DB code: S00923

RLCP classification 1.15.8245.1168 : Hydrolysis
CATH domain 3.90.79.10 : Nucleoside Triphosphate Pyrophosphohydrolase Catalytic domain
E.C. 3.6.1.13 3.6.1.18
CSA
M-CSA
MACiE

CATH domain Related DB codes (homologues)
3.90.79.10 : Nucleoside Triphosphate Pyrophosphohydrolase S00814 S00815 S00920 S00921 S00922 S00924 S00454

Uniprot Enzyme Name
UniprotKB Protein name Synonyms RefSeq Pfam
Q5SJY9
MutT/nudix family protein
YP_144129.1 (Protein)
NC_006461.1 (DNA/RNA sequence)
PF00293 (NUDIX)
[Graphical View]

KEGG enzyme 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 )

UniprotKB: Accession Number Entry name Activity Subunit Subcellular location Cofactor
Q5SJY9 Q5SJY9_THET8

KEGG Pathways
Map code Pathways E.C.
MAP00230 Purine metabolism 3.6.1.13
MAP00740 Riboflavin metabolism 3.6.1.18

Compound table
Cofactors Substrates Products Intermediates
KEGG-id C00305 C00301 C00016 C00001 C00020 C00117 C00061
E.C. 3.6.1.13
3.6.1.18
3.6.1.13
3.6.1.18
3.6.1.13
3.6.1.18
3.6.1.13
3.6.1.18
3.6.1.13
3.6.1.18
Compound Magnesium ADP-ribose FAD H2O AMP D-ribose 5-phosphate FMN
Type divalent metal (Ca2+, Mg2+) amine group,carbohydrate,nucleotide amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carbohydrate,nucleotide H2O amine group,nucleotide carbohydrate,phosphate group/phosphate ion amide group,amine group,aromatic ring (only carbon atom),aromatic ring (with nitrogen atoms),carbohydrate,phosphate group/phosphate ion
ChEBI 18420
 18420
 		16238
 16238
 		15377
 15377
 		16027
 16027
 		52742
 52742
 		17621
 17621
PubChem 888
 888
 		445794
 445794
 		643975
 643975
 		22247451
 962
 22247451
 962
 		6083
 6083
 		439167
 439167
 		643976
 643976
2yvmA00 Bound:2x_MG Unbound Unbound Unbound Unbound Unbound
2yvnA00 Unbound Unbound Unbound Unbound Unbound Unbound
2yvoA00 Bound:3x_MG Unbound Unbound Bound:AMP Unbound Unbound
2yvpA00 Bound:3x_MG Analogue:RBY Unbound Unbound Unbound Unbound

Reference for Active-site residues
resource references E.C.
literature [6], [9]

Active-site residues
PDB Catalytic residues Cofactor-binding residues Modified residues Main-chain involved in catalysis Comment
2yvmA00 ARG 62;GLU 136 ALA 74(Magnesium-1);GLU 90(Magnesium-2 & 3);GLU 94(Magnesium-1 & 2);GLU 139(Magnesium-2)
2yvnA00 ARG 62;GLU 136 ALA 74(Magnesium-1);GLU 90(Magnesium-2 & 3);GLU 94(Magnesium-1 & 2);GLU 139(Magnesium-2)
2yvoA00 ARG 62;GLU 136 ALA 74(Magnesium-1);GLU 90(Magnesium-2 & 3);GLU 94(Magnesium-1 & 2);GLU 139(Magnesium-2)
2yvpA00 ARG 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
References Sections No. of steps in catalysis
[2]
FIGURE6
[6]
Table1, Fig.5
[9]
p.1115-1116

