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Information on EC 2.7.7.96 - ADP-D-ribose pyrophosphorylase
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EC Tree
2.7.7.96 ADP-D-ribose pyrophosphorylaseIUBMB Comments
The human enzyme produces ATP in nuclei in situations of high energy demand, such as chromatin remodeling. The reaction is dependent on the presence of diphosphate. In its absence the enzyme catalyses the reaction of EC 3.6.1.13, ADP-ribose diphosphatase. cf. EC 2.7.7.35, ADP ribose phosphorylase.
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The enzyme appears in viruses and cellular organisms
Synonyms
nudix5, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
diphosphate adenylyltransferase
-
-
ambiguous
-
diphosphate-ADP-D-ribose adenylyltransferase
-
-
-
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NUDIX5
NUDT5
NUDIX5
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-
-
-
NUDT5
-
-
-
-
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + D-ribose 5-phosphate = diphosphate + ADP-D-ribose
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-
-
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SYSTEMATIC NAME
IUBMB Comments
ATP:D-ribose 5-phosphate adenylyltransferase
The human enzyme produces ATP in nuclei in situations of high energy demand, such as chromatin remodeling. The reaction is dependent on the presence of diphosphate. In its absence the enzyme catalyses the reaction of EC 3.6.1.13, ADP-ribose diphosphatase. cf. EC 2.7.7.35, ADP ribose phosphorylase.
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
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enzyme NUDIX5 catalyzes not only the formation of AMP but also the synthesis of ATP within the cell nucleus
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-
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additional information
?
-
8-oxo-dGDP is a poor substrate for enzyme NUDT5 at physiological pH
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-
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NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
additional information
?
-
enzyme NUDIX5 catalyzes not only the formation of AMP but also the synthesis of ATP within the cell nucleus
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-
-
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3,8-trimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
slight inhibition
7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(2-oxa-6-azaspiro[3.3]heptan-6-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(4-methylpiperazin-1-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(4-methylpiperidin-1-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(methylamino)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(morpholin-4-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(piperazin-1-yl)-3,7-dihydro-1H-purine-2,6-dione
lead compound, blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. Inhibitor-enzyme complex structure analysis, overview. TH5427 has no effect on NUDT9-mediated hydrolysis of ADPR, indicating discrimination amongst ADP-ribose hydrolases
7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(piperidin-1-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(propan-2-yl)-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-propyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-(4-ethylpiperazin-1-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-(4-hexylpiperazin-1-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-(diethylamino)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-(dimethylamino)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-(ethylsulfanyl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-methoxy-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-[(2-hydroxyethyl)amino]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-[4-(2-hydroxyethyl)piperidin-1-yl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-[di(prop-2-en-1-yl)amino]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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8-(4-butylpiperazin-1-yl)-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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8-(azepan-1-yl)-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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8-(cyclohexylsulfanyl)-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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8-benzyl-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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8-bromo-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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8-chloro-7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
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tert-butyl 4-(7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)piperazine-1-carboxylate
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additional information
small molecule screening, and identification of potent NUDT5 inhibitors, which are optimized to promote maximal NUDT5 cellular target engagement by CETSA. Inhibitors chelerythrine (a PKC inhibitor), LY294002 (a PI3K inhibitor), as well as 4-coumaric acid and flavone have no direct inhibitory effect on NUDT5 activity in the enzyme-coupled malachite green assay
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
nitric oxide
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nitric oxide stimulates nonenzymatic ADP-ribosylation of NUDT5 at cysteine residues using ADP-ribose and consequently activates its enzyme activity
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IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000029
7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3-dimethyl-8-(piperazin-1-yl)-3,7-dihydro-1H-purine-2,6-dione
Homo sapiens
pH 7.5, 22°C
0.000039
7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-8-(4-ethylpiperazin-1-yl)-1,3-dimethyl-3,7-dihydro-1H-purine-2,6-dione
Homo sapiens
pH 7.5, 22°C
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
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LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
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GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
