EzCatDB: S00921
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DB codeS00921
RLCP classification1.15.8245.1168 : Hydrolysis
CATH domainDomain 13.90.79.10 : Nucleoside Triphosphate PyrophosphohydrolaseCatalytic domain
E.C.3.6.1.13
CSA1mqw

CATH domainRelated DB codes (homologues)
3.90.79.10 : Nucleoside Triphosphate PyrophosphohydrolaseS00814,S00815,S00920,S00922,S00923,S00924,S00454

Enzyme Name
UniProtKBKEGG

O33199
Protein name
ADP-ribose diphosphatase
ADPribose pyrophosphatase
Adenosine diphosphoribose pyrophosphatase
ADPR-PPase
SynonymsPutative uncharacterized protein
MutT/nudix family protein
RefSeqNP_216216.1 (Protein)
NC_000962.3 (DNA/RNA sequence)
NP_336194.1 (Protein)
NC_002755.2 (DNA/RNA sequence)
YP_006515092.1 (Protein)
NC_018143.1 (DNA/RNA sequence)
PfamPF00293 (NUDIX)
[Graphical view]

KEGG pathways
MAP codePathways
MAP00230Purine metabolism

UniProtKB:Accession NumberO33199
Entry nameO33199_MYCTU
Activity
Subunit
Subcellular location
Cofactor

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00305C00034C00301C00001C00020C00117
CompoundMagnesiumManganeseADP-riboseH2OAMPD-ribose 5-phosphate
Typedivalent metal (Ca2+, Mg2+)heavy metalamine group,carbohydrate,nucleotideH2Oamine group,nucleotidecarbohydrate,phosphate group/phosphate ion
ChEBI18420
18291
35154

15377
16027
52742
PubChem888
23930
445794
962
22247451
6083
439167
              
1mk1A00UnboundUnboundBound:APR UnboundUnbound
1mp2A00UnboundUnboundUnbound UnboundUnbound
1mqeA00Analogue:GD3UnboundBound:APR UnboundUnbound
1mqwA00UnboundBound:3x_MNAnalogue:ADV UnboundUnbound
1mr2A00UnboundBound:_MNAnalogue:A12 UnboundUnbound

Active-site residues
resource
literature [4], [6]
pdbCatalytic residuesCofactor-binding residuescomment
           
1mk1A00ARG 64;       
ALA 76(Magnesium-3);GLU 93(Magnesium-1 & 2);GLU 97(Magnesium-2 & 3);       (Magnesium-2)
invisible 29-33, 136-145
1mp2A00ARG 64;       
ALA 76(Magnesium-3);GLU 93(Magnesium-1 & 2);GLU 97(Magnesium-2 & 3);       (Magnesium-2)
invisible 29-33, 136-145
1mqeA00ARG 64;       
ALA 76(Magnesium-3);GLU 93(Magnesium-1 & 2);GLU 97(Magnesium-2 & 3);       (Magnesium-2)
invisible 29-33, 136-145
1mqwA00ARG 64;GLU 142
ALA 76(Magnesium-3);GLU 93(Magnesium-1 & 2);GLU 97(Magnesium-2 & 3);GLU 142(Magnesium-2)
 
1mr2A00ARG 64;       
ALA 76(Magnesium-3);GLU 93(Magnesium-1 & 2);GLU 97(Magnesium-2 & 3);       (Magnesium-2)
invisible 29-33, 136-145

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[2]FIGURE6
[4]p.1020
[6]Table1, Fig.5

