EzCatDB: S00920
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DB codeS00920
RLCP classification1.15.8240.1167 : Hydrolysis
CATH domainDomain 13.90.79.10 : Nucleoside Triphosphate PyrophosphohydrolaseCatalytic domain
E.C.3.6.1.17

CATH domainRelated DB codes (homologues)
3.90.79.10 : Nucleoside Triphosphate PyrophosphohydrolaseS00814,S00815,S00921,S00922,S00923,S00924,S00454

Enzyme Name
UniProtKBKEGG

O04841
Protein name
Bis(5'-nucleosyl)-tetraphosphatase (asymmetrical)
Bis(5'-guanosyl)-tetraphosphatase
Bis(5'-adenosyl)-tetraphosphatase
Diguanosinetetraphosphatase (asymmetrical)
Dinucleosidetetraphosphatase (asymmetrical)
Diadenosine P1,P4-tetraphosphatase
Dinucleoside tetraphosphatase
1-P,4-P-bis(5'-nucleosyl)-tetraphosphate nucleotidohydrolase
SynonymsDiadenosine 5'',5''''''-P1,P4-tetraphosphate hydrolase
EC 3.6.1.17
PfamPF00293 (NUDIX)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00230Purine metabolism
MAP00240Pyrimidine metabolism

UniProtKB:Accession NumberO04841
Entry nameO04841_LUPAN
Activity
Subunit
Subcellular location
Cofactor

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC02148C01260C01261C00001C00002C00020C00044C00144
CompoundDivalent metalP1,P4-Bis(5'-adenosyl) tetraphosphateP1,P4-bis(5'-guanosyl) tetraphosphateH2OATPAMPGTPGMP
Typedivalent metal (Ca2+, Mg2+)amide group,amine group,nucleotideamide group,amine group,nucleotideH2Oamine group,nucleotideamine group,nucleotideamide group,amine group,nucleotideamide group,amine group,nucleotide
ChEBI
17422
15883
15377
15422
16027
15996
17345
PubChem
21706
165186
962
22247451
5957
6083
6830
6804
                
1f3yA00UnboundUnboundUnbound UnboundUnboundUnboundUnbound
1jknA00UnboundUnboundUnbound Bound:ATPUnboundUnboundUnbound

Active-site residues
resource
Literature [5], [7], [8], [9]
pdbCatalytic residuesCofactor-binding residues
          
1f3yA00ARG 33;GLU 60;LYS 150
GLN 44(Magnesium-2);GLU 60;GLU 130(Magnesium-1);GLU 64(Magnesium-1,2)
1jknA00ARG 33;GLU 60;LYS 150
GLN 44(Magnesium-2);GLU 60;GLU 130(Magnesium-1);GLU 64(Magnesium-1,2)

