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Literature summary for 3.2.1.143 extracted from

  • Tucker, J.A.; Bennett, N.; Brassington, C.; Durant, S.T.; Hassall, G.; Holdgate, G.; McAlister, M.; Nissink, J.W.; Truman, C.; Watson, M.
    Structures of the human poly (ADP-ribose) glycohydrolase catalytic domain confirm catalytic mechanism and explain inhibition by ADP-HPD derivatives (2012), PLoS ONE, 7, e50889.
    View publication on PubMedView publication on EuropePMC

Application

Application Comment Organism
drug development the enzyme is a target for drug design Homo sapiens

Cloned(Commentary)

Cloned (Comment) Organism
expression of His-tagged wild-type and mutant enzymes and selenomethionine-labeled enzyme in Escherichia coli strain BL21 (DE3) GOLD Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
purified recombinant mutant K616A/Q617A/K618A/E688A/K689A/K690A, also in selenomethionine-labeld form, in complex with inhibitors, sitting drop vapour diffusion, mixing protein in SEC buffer at 7.5 mg/mL with a precipitant consisting of 28% PEG 3350, 0.2 M magnesium chloride, 0.1 M PCTP (0.04 M sodium propionate, 0.02 M sodium cacodylate, 0.04 M Bis-Tris propane), pH 7.5, in a 1:1 ratio to give a 0.004 ml drop, 20°C, X-ray diffraction structure determination and analysis at 1.75-1.83 A resolution, molecular replacement Homo sapiens

Protein Variants

Protein Variants Comment Organism
E688A site-directed mutagenesis, a surface entropy reduction mutation Homo sapiens
K616A site-directed mutagenesis, a surface entropy reduction mutation Homo sapiens
K616A/Q617A/K618A/E688A/K689A/K690A site-directed mutagenesis, six surface entropy reduction mutations Homo sapiens
K618A site-directed mutagenesis, a surface entropy reduction mutation Homo sapiens
K689A site-directed mutagenesis, a surface entropy reduction mutation Homo sapiens
K690A site-directed mutagenesis, a surface entropy reduction mutation Homo sapiens
Q617A site-directed mutagenesis, a surface entropy reduction mutation Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
8-n-octyl-amino-adenosine 5'-diphosphate (hydroxymethyl)pyrrolidinediol binding structure with mutant enzyme K616A/Q617A/K618A/E688A/K689A/K690A Homo sapiens
adenosine 5'-diphosphate (hydroxymethyl)pyrrolidinediol ADP-HPD, binding structure with mutant enzyme K616A/Q617A/K618A/E688A/K689A/K690A Homo sapiens
ADP-ribose binding structure with mutant enzyme K616A/Q617A/K618A/E688A/K689A/K690A Homo sapiens
additional information structure-activity relationship analysis of the enzyme inhibitors by isothermal titration calorimetry and surface plasmon resonance, molecular modelling, overview Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
additional information Homo sapiens poly(ADP-ribose) glycohydrolase is the only enzyme known to catalyse hydrolysis of the O-glycosidic linkages of ADP-ribose polymers ?
-
?

Organism

Organism UniProt Comment Textmining
Homo sapiens Q86W56
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant N-terminally, TEV protease-cleavable His6-tagged wild-type and mutant enzymes, and selenomethionine-labeled enzyme from Escherichia coli strains BL21 (DE3) GOLD and B834 (DE3) by nickel affinity chromatography and gel filtration Homo sapiens

Reaction

Reaction Comment Organism Reaction ID
(ADP-ribose)n + H2O = (ADP-ribose)n-1 + ADP-ribose enzyme catalytic mechanism, overview Homo sapiens

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
additional information poly(ADP-ribose) glycohydrolase is the only enzyme known to catalyse hydrolysis of the O-glycosidic linkages of ADP-ribose polymers Homo sapiens ?
-
?

Synonyms

Synonyms Comment Organism
PARG
-
Homo sapiens
poly (ADP-ribose) glycohydrolase
-
Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
25
-
assay at Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7
-
assay at Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.0011
-
with mutant enzyme K616A/Q617A/K618A/E688A/K689A/K690A, pH 7.0, 25°C Homo sapiens adenosine 5'-diphosphate (hydroxymethyl)pyrrolidinediol
0.0031
-
with wild-type enzyme, pH 7.0, 25°C Homo sapiens adenosine 5'-diphosphate (hydroxymethyl)pyrrolidinediol
0.0163
-
with wild-type enzyme, pH 7.0, 25°C Homo sapiens 8-n-octyl-amino-adenosine 5'-diphosphate (hydroxymethyl)pyrrolidinediol

General Information

General Information Comment Organism
evolution conservation of overall fold amongst mammalian enzyme glycohydrolase domains, additional flexible regions in the catalytic site, overview Homo sapiens
malfunction enzyme deficiency leads to cell death whilst enzyme depletion causes sensitisation to certain DNA damaging agents Homo sapiens
additional information structure-based mechanism for the reported endo- and exo-glycohydrolase activities in human enzyme, overview Homo sapiens