references
[1]
CommentsX-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF NATIVE ENZYME, COMPLEX WITH ADP-RIBOSE, COMPLEX WITH GADOLINIUM.
PubMed ID11323725
JournalNat Struct Biol
Year2001
Volume8
Pages467-72
AuthorsGabelli SB, Bianchet MA, Bessman MJ, Amzel LM
TitleThe structure of ADP-ribose pyrophosphatase reveals the structural basis for the versatility of the Nudix family.
Related PDB1g0s,1g9q,1ga7
Related UniProtKBQ93K97
[2]
CommentsX-RAY CRYSTALLOGRAPHY (2.07 ANGSTROMS), CATALYTIC MECHANISM.
PubMed ID12135348
JournalBiochemistry
Year2002
Volume41
Pages9279-85
AuthorsGabelli SB, Bianchet MA, Ohnishi Y, Ichikawa Y, Bessman MJ, Amzel LM
TitleMechanism of the Escherichia coli ADP-ribose pyrophosphatase, a Nudix hydrolase.
Related PDB1khz
Related UniProtKBQ93K97
[3]
PubMed ID12948489
JournalJ Mol Biol
Year2003
Volume332
Pages385-98
AuthorsShen BW, Perraud AL, Scharenberg A, Stoddard BL
TitleThe crystal structure and mutational analysis of human NUDT9.
Related PDB1q33,1qvj
[4]
PubMed ID12906832
JournalStructure
Year2003
Volume11
Pages1015-23
AuthorsKang LW, Gabelli SB, Cunningham JE, O'Handley SF, Amzel LM
TitleStructure and mechanism of MT-ADPRase, a nudix hydrolase from Mycobacterium tuberculosis.
Related PDB1mk1,1mp2,1mqe,1mqw,1mr2
[5]
PubMed ID15210687
JournalJ Biol Chem
Year2004
Volume279
Pages37163-74
AuthorsYoshiba S, Ooga T, Nakagawa N, Shibata T, Inoue Y, Yokoyama S, Kuramitsu S, Masui R
TitleStructural insights into the Thermus thermophilus ADP-ribose pyrophosphatase mechanism via crystal structures with the bound substrate and metal.
Related PDB1v8i,1v8l,1v8m,1v8n,1v8r,1v8s,1v8t,1v8u,1v8v,1v8w,1v8y
[6]
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.
[7]
PubMed ID15981998
JournalBiochemistry
Year2005
Volume44
Pages9320-9
AuthorsOoga T, Yoshiba S, Nakagawa N, Kuramitsu S, Masui R
TitleMolecular mechanism of the Thermus thermophilus ADP-ribose pyrophosphatase from mutational and kinetic studies.
[8]
PubMed ID17052728
JournalJ Mol Biol
Year2006
Volume364
Pages1021-33
AuthorsZha M, Zhong C, Peng Y, Hu H, Ding J
TitleCrystal structures of human NUDT5 reveal insights into the structural basis of the substrate specificity.
Related PDB2dsb,2dsc,2dsd
[9]
PubMed ID18039767
JournalJ Bacteriol
Year2008
Volume190
Pages1108-17
AuthorsWakamatsu T, Nakagawa N, Kuramitsu S, Masui R
TitleStructural basis for different substrate specificities of two ADP-ribose pyrophosphatases from Thermus thermophilus HB8.
[10]
PubMed ID18462755
JournalJ Mol Biol
Year2008
Volume379
Pages568-78
AuthorsZha M, Guo Q, Zhang Y, Yu B, Ou Y, Zhong C, Ding J
TitleMolecular mechanism of ADP-ribose hydrolysis by human NUDT5 from structural and kinetic studies.
Related PDB3bm4
[11]
PubMed ID21768126
JournalNucleic Acids Res
Year2011
Volume39
Pages8972-83
AuthorsArimori T, Tamaoki H, Nakamura T, Kamiya H, Ikemizu S, Takagi Y, Ishibashi T, Harashima H, Sekiguchi M, Yamagata Y
TitleDiverse substrate recognition and hydrolysis mechanisms of human NUDT5.
Related PDB3ac9,3aca,3l85

comments
This enzyme belongs to Nudix (nucleoside diphosphate linked to x) hydrolase family.
There are several types of ADP-ribose pyrophosphatases from various organisms (EzCatDB; S00814, S00922, S00923, S00924, D00880), in terms of substrate specificities, metal binding, active sites and reaction mechanisms.
This enzyme can bind either magnesium or manganese. The metal numbering is based on the literature [6]. Magnesium-1 is bound to Glu93 and alpha-phosphate of ADP-ribose, whereas Magnesium-2 is bound to Glu93, Glu97, Glu142 and alpha-phosphate. Magnesium-3 is bound to mainchain carbonyl of Ala76, Glu97 and both of the phosphate groups. The water that is bound to magnesium-1 and magnesium-2 is the nucleophile, which attacks on the alpha-phosphate of ADP-ribose.
According to the literature [4] and [6], the reaction proceeds as follows:
(0) A water molecule is bound to Magnesium(or manganse)-1 and -2. These magnesium ions may lower the pKa of the water molecule so that the water molecule can be a better nucleophile, and also stabilize the negative charge on the alpha-phosphate group. On the other hand, magnesium-3 that bridges the two phosphate groups may stabilize the negative charge of the leaving group, beta-phosphate.
(1) Glu142 acts as a general base to deprotonate the water molecule, forming a hydroxide ion.
(2) The hydroxide ion makes a nucleophilic attack on the alpha-phosphate of ADP-ribose. (SN2-like reaction)
(3) Arg76 and magnesium-3 may stabilize the negative charge on the leaving beta-phosphate group.

createdupdated
2009-12-252013-03-15


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)
Supported by the commission for the Development of Artificial Gene Synthesis Technology for Creating Innovative Biomaterial from the Ministry of Economy, Trade and Industry (METI) (October 2012 - )
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