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Information on EC 3.1.3.32 - polynucleotide 3'-phosphatase and Organism(s) Homo sapiens
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3.1.3.32 polynucleotide 3'-phosphataseIUBMB Comments
Also hydrolyses nucleoside 2'-, 3'- and 5'-monophosphates, but only 2'- and 3'-phosphopolynucleotides.
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Word Map
- 3.1.3.32
- 3'-phosphate
-
exonuclease
-
5'-kinase
- ape1
-
5\'-hydroxyl
-
3'-blocking
- xrcc4
-
end-healing
- apraxia
-
apurinic
- aprataxin
- diesterase
-
end-processing
-
3'-phosphorylated
-
strand-breaks
-
3'-phosphoesterase
-
3'-phosphoglycolate
-
phosphoesterase
-
tyrosyl-dna
- analysis
- ap-endonuclease
- pharmacology
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
3'-phosphatase, polynucleotide kinase/phosphatase, dna 3'-phosphatase, 3' phosphatase, polynucleotide kinase phosphatase, polynucleotide kinase 3'-phosphatase, polynucleotide kinase-phosphatase, atzdp, t4 polynucleotide kinase/phosphatase, snqi-pnk, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
2'(3')-polynucleotidase
-
-
-
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3'-phosphatase/5'-OH kinase
-
-
-
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5' polynucleotidekinase 3' phosphatase
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-
-
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chromatin 3'-phosphatase
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-
-
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deoxyribonucleate 3'-phosphatase
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-
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DNA 3'-phosphatase
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-
-
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phosphatase, polynucleotide 3'-
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-
-
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PNKP
polynucleotide kinase 3'-phosphatase
SNQI-PNK
-
-
-
-
PNKP
-
-
-
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polynucleotide kinase 3'-phosphatase
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-
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
hydrolysis of phosphoric ester
-
-
-
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Phosphorylation
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-
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SYSTEMATIC NAME
IUBMB Comments
polynucleotide 3'-phosphohydrolase
Also hydrolyses nucleoside 2'-, 3'- and 5'-monophosphates, but only 2'- and 3'-phosphopolynucleotides.
CAS REGISTRY NUMBER
COMMENTARY
37288-16-7
-
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
3'-phopsho-5'-hydroxy-DNA
?
role in repair of DNA strand breaks caused by oxidative damage
-
-
?
additional information
?
-
-
structure of the human PNKP FHA domain bound to a doubly phosphorylated phosphopeptide derived from XRCC1, overview
-
-
?
additional information
?
-
-
the enzyme acts on mitochondrial DNA and interacts with the mitochondrial proteins, overview
-
-
?
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
3'-phopsho-5'-hydroxy-DNA
?
role in repair of DNA strand breaks caused by oxidative damage
-
-
?
additional information
?
-
-
structure of the human PNKP FHA domain bound to a doubly phosphorylated phosphopeptide derived from XRCC1, overview
-
-
?
additional information
?
-
-
the enzyme acts on mitochondrial DNA and interacts with the mitochondrial proteins, overview
-
-
?
