S00815
type: Enzyme
rlcp: p1166
cath: Nucleoside Triphosphate Pyrophosphohydrolase
ec: https://purl.uniprot.org/enzyme/3.6.1.17
uniprot: Q9U2M7
uniprot: P50583
kegg enzyme: Bis(5'-nucleosyl)-tetraphosphatase (asymmetrical)
kegg enzyme: Bis(5'-guanosyl)-tetraphosphatase
kegg enzyme: Bis(5'-adenosyl)-tetraphosphatase
kegg enzyme: Diguanosinetetraphosphatase (asymmetrical)
kegg enzyme: Dinucleosidetetraphosphatase (asymmetrical)
kegg enzyme: Diadenosine P1,P4-tetraphosphatase
kegg enzyme: Dinucleoside tetraphosphatase
kegg enzyme: 1-P,4-P-bis(5'-nucleosyl)-tetraphosphate nucleotidohydrolase
kegg pathway: Purine metabolism
kegg pathway: Pyrimidine metabolism
kegg cofactor: Divalent metal
kegg substrate: P1,P4-Bis(5'-adenosyl) tetraphosphate
kegg substrate: P1,P4-bis(5'-guanosyl) tetraphosphate
kegg substrate: H2O
kegg product: ATP
kegg product: AMP
kegg product: GTP
kegg product: GMP
pdb: 1kt9A00
pdb: 1ktgA00
pdb: 1ktgB00
pdb: 1xsaA00
pdb: 1xsbA00
pdb: 1xscA00
pdb: 3u53A00
pdb: 3u53B00
pdb: 3u53C00
pdb: 3u53D00
pdb bound state: Unbound
  compound: P1,P4-Bis(5'-adenosyl) tetraphosphate
  pdb: 1kt9A00
pdb bound state: Unbound
  compound: P1,P4-Bis(5'-adenosyl) tetraphosphate
  pdb: 1ktgA00
pdb bound state: Unbound
  compound: P1,P4-Bis(5'-adenosyl) tetraphosphate
  pdb: 1ktgB00
pdb bound state: Unbound
  compound: P1,P4-Bis(5'-adenosyl) tetraphosphate
  pdb: 1xsaA00
pdb bound state: Unbound
  compound: P1,P4-Bis(5'-adenosyl) tetraphosphate
  pdb: 1xsbA00
pdb bound state: Unbound
  compound: P1,P4-Bis(5'-adenosyl) tetraphosphate
  pdb: 1xscA00
pdb bound state: Unbound
  compound: P1,P4-Bis(5'-adenosyl) tetraphosphate
  pdb: 3u53A00
pdb bound state: Unbound
  compound: P1,P4-Bis(5'-adenosyl) tetraphosphate
  pdb: 3u53B00
pdb bound state: Unbound
  compound: P1,P4-Bis(5'-adenosyl) tetraphosphate
  pdb: 3u53C00
pdb bound state: Unbound
  compound: P1,P4-Bis(5'-adenosyl) tetraphosphate
  pdb: 3u53D00
pdb bound state: Unbound
  compound: P1,P4-bis(5'-guanosyl) tetraphosphate
  pdb: 1kt9A00
pdb bound state: Unbound
  compound: P1,P4-bis(5'-guanosyl) tetraphosphate
  pdb: 1ktgA00
pdb bound state: Unbound
  compound: P1,P4-bis(5'-guanosyl) tetraphosphate
  pdb: 1ktgB00
pdb bound state: Unbound
  compound: P1,P4-bis(5'-guanosyl) tetraphosphate
  pdb: 1xsaA00
pdb bound state: Unbound
  compound: P1,P4-bis(5'-guanosyl) tetraphosphate
  pdb: 1xsbA00
pdb bound state: Unbound
  compound: P1,P4-bis(5'-guanosyl) tetraphosphate
  pdb: 1xscA00
pdb bound state: Unbound
  compound: P1,P4-bis(5'-guanosyl) tetraphosphate
  pdb: 3u53A00
pdb bound state: Unbound
  compound: P1,P4-bis(5'-guanosyl) tetraphosphate
  pdb: 3u53B00
pdb bound state: Unbound
  compound: P1,P4-bis(5'-guanosyl) tetraphosphate
  pdb: 3u53C00
pdb bound state: Unbound
  compound: P1,P4-bis(5'-guanosyl) tetraphosphate
  pdb: 3u53D00
pdb bound state: Unbound
  compound: Divalent metal
  pdb: 1kt9A00
pdb bound state: Unbound
  compound: Divalent metal
  pdb: 1xsaA00
pdb bound state: Unbound
  compound: Divalent metal
  pdb: 1xsbA00
pdb bound state: Unbound
  compound: Divalent metal
  pdb: 1xscA00
pdb bound state: Unbound
  compound: Divalent metal
  pdb: 3u53A00
pdb bound state: Unbound
  compound: Divalent metal
  pdb: 3u53B00
pdb bound state: Unbound
  compound: Divalent metal
  pdb: 3u53C00
pdb bound state: Unbound
  compound: Divalent metal
