croce CM, Ohta M, Huebner K
Title Fhit, a putative tumor suppressor in humans, is a dinucleoside 5',5"'-P1,P3-triphosphate hydrolase.
Related PDB
Related UniProtKB P49789
[3]
Resource
Comments
Medline ID
PubMed ID 9164465
Journal Nat Struct Biol
Year 1997
Volume 4
Pages 231-8
Authors Brenner C, Garrison P, Gilmour J, Peisach D, Ringe D, Petsko GA, Lowenstein JM
Title Crystal structures of HINT demonstrate that histidine triad proteins are GalT-related nucleotide-binding proteins.
Related PDB
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 9543008
Journal Protein Eng
Year 1997
Volume 10
Pages 1461-3
Authors Brenner C, Pace HC, Garrison PN, Robinson AK, Rosler A, Liu XH, Blackburn GM, Croce CM, Huebner K, Barnes LD
Title Purification and crystallization of complexes modeling the active state of the fragile histidine triad protein.
Related PDB
Related UniProtKB
[5]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.5 ANGSTROMS).
Medline ID 97465981
PubMed ID 9323207
Journal Science
Year 1997
Volume 278
Pages 286-90
Authors Lima CD, Klein MG, Hendrickson WA
Title Structure-based analysis of catalysis and substrate definition in the HIT protein family.
Related PDB 4fit 5fit 6fit
Related UniProtKB P49789
[6]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS).
Medline ID 97410386
PubMed ID 9261067
Journal Structure
Year 1997
Volume 5
Pages 763-74
Authors Lima CD, D'Amico KL, Naday I, Rosenbaum G, Westbrook EM, Hendrickson WA
Title MAD analysis of FHIT, a putative human tumor suppressor from the HIT protein family.
Related PDB 1fit 2fit 3fit
Related UniProtKB P49789
[7]
Resource
Comments
Medline ID
PubMed ID 9708352
Journal Nucleosides Nucleotides
Year 1998
Volume 17
Pages 301-8
Authors Blackburn GM, Liu X, Rosler A, Brenner C
Title Two hydrolase resistant analogues of diadenosine 5',5"'-P1,P3-triphosphate for studies with Fhit, the human fragile histidine triad protein.
Related PDB
Related UniProtKB
[8]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS).
Medline ID 98245105
PubMed ID 9576908
Journal Proc Natl Acad Sci U S A
Year 1998
Volume 95
Pages 5484-9
Authors Pace HC, Garrison PN, Robinson AK, Barnes LD, Draganescu A, Rosler A, Blackburn GM, Siprashvili Z, Croce CM, Huebner K, Brenner C
Title Genetic, biochemical, and crystallographic characterization of Fhit-substrate complexes as the active signaling form of Fhit.
Related PDB 1fhi 2fhi
Related UniProtKB P49789
[9]
Resource
Comments
Medline ID
PubMed ID 10090754
Journal Biochemistry
Year 1999
Volume 38
Pages 3668-76
Authors Abend A, Garrison PN, Barnes LD, Frey PA
Title Stereochemical retention of the configuration in the action of Fhit on phosphorus-chiral substrates.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 10497298
Journal J Cell Physiol
Year 1999
Volume 181
Pages 179-87
Authors Brenner C, Bieganowski P, Pace HC, Huebner K
Title The histidine triad superfamily of nucleotide-binding proteins.
Related PDB
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 10959838
Journal Curr Biol
Year 2000
Volume 10
Pages 907-17
Authors Pace HC, Hodawadekar SC, Draganescu A, Huang J, Bieganowski P, Pekarsky Y, Croce CM, Brenner C
Title Crystal structure of the worm NitFhit Rosetta Stone protein reveals a Nit tetramer binding two Fhit dimers.
Related PDB
Related UniProtKB
[12]
Resource
Comments
Medline ID
PubMed ID 10671479
Journal J Biol Chem
Year 2000
Volume 275
Pages 4555-60
Authors Draganescu A, Hodawadekar SC, Gee KR, Brenner C
Title Fhit-nucleotide specificity probed with novel fluorescent and fluorogenic substrates.
Related PDB
Related UniProtKB
[13]
Resource
Comments
Medline ID
PubMed ID 10733886
Journal Protein Expr Purif
Year 2000
Volume 18
Pages 320-6
Authors Pawelczyk T, Kowara R, Golebiowski F, Matecki A
Title Expression in Escherichia coli and simple purification of human Fhit protein.
Related PDB
Related UniProtKB
[14]
Resource
Comments
Medline ID
PubMed ID 11902576
Journal Nat Rev Cancer
Year 2001
Volume 1
Pages 214-21
Authors Huebner K, Croce CM
Title FRA3B and other common fragile sites: the weakest links.
Related PDB
Related UniProtKB
[15]
Resource
Comments
Medline ID
PubMed ID 12119013
Journal Biochemistry
Year 2002
Volume 41
Pages 9003-14
Authors Brenner C
Title Hint, Fhit, and GalT: function, structure, evolution, and mechanism of three branches of the histidine triad superfamily of nucleotide hydrolases and transferases.
Related PDB
Related UniProtKB
[16]
Resource
Comments
Medline ID
PubMed ID 11896678
Journal Chem Res Toxicol
Year 2002
Volume 15
Pages 319-25
Authors Kowara R, Karaczyn AA, Fivash MJ Jr, Kasprzak KS
Title In vitro inhibition of the enzymatic activity of tumor suppressor FHIT gene product by carcinogenic transition metals.
Related PDB
Related UniProtKB
[17]
Resource
Comments
Medline ID
PubMed ID 15182206
Journal Biochemistry
Year 2004
Volume 43
Pages 7637-42
Authors Huang K, Arabshahi A, Wei Y, Frey PA
Title The mechanism of action of the fragile histidine triad, Fhit: isolation of a covalent adenylyl enzyme and chemical rescue of H96G-Fhit.
Related PDB
Related UniProtKB
[18]
Resource
Comments
Medline ID
PubMed ID 16359767
Journal Biochimie
Year 2006
Volume 88
Pages 461-71
Authors Asensio AC, Rodriguez-Ferrer CR, Oaknin S, Rotllan P
Title Biochemical and immunochemical characterisation of human diadenosine triphosphatase provides evidence for its identification with the tumour suppressor Fhit protein.
Related PDB
Related UniProtKB

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

Created Updated
2004-07-09 2009-02-26