References
[1]
Resource
Comments X-RAY CRYSTALLOGRAPHY (1.9 ANGSTROMS) OF NATIVE ENZYME, COMPLEX WITH ADP-RIBOSE, COMPLEX WITH GADOLINIUM.
Medline ID
PubMed ID 11323725
Journal Nat Struct Biol
Year 2001
Volume 8
Pages 467-72
Authors Gabelli SB, Bianchet MA, Bessman MJ, Amzel LM
Title The structure of ADP-ribose pyrophosphatase reveals the structural basis for the versatility of the Nudix family.
Related PDB 1g0s 1g9q 1ga7
Related UniProtKB Q93K97
[2]
Resource
Comments X-RAY CRYSTALLOGRAPHY (2.07 ANGSTROMS), CATALYTIC MECHANISM.
Medline ID
PubMed ID 12135348
Journal Biochemistry
Year 2002
Volume 41
Pages 9279-85
Authors Gabelli SB, Bianchet MA, Ohnishi Y, Ichikawa Y, Bessman MJ, Amzel LM
Title Mechanism of the Escherichia coli ADP-ribose pyrophosphatase, a Nudix hydrolase.
Related PDB 1khz
Related UniProtKB Q93K97
[3]
Resource
Comments
Medline ID
PubMed ID 12948489
Journal J Mol Biol
Year 2003
Volume 332
Pages 385-98
Authors Shen BW, Perraud AL, Scharenberg A, Stoddard BL
Title The crystal structure and mutational analysis of human NUDT9.
Related PDB 1q33 1qvj
Related UniProtKB
[4]
Resource
Comments
Medline ID
PubMed ID 12906832
Journal Structure
Year 2003
Volume 11
Pages 1015-23
Authors Kang LW, Gabelli SB, Cunningham JE, O'Handley SF, Amzel LM
Title Structure and mechanism of MT-ADPRase, a nudix hydrolase from Mycobacterium tuberculosis.
Related PDB 1mk1 1mp2 1mqe 1mqw 1mr2
Related UniProtKB
[5]
Resource
Comments
Medline ID
PubMed ID 15210687
Journal J Biol Chem
Year 2004
Volume 279
Pages 37163-74
Authors Yoshiba S, Ooga T, Nakagawa N, Shibata T, Inoue Y, Yokoyama S, Kuramitsu S, Masui R
Title Structural insights into the Thermus thermophilus ADP-ribose pyrophosphatase mechanism via crystal structures with the bound substrate and metal.
Related PDB 1v8i 1v8l 1v8m 1v8n 1v8r 1v8s 1v8t 1v8u 1v8v 1v8w 1v8y
Related UniProtKB
[6]
Resource
Comments
Medline ID
PubMed ID 15581572
Journal Arch Biochem Biophys
Year 2005
Volume 433
Pages 129-43
Authors Mildvan AS, Xia Z, Azurmendi HF, Saraswat V, Legler PM, Massiah MA, Gabelli SB, Bianchet MA, Kang LW, Amzel LM
Title Structures and mechanisms of Nudix hydrolases.
Related PDB
Related UniProtKB
[7]
Resource
Comments
Medline ID
PubMed ID 15981998
Journal Biochemistry
Year 2005
Volume 44
Pages 9320-9
Authors Ooga T, Yoshiba S, Nakagawa N, Kuramitsu S, Masui R
Title Molecular mechanism of the Thermus thermophilus ADP-ribose pyrophosphatase from mutational and kinetic studies.
Related PDB
Related UniProtKB
[8]
Resource
Comments
Medline ID
PubMed ID 17052728
Journal J Mol Biol
Year 2006
Volume 364
Pages 1021-33
Authors Zha M, Zhong C, Peng Y, Hu H, Ding J
Title Crystal structures of human NUDT5 reveal insights into the structural basis of the substrate specificity.
Related PDB 2dsb 2dsc 2dsd
Related UniProtKB
[9]
Resource
Comments
Medline ID
PubMed ID 18039767
Journal J Bacteriol
Year 2008
Volume 190
Pages 1108-17
Authors Wakamatsu T, Nakagawa N, Kuramitsu S, Masui R
Title Structural basis for different substrate specificities of two ADP-ribose pyrophosphatases from Thermus thermophilus HB8.
Related PDB
Related UniProtKB
[10]
Resource
Comments
Medline ID
PubMed ID 18462755
Journal J Mol Biol
Year 2008
Volume 379
Pages 568-78
Authors Zha M, Guo Q, Zhang Y, Yu B, Ou Y, Zhong C, Ding J
Title Molecular mechanism of ADP-ribose hydrolysis by human NUDT5 from structural and kinetic studies.
Related PDB 3bm4
Related UniProtKB
[11]
Resource
Comments
Medline ID
PubMed ID 21768126
Journal Nucleic Acids Res
Year 2011
Volume 39
Pages 8972-83
Authors Arimori T, Tamaoki H, Nakamura T, Kamiya H, Ikemizu S, Takagi Y, Ishibashi T, Harashima H, Sekiguchi M, Yamagata Y
Title Diverse substrate recognition and hydrolysis mechanisms of human NUDT5.
Related PDB 3ac9 3aca 3l85
Related UniProtKB

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.

Created Updated
2009-12-25 2013-03-18