  pdb: 3u53D00
pdb bound state: Unbound
  compound: ATP
  pdb: 1kt9A00
pdb bound state: Analogue
  compound: ATP
  pdb: 1ktgA00
  ligand het code: AMP
pdb bound state: Unbound
  compound: ATP
  pdb: 1ktgB00
active site residues resources: The structure of Ap(4)A hydrolase complexed with ATP-MgF(x) reveals the basis of substrate binding.
active site residues resources: Structures and mechanisms of Nudix hydrolases.
active site residues resources: Structure and substrate-binding mechanism of human Ap4A hydrolase.
active site residues resources: 1H, 13C, and 15N resonance assignments of the 17 kDa Ap4A hydrolase from Homo sapiens in the presence and absence of ATP.
references: Regiospecificity of the hydrolysis of diadenosine polyphosphates catalyzed by three specific pyrophosphohydrolases.
references: The three-dimensional structure of the Nudix enzyme diadenosine tetraphosphate hydrolase from Lupinus angustifolius L.
references: Cloning, characterisation and crystallisation of a diadenosine 5',5"'-P(1),P(4)-tetraphosphate pyrophosphohydrolase from Caenorhabditis elegans.
references: Crystallization of a complex of Caenorhabditis elegans diadenosine tetraphosphate hydrolase and a non-hydrolysable substrate analogue, AppCH2ppA.
references: The crystal structure of diadenosine tetraphosphate hydrolase from Caenorhabditis elegans in free and binary complex forms.
references: The structure of Ap(4)A hydrolase complexed with ATP-MgF(x) reveals the basis of substrate binding.
references: Analysis of the catalytic and binding residues of the diadenosine tetraphosphate pyrophosphohydrolase from Caenorhabditis elegans by site-directed mutagenesis.
references: Structures and mechanisms of Nudix hydrolases.
references: Structure and substrate-binding mechanism of human Ap4A hydrolase.
references: 1H, 13C, and 15N resonance assignments of the 17 kDa Ap4A hydrolase from Homo sapiens in the presence and absence of ATP.
comment: This enzyme belongs to Nudix (nucleoside diphosphate linked to X) hydrolase superfamily. The family of this enzyme (asymmetrical Ap4A hydrolase) can be subdivided into two groups: the "animal-type" group that includes the enzymes from animal and archaea, and the "plant-type" one that includes ones from plant and bacteria (see [5]). This enzyme belongs to the animal-type group. The plant-type enzymes correspond to the entry S00920 in EzCatDB. According to the literature [8], Mg-3 is bound to the three phosphates of the leaving ATP, which are phosphates-1, -2 and -3 of substrate Ap4A. The catalytic water is bound to Mg-1, which is coordinated by Glu52, Glu56 and Glu103 (of 1ktg). Mg-2 is coordinated by mainchain carbonyl of Lys36, sidechain of Glu56, and phosphates-2 and -3. The reaction of this enzyme may proceed as follows (see [5], [7] and [8]). (1) Glu52 (of 1ktg) acts as a general base to deprotonate the water molecule, which is bound to Mg-1. Mg-1, which is bound to Glu52, Glu56 and Glu103, may lower the pKa of the catalytic water, so that it can be deprotonated easily. (2) The activated water makes a nucleophilic attack on phosphate-4 of Ap4P. (3) Mg-2 and Mg-3 stabilize the negative charge on the leaving phosphate groups of ATP. The sidechains of Lys36 and Lys83 also stabilize the negative charge as well. The nucleophilic substitution reaction seems to be SN2-like.