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[8]Fig. 6

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]
PubMed ID11183782
JournalJ Mol Biol
Year2000
Volume302
Pages1165-77
AuthorsSwarbrick JD, Bashtannyk T, Maksel D, Zhang XR, Blackburn GM, Gayler KR, Gooley PR
TitleThe three-dimensional structure of the Nudix enzyme diadenosine tetraphosphate hydrolase from Lupinus angustifolius L.
Related PDB1f3y
Related UniProtKBO04841
[3]
CommentsNUCLEOTIDE SEQUENCE [GENOMIC DNA], X-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS), FUNCTION, COFACTOR.
PubMed ID11738085
JournalBiochim Biophys Acta
Year2001
Volume1550
Pages27-36
AuthorsAbdelghany HM, Gasmi L, Cartwright JL, Bailey S, Rafferty JB, McLennan AG
TitleCloning, characterisation and crystallisation of a diadenosine 5',5"'-P(1),P(4)-tetraphosphate pyrophosphohydrolase from Caenorhabditis elegans.
[4]
CommentsX-RAY CRYSTALLOGRAPHY (2.0 ANGSTROMS).
PubMed ID11856844
JournalActa Crystallogr D Biol Crystallogr
Year2002
Volume58
Pages526-8
AuthorsBailey S, Sedelnikova SE, Blackburn GM, Abdelghany HM, McLennan AG, Rafferty JB
TitleCrystallization of a complex of Caenorhabditis elegans diadenosine tetraphosphate hydrolase and a non-hydrolysable substrate analogue, AppCH2ppA.
Related UniProtKBQ9U2M7
[5]
CommentsX-RAY CRYSTALLOGRAPHY (1.8 ANGSTROMS), SUBUNIT.
PubMed ID11937063
JournalStructure
Year2002
Volume10
Pages589-600
AuthorsBailey S, Sedelnikova SE, Blackburn GM, Abdelghany HM, Baker PJ, McLennan AG, Rafferty JB
TitleThe crystal structure of diadenosine tetraphosphate hydrolase from Caenorhabditis elegans in free and binary complex forms.
Related PDB1kt9,1ktg
Related UniProtKBQ9U2M7
[6]
PubMed ID11839306
JournalStructure
Year2002
Volume10
Pages205-13
AuthorsFletcher JI, Swarbrick JD, Maksel D, Gayler KR, Gooley PR
TitleThe structure of Ap(4)A hydrolase complexed with ATP-MgF(x) reveals the basis of substrate binding.
Related PDB1jkn
Related UniProtKBO04841
[7]
CommentsMUTAGENESIS.
PubMed ID12475970
JournalJ Biol Chem
Year2003
Volume278
Pages4435-9
AuthorsAbdelghany HM, Bailey S, Blackburn GM, Rafferty JB, McLennan AG
TitleAnalysis of the catalytic and binding residues of the diadenosine tetraphosphate pyrophosphohydrolase from Caenorhabditis elegans by site-directed mutagenesis.
Related UniProtKBQ9U2M7
[8]
PubMed ID15581572
JournalArch Biochem Biophys
Year2005
Volume433
Pages129-43
AuthorsMildvan AS, Xia Z, Azurmendi HF, Saraswat V, Legler PM, Massiah MA, Gabelli SB, Bianchet MA, Kang LW, Amzel LM
TitleStructures and mechanisms of Nudix hydrolases.
[9]
CommentsSTRUCTURE BY NMR.
PubMed ID15596429
JournalJ Biol Chem
Year2005
Volume280
Pages8471-81
AuthorsSwarbrick JD, Buyya S, Gunawardana D, Gayler KR, McLennan AG, Gooley PR
TitleStructure and substrate-binding mechanism of human Ap4A hydrolase.
Related PDB1xsa,1xsb,1xsc
Related UniProtKBP50583
[10]
PubMed ID15772762
JournalJ Biomol NMR
Year2005
Volume31
Pages181-2
AuthorsSwarbrick JD, Buyya S, Gunawardana D, Fletcher JI, Branson K, Smith B, Pepe S, McLennan AG, Gayler KR, Gooley PR
Title1H, 13C, and 15N resonance assignments of the 17 kDa Ap4A hydrolase from Homo sapiens in the presence and absence of ATP.

comments
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 plant-type group. The animal-type enzymes correspond to the entry S00815 in EzCatDB.
In comparison with the structure of the animal type enzymes (S00815 in EzCatDB), 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 Glu60, Glu64 and Glu130 (of 1f3y). Mg-2 is coordinated by mainchain carbonyl of Gln44, sidechain of Glu64, and phosphates-2 and -3.
The reaction of this enzyme may proceed as follows (see [5], [7] and [8]).
(1) Glu60 (of 1f3y) acts as a general base to deprotonate the water molecule, which is bound to Mg-1. Mg-1, which is bound to Glu60, Glu64 and Glu130, 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 Arg33 and Lys150 also stabilize the negative charge as well. The nucleophilic substitution reaction seems to be SN2-like.

createdupdated
2011-02-042013-02-27


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