enzyme inhibition by inhibitor TH5427 blocks progestin-dependent, PAR-derived nuclear ATP synthesis and subsequent chromatin remodeling, gene regulation and proliferation in breast cancer cells. Following depletion with NUDT5 siRNAs prior to cell lysis, ADPR hydrolysis is markedly attenuated compared to non-targeting siRNA controls. This can be rescued by the addition of recombinant NUDT5 protein. siRNA-mediated knockdown of NUDT5 alone does not appreciably induce DNA damage signaling in U2-OS cells, as measured by multiple DNA damage markers
metabolism
physiological function
additional information
NUDIX5 homodimer exists in equilibrium between the dominant ADPR hydrolysing conformation and a minor ATP synthesising conformation, in which the relative orientation of the monomer flips yielding more open active sites that can accommodate the presence of diphosphate required for ATP synthesis
metabolism
chromatin remodelling measured by histones H1 and H2A displacement at later stages after PAR accumulation and degradation, is dependent on PARP1, PARG, and NUDIX5
physiological function
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ADP-ribose-derived nuclear ATP synthesis by NUDIX5 is required for chromatin remodeling
physiological function
enzyme NUDT5 is implicated in ADP-ribose and 8-oxo-guanine metabolism and is a rheostat of hormone-dependent gene regulation and proliferation in breast cancer cells. NUDT5 catalyzes the breakdown of ADPR to ribose-5-phosphate (R5P) and adenosine 5'-monophosphate (AMP), which permits recovery of NAD+ pools after DNA damage and poly(ADPR) polymerase (PARP) activation. In addition, NUDT5 is responsible for the production of PAR-mediated nuclear ATP and, thus, subsequent ATP-dependent chromatin remodeling and gene regulation following progestin or estrogen stimulation in breast cancer cells. NUDT5 activity is critical to elicit nuclear ATP production following hormone stimulation
physiological function
in response to hormones, i.e. synthetic promegestone (R5020 or 17alpha,21-dimethyl-19-norpregna-4,9-diene-3,20-dione), a nuclear ATP synthesis mechanism is activated that utilizes ADP-ribose and diphosphate as substrates. Enzyme NUDIX5 utilizes an increase in ADP-D-ribose and diphosphate to generate ATP. ATP produced in the nucleus is used for stable displacement of H1 and H2A/H2B opening the chromatin for access of transcriptional regulators leading to gene activation/repression and ultimately to cell proliferation. NUDIX5 interacts with both poly-ADP-ribose glycohydrolase (PARG) and poly-ADP-ribose (PAR) by co-immunoprecipitation following hormone treatment
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UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). NUDT5_MOUSE
218
0
23984
Swiss-Prot
other Location (Reliability: 1)
NUDT5_PONAB
216
0
24070
Swiss-Prot
other Location (Reliability: 1)
NUDT5_RAT
219
0
24117
Swiss-Prot
other Location (Reliability: 1)
NUDT5_HUMAN
219
0
24328
Swiss-Prot
other Location (Reliability: 1)
A0A812EP20_SEPPH
210
0
23282
TrEMBL
other Location (Reliability: 2)
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PDB
SCOP
CATH
UNIPROT
ORGANISM
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MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oligomer
phosphorylation of T45 is predicted to prevent the flipping of NUDIX5 monomers, hindering the formation of the hexamer. Thus, dephosphorylation of NUDIX5 may trigger the switch to a conformational change that activates the energy generating molecular machine. NUDIX5 homodimer exists in equilibrium between the dominant ADPR hydrolysing conformation and a minor ATP synthesising conformation, in which the relative orientation of the monomer flips yielding more open active sites that can accommodate the presence of PPi required for ATP synthesis
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POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
phosphorylation of T45 is predicted to prevent the flipping of NUDIX5 monomers, hindering the formation of the hexamer. Thus, dephosphorylation of NUDIX5 may trigger the switch to a conformational change that activates the energy generating molecular machine
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CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
analysis of a crystal structure of human NUDIX5/NUDT5 homodimer bound with one ADPR on each of the 2 active sites
purified recombinant enzyme NUDT5 in complex with inhibitors TH1713 and TH5427, X-ray diffraction structure determination and analysis at 2.2-2.6 A resolution
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
siRNA-mediated knockdown of NUDT5. Following depletion with NUDT5 siRNAs prior to cell lysis, ADPR hydrolysis is markedly attenuated compared to non-targeting siRNA controls. This can be rescued by the addition of recombinant NUDT5 protein
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PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant N-terminally His6-tagged NUDT5 from Escherichia coli strain BL21(DE3) by nickel affinity chromatography
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant expression of N-terminally His6-tagged NUDT5 in Escherichia coli strain BL21(DE3)
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REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Yu, H.N.; Song, E.K.; Yoo, S.M.; Lee, Y.R.; Han, M.K.; Yim, C.Y.; Kwak, J.Y.; Kim, J.S.
Activation of NUDT5, an ADP-ribose pyrophosphatase, by nitric oxide-mediated ADP-ribosylation
Biochem. Biophys. Res. Commun.
354
764-768
2007
Homo sapiens
brenda
Wright, R.H.; Lioutas, A.; Le Dily, F.; Soronellas, D.; Pohl, A.; Bonet, J.; Nacht, A.S.; Samino, S.; Font-Mateu, J.; Vicent, G.P.; Wierer, M.; Trabado, M.A.; Schelhorn, C.; Carolis, C.; Macias, M.J.; Yanes, O.; Oliva, B.; Beato, M.
ADP-ribose-derived nuclear ATP synthesis by NUDIX5 is required for chromatin remodeling
Science
352
1221-1225
2016
Homo sapiens
brenda
Page, B.D.G.; Valerie, N.C.K.; Wright, R.H.G.; Wallner, O.; Isaksson, R.; Carter, M.; Rudd, S.G.; Loseva, O.; Jemth, A.S.; Almloef, I.; Font-Mateu, J.; Llona-Minguez, S.; Baranczewski, P.; Jeppsson, F.; Homan, E.; Almqvist, H.; Axelsson, H.; Regmi, S.; Gustavsson, A.L.; Lundbaeck, T.; Scobie, M.; Stroemberg, K.; Stenamrk, P.; Beato, M.; Helleday, T.
Targeted NUDT5 inhibitors block hormone signaling in breast cancer cells
Nat. Commun.
9
250
2018
Homo sapiens (Q9UKK9)
brenda
Wright, R.; Fernandez-Fuentes, N.; Oliva, B.; Beato, M.
Insight into the machinery that oils chromatin dynamics
Nucleus
7
532-539
2016
Homo sapiens (Q9UKK9)
brenda
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Release 2023.1 (January 2023)
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