Nucleoside Triphosphate Pyrophosphohydrolase
type: Cath
references: http://www.cathdb.info/version/latest/superfamily/3.90.79.10
catalytic domain: index.html

Purine metabolism
type: KeggPathway
references: KEGG:MAP00230

Pyrimidine metabolism
type: KeggPathway
references: KEGG:MAP00240

Divalent metal
type: KeggCofactor
references: KEGG:C02148
compound type: divalent metal (Ca2+, Mg2+)

P1,P4-Bis(5'-adenosyl) tetraphosphate
type: KeggSubstrate
references: KEGG:C01260
compound type: amide group
compound type: amine group
compound type: nucleotide
references: CHEBI:17422
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

P1,P4-bis(5'-guanosyl) tetraphosphate
type: KeggSubstrate
references: KEGG:C01261
compound type: amide group
compound type: amine group
compound type: nucleotide
references: CHEBI:15883
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

H2O
type: KeggSubstrate
references: KEGG:C00001
compound type: H2O
references: CHEBI:15377
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

ATP
type: KeggProduct
references: KEGG:C00002
compound type: amine group
compound type: nucleotide
references: CHEBI:15422
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

AMP
type: KeggProduct
references: KEGG:C00020
compound type: amine group
compound type: nucleotide
references: CHEBI:16027
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

GTP
type: KeggProduct
references: KEGG:C00044
compound type: amide group
compound type: amine group
compound type: nucleotide
references: CHEBI:15996
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

GMP
type: KeggProduct
references: KEGG:C00144
compound type: amide group
compound type: amine group
compound type: nucleotide
references: CHEBI:17345
references: http://pubchem.ncbi.nlm.nih.gov/summary/summary.cgi

1kt9A00
type: Pdb
references: 1kt9
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1kt9
catalytic residue: GLU 52;LYS 36;LYS 83
cofactor binding residue: LYS 36(Magnesium-2);GLU 52; (Magnesium-1);GLU 56(Magnesium-1,2)
comment: invisible 26, 103-105

1ktgA00
type: Pdb
references: 1ktg
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1ktg
catalytic residue: GLU 52;LYS 36;LYS 83
cofactor binding residue: LYS 36(Magnesium-2);GLU 52;GLU 103(Magnesium-1);GLU 56(Magnesium-1,2)

1ktgB00
type: Pdb
references: 1ktg
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1ktg
catalytic residue: GLU 52;LYS 36;LYS 83
cofactor binding residue: LYS 36(Magnesium-2);GLU 52;GLU 103(Magnesium-1);GLU 56(Magnesium-1,2)
comment: invisible 79-81

1xsaA00
type: Pdb
references: 1xsa
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1xsa
catalytic residue: ;LYS 47;LYS 94
cofactor binding residue: LYS 47(Magnesium-2); ;GLU 115(Magnesium-1);GLU 67(Magnesium-1,2)
comment: mutant E63A

1xsbA00
type: Pdb
references: 1xsb
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1xsb
catalytic residue: ;LYS 47;LYS 94
cofactor binding residue: LYS 47(Magnesium-2); ;GLU 115(Magnesium-1);GLU 67(Magnesium-1,2)
comment: mutant E63A

1xscA00
type: Pdb
references: 1xsc
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:1xsc
catalytic residue: ;LYS 47;LYS 94
cofactor binding residue: LYS 47(Magnesium-2); ;GLU 115(Magnesium-1);GLU 67(Magnesium-1,2)
comment: mutant E63A

3u53A00
type: Pdb
references: 3u53
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:3u53
catalytic residue: GLU 58;LYS 42;LYS 89
cofactor binding residue: LYS 42(Magnesium-2);GLU 58;GLU 110(Magnesium-1);GLU 62(Magnesium-1,2)

3u53B00
type: Pdb
references: 3u53
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:3u53
catalytic residue: GLU 58;LYS 42;LYS 89
cofactor binding residue: LYS 42(Magnesium-2);GLU 58;GLU 110(Magnesium-1);GLU 62(Magnesium-1,2)

3u53C00
type: Pdb
references: 3u53
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:3u53
catalytic residue: GLU 58;LYS 42;LYS 89
cofactor binding residue: LYS 42(Magnesium-2);GLU 58;GLU 110(Magnesium-1);GLU 62(Magnesium-1,2)

3u53D00
type: Pdb
references: 3u53
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: PDB:3u53
catalytic residue: GLU 58;LYS 42;LYS 89
cofactor binding residue: LYS 42(Magnesium-2);GLU 58;GLU 110(Magnesium-1);GLU 62(Magnesium-1,2)

Regiospecificity of the hydrolysis of diadenosine polyphosphates catalyzed by three specific pyrophosphohydrolases.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/8286347
journal: Biochemistry
volume: 33
pages: 235-40
published year: 1994
authors:
  item: Guranowski A
  item: Brown P
  item: Ashton PA
  item: Blackburn GM

The three-dimensional structure of the Nudix enzyme diadenosine tetraphosphate hydrolase from Lupinus angustifolius L.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11183782
journal: J Mol Biol
volume: 302
pages: 1165-77
published year: 2000
authors:
  item: Swarbrick JD
  item: Bashtannyk T
  item: Maksel D
  item: Zhang XR
  item: Blackburn GM
  item: Gayler KR
  item: Gooley PR
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: O04841

