EzCatDB: S00923
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DB codeS00923
RLCP classification1.15.8245.1168 : Hydrolysis
CATH domainDomain 13.90.79.10 : Nucleoside Triphosphate PyrophosphohydrolaseCatalytic domain
E.C.3.6.1.13,3.6.1.18

CATH domainRelated DB codes (homologues)
3.90.79.10 : Nucleoside Triphosphate PyrophosphohydrolaseS00814,S00815,S00920,S00921,S00922,S00924,S00454

Enzyme Name
UniProtKBKEGG

Q5SJY9
Protein name
ADP-ribose diphosphatase
   (EC 3.6.1.13)

ADPribose pyrophosphatase
   (EC 3.6.1.13)

Adenosine diphosphoribose pyrophosphatase
   (EC 3.6.1.13)

ADPR-PPase
   (EC 3.6.1.13)

FAD diphosphatase
   (EC 3.6.1.18)

FAD pyrophosphatase
   (EC 3.6.1.18)

riboflavin adenine dinucleotide pyrophosphatase
   (EC 3.6.1.18)

flavin adenine dinucleotide pyrophosphatase
   (EC 3.6.1.18)

riboflavine adenine dinucleotide pyrophosphatase
   (EC 3.6.1.18)

flavine adenine dinucleotide pyrophosphatase
   (EC 3.6.1.18)

SynonymsMutT/nudix family protein
RefSeqYP_144129.1 (Protein)
NC_006461.1 (DNA/RNA sequence)
PfamPF00293 (NUDIX)
[Graphical view]

KEGG pathways
MAP codePathwaysE.C.
MAP00230Purine metabolism3.6.1.13
MAP00740Riboflavin metabolism3.6.1.18

UniProtKB:Accession NumberQ5SJY9
Entry nameQ5SJY9_THET8
Activity
Subunit
Subcellular location
Cofactor

Compound table: links to PDB-related databases & PoSSuM

CofactorsSubstratesProducts
KEGG-idC00305C00301C00016C00001C00020C00117C00061
E.C.3.6.1.13,3.6.1.183.6.1.133.6.1.183.6.1.13,3.6.1.183.6.1.13,3.6.1.183.6.1.133.6.1.18
CompoundMagnesiumADP-riboseFADH2OAMPD-ribose 5-phosphateFMN
Typedivalent metal (Ca2+, Mg2+)amine group,carbohydrate,nucleotideamide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carbohydrate,nucleotideH2Oamine group,nucleotidecarbohydrate,phosphate group/phosphate ionamide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carbohydrate,phosphate group/phosphate ion
ChEBI18420

16238
15377
16027
52742
17621
PubChem888
445794
643975
962
22247451
6083
439167
643976
               
2yvmA00Bound:2x_MGUnboundUnbound UnboundUnboundUnbound
2yvnA00UnboundUnboundUnbound UnboundUnboundUnbound
2yvoA00Bound:3x_MGUnboundUnbound Bound:AMPUnboundUnbound
2yvpA00Bound:3x_MGAnalogue:RBYUnbound UnboundUnboundUnbound

Active-site residues
resource
literature [6], [9]
pdbCatalytic residuesCofactor-binding residues
          
2yvmA00ARG 62;GLU 136
ALA 74(Magnesium-1);GLU 90(Magnesium-2 & 3);GLU 94(Magnesium-1 & 2);GLU 139(Magnesium-2)
2yvnA00ARG 62;GLU 136
ALA 74(Magnesium-1);GLU 90(Magnesium-2 & 3);GLU 94(Magnesium-1 & 2);GLU 139(Magnesium-2)
2yvoA00ARG 62;GLU 136
ALA 74(Magnesium-1);GLU 90(Magnesium-2 & 3);GLU 94(Magnesium-1 & 2);GLU 139(Magnesium-2)
2yvpA00ARG 62;GLU 136
ALA 74(Magnesium-1);GLU 90(Magnesium-2 & 3);GLU 94(Magnesium-1 & 2);GLU 139(Magnesium-2)

References for Catalytic Mechanism
ReferencesSectionsNo. of steps in catalysis
[2]FIGURE6
[6]Table1, Fig.5
[9]p.1115-1116

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, S00921, S00922, S00924, D00880), in terms of substrate specificities, metal binding, active sites and reaction mechanisms.
This enzyme also hydrolyzes FAD as well as ADP-ribose (see [9]).
The magnesium numbering is based on the literature [9], in contrast to those homologous enzymes (EzCatDB; S00814, S00921, S00922), whose numberings are opposite, based on literature [6]. Magnesium-3 is bound to Glu90 and alpha-phosphate of ADP-ribose, whereas Magnesium-2 is bound to Glu90, Glu94, Glu139 and alpha-phosphate. Magnesium-1 is bound to mainchain carbonyl of Ala74, Glu94 and both of the phosphate groups. The water that is bound to magnesium-2 and magnesium-3 is the nucleophile, which attacks on the alpha-phosphate of ADP-ribose.
According to the literature [6] and [9], the reaction proceeds as follows:
(0) A water molecule is bound to Magnesium-2 and -3. 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-1 that bridges the two phosphate groups may stabilize the negative charge of the leaving group, beta-phosphate.
(1) Glu136 may act as a weak base to deprotonate the water molecule, forming a hydroxide ion. (The contribution of this general base is smaller than those acidic residues, Glu90 and Glu94, which bind magnesium-2 and -3, according to the literature [9].)
(2) The hydroxide ion makes a nucleophilic attack on the alpha-phosphate of ADP-ribose. (SN2-like reaction)
(3) Arg62 and magnesium-1 may stabilize the negative charge on the leaving beta-phosphate group.

createdupdated
2009-12-252013-03-18


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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