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Literature summary for 2.7.7.96 extracted from

  • 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 (2018), Nat. Commun., 9, 250 .
    View publication on PubMedView publication on EuropePMC
Search for more literature for 2.7.7.96

Cloned(Commentary)

Cloned (Comment) Organism
recombinant expression of N-terminally His6-tagged NUDT5 in Escherichia coli strain BL21(DE3) Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
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 Homo sapiens

Protein Variants

Protein Variants Comment Organism
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 Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
7-[[5-(3,4-dichlorophenyl)-1,3,4-oxadiazol-2-yl]methyl]-1,3,8-trimethyl-3,7-dihydro-1H-purine-2,6-dione
-
 Homo sapiens
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 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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
-
 Homo sapiens
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 Homo sapiens
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
-
 Homo sapiens

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + D-ribose 5-phosphate Homo sapiens
-
 diphosphate + ADP-D-ribose
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q9UKK9
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant N-terminally His6-tagged NUDT5 from Escherichia coli strain BL21(DE3) by nickel affinity chromatography Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
breast cancer cell
-
 Homo sapiens
-
HeLa cell
-
 Homo sapiens
-
HL-60 cell
-
 Homo sapiens
-
T-47D cell
-
 Homo sapiens
-
U2-OS cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + D-ribose 5-phosphate
-
 Homo sapiens diphosphate + ADP-D-ribose
-
 ?
additional information 8-oxo-dGDP is a poor substrate for enzyme NUDT5 at physiological pH Homo sapiens ?
-
-

Synonyms

Synonyms Comment Organism
NUDIX5
-
 Homo sapiens
NUDT5
-
 Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
22
-
 assay at Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7.5
-
 assay at Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.000029
-
 pH 7.5, 22°C Homo sapiens 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
0.000039
-
 pH 7.5, 22°C Homo sapiens 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
0.000054
-
 pH 7.5, 22°C Homo sapiens 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

General Information

General Information Comment Organism
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 Homo sapiens
metabolism involvement of NUDT5 in ADP-ribose metabolism, overview Homo sapiens
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 Homo sapiens