Cloning, characterisation and crystallisation of a diadenosine 5',5"'-P(1),P(4)-tetraphosphate pyrophosphohydrolase from Caenorhabditis elegans.
type: BibliographicResource
comment: NUCLEOTIDE SEQUENCE [GENOMIC DNA], X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS), FUNCTION, COFACTOR.
references: http://www.ncbi.nlm.nih.gov/pubmed/11738085
journal: Biochim Biophys Acta
volume: 1550
pages: 27-36
published year: 2001
authors:
  item: Abdelghany HM
  item: Gasmi L
  item: Cartwright JL
  item: Bailey S
  item: Rafferty JB
  item: McLennan AG

Crystallization of a complex of Caenorhabditis elegans diadenosine tetraphosphate hydrolase and a non-hydrolysable substrate analogue, AppCH2ppA.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
references: http://www.ncbi.nlm.nih.gov/pubmed/11856844
journal: Acta Crystallogr D Biol Crystallogr
volume: 58
pages: 526-8
published year: 2002
authors:
  item: Bailey S
  item: Sedelnikova SE
  item: Blackburn GM
  item: Abdelghany HM
  item: McLennan AG
  item: Rafferty JB
references: Q9U2M7

The crystal structure of diadenosine tetraphosphate hydrolase from Caenorhabditis elegans in free and binary complex forms.
type: BibliographicResource
comment: X-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS), SUBUNIT.
references: http://www.ncbi.nlm.nih.gov/pubmed/11937063
journal: Structure
volume: 10
pages: 589-600
published year: 2002
authors:
  item: Bailey S
  item: Sedelnikova SE
  item: Blackburn GM
  item: Abdelghany HM
  item: Baker PJ
  item: McLennan AG
  item: Rafferty JB
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: Q9U2M7

The structure of Ap(4)A hydrolase complexed with ATP-MgF(x) reveals the basis of substrate binding.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/11839306
journal: Structure
volume: 10
pages: 205-13
published year: 2002
authors:
  item: Fletcher JI
  item: Swarbrick JD
  item: Maksel D
  item: Gayler KR
  item: Gooley PR
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: O04841

Analysis of the catalytic and binding residues of the diadenosine tetraphosphate pyrophosphohydrolase from Caenorhabditis elegans by site-directed mutagenesis.
type: BibliographicResource
comment: MUTAGENESIS.
references: http://www.ncbi.nlm.nih.gov/pubmed/12475970
journal: J Biol Chem
volume: 278
pages: 4435-9
published year: 2003
authors:
  item: Abdelghany HM
  item: Bailey S
  item: Blackburn GM
  item: Rafferty JB
  item: McLennan AG
references: Q9U2M7

Structures and mechanisms of Nudix hydrolases.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/15581572
journal: Arch Biochem Biophys
volume: 433
pages: 129-43
published year: 2005
authors:
  item: Mildvan AS
  item: Xia Z
  item: Azurmendi HF
  item: Saraswat V
  item: Legler PM
  item: Massiah MA
  item: Gabelli SB
  item: Bianchet MA
  item: Kang LW
  item: Amzel LM

Structure and substrate-binding mechanism of human Ap4A hydrolase.
type: BibliographicResource
comment: STRUCTURE BY NMR.
references: http://www.ncbi.nlm.nih.gov/pubmed/15596429
journal: J Biol Chem
volume: 280
pages: 8471-81
published year: 2005
authors:
  item: Swarbrick JD
  item: Buyya S
  item: Gunawardana D
  item: Gayler KR
  item: McLennan AG
  item: Gooley PR
references: http://www.ebi.ac.uk/thornton-srv/databases/cgi-bin/pdbsum/GetPage.pl
references: P50583

1H, 13C, and 15N resonance assignments of the 17 kDa Ap4A hydrolase from Homo sapiens in the presence and absence of ATP.
type: BibliographicResource
references: http://www.ncbi.nlm.nih.gov/pubmed/15772762
journal: J Biomol NMR
volume: 31
pages: 181-2
published year: 2005
authors:
  item: Swarbrick JD
  item: Buyya S
  item: Gunawardana D
  item: Fletcher JI
  item: Branson K
  item: Smith B
  item: Pepe S
  item: McLennan AG
  item: Gayler KR
  item: Gooley PR

Analogue
compound: GTP
pdb: 1ktgA00
ligand het code: PO4

ReferenceForCatalyticMechanism
reference index: 5

ReferenceForCatalyticMechanism
reference index: 7

ReferenceForCatalyticMechanism
reference index: 8
reference section: Fig. 6