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(1-hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione
2-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione
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A6B4C3
2-(hydroxy(phenyl)methyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione
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A1B4C3
2-(hydroxy(thiophen-2-yl)methyl)-6-methyl-1-(phenylamino)-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione
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A39B1C2
tert-butyl 2-(1-hydroxy-2,2-diphenylethyl)-6-methyl-5,7-dioxo-2,4a,5,6,7,7a-hexahydro-1H-pyrrolo[3,4-b]pyridin-1-ylcarbamate
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A26B11C2
2-(1-hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione
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A12B4C3
2-(1-hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione
-
i.e. A12B4C3, a potent, noncompetitive inhibitor of the phosphatase activity of human polynucleotide kinase/phosphatase in vitro. The inhibitor can form a ternary complex with PNKP and a DNA substrate, the inhibitor does not prevent DNA from binding to the phosphatase DNA binding site, but disrupts the secondary structure of PNKP, interaction between Trp402 of PNKP and the inhibitor. A12B4C3 sensitizes A549 human lung cancer cells to the topoisomerase I poison, camptothecin, but not the topoisomerase II poison, etoposide, in a manner similar to small interferingRNAagainst PNKP
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.00006
2-(1-hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione
Homo sapiens
-
near maximal inhibition with 0.010 mM
0.0003
2-(hydroxy(3,4,5-trimethoxyphenyl)methyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4-b]pyridine-5,7(2H,4aH)-dione
Homo sapiens
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
genotype variant NKP T5644G in polynucleotide kinase 3' phosphatase (PNKP) and risk of adenoma recurrence analyzed by unconditional logistic regression models, SNP genotyping, allele-specific PCR and mass spectromety, no association or effect modification between genotype, dietary components and risk of adenoma recurrence, PNKP T5644G variant not involved in adenoma recurrence
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
bifunctional, c.f. EC 2.7.1.78; polyp prevention trial participants
SwissProt
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
the enzyme contains a functional mitochondrial-targeting signal, consisting of amino acids 432-441 (ARYVQCARAA), close to its C-terminus
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
additional information
-
PNKP function is modulated by interaction with the DNA repair scaffold proteins XRCC1 and XRCC4, which is mediated by binding of the PNKP FHA domain to phosphorylated motifs on XRCC1 and XRCC4, overview
malfunction
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mutations that lead to alterations in PNKP, similar to mutations in genes encoding other strand break repair proteins, are associated with a severe autosomal recessive neurological disorder
metabolism
-
aprataxin polynucleotide kinase/phosphatase-like factor (APLF) facilitates nonhomologous end joining (NHEJ) and associates with the core NHEJ components XRCC4-DNA ligase IV and Ku. The APLF-Ku interaction is functionally important in DNA repair and may be important for APLF stability
metabolism
-
interaction between XRCC1 and polynucleotide kinase 3'-phosphatase is critical for the retention of XRCC1 at DNA damage sites and DNA damage repair
physiological function
-
polynucleotide kinase/phosphatase serves a crucial role in the repair of DNA strand breaks by catalyzing the restoration of 5'-phosphate and 3'-hydroxyl termini. It is involved in single-strand break repair and participates in several DNA repair pathways through interactions with other DNA repair proteins, notably XRCC1 and XRCC4, regulation and enzyme recruitment, overview. Physiological importance of PNKP in maintaining the genomic stability of normal tissues, particularly developing neural cells, as well as enhancing the resistance of cancer cells to genotoxic therapeutic agents. The enzyme also performs base excision and double-strand break repair, overview
physiological function
-
the enzyme is involved in repair of DNA single and double strand breaks following exposure of cells to ionizing radiation
physiological function
-
the mitochondrial enzyme polynucleotide kinase/phosphatase is required in mitochondrial DNA repair, overview
physiological function
-
PNKP stably associates with ataxin-3. Purified wild-type ataxin-3 stimulates, and the mutant form specifically inhibits, PNKP's 3'-phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity
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). PNKP_HUMAN
521
0
57076
Swiss-Prot
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
57100
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
PNK phosphatase is a multidomain enzyme that consists of an N-terminal forkhead-associated domain and a C-terminal catalytic domain composed of fused phosphatase and kinase subdomains, structure of mammalian PNK phosphatase, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
kinase negative PNKP is generated by site-directed mutagenesis using RNAi-resistant PNKP cDNA. Phosphatase negative PNKP is generated by site-directed mutagenesis using RNAi-resistant PNKP cDNA, enzyme-deficient A-549 cells are constructed by expression of shRNA
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
N-terminal region (residues 1-139), immobilized metal ion affinity chromatography, gel filtration
recombinant N-terminally His-tagged wild-type and mutant enzymes from Escherichia coli by nickel affinity chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of N-or C-terminally His-tagged enzyme in A-549 cells, expression of N-terminally His-tagged wild-type and mutant enzymes in Escherichia coli
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expression of wild-type and mutant enzymes in Escherichia coli strain DE3(BL21) pLysS
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N-terminal region (residues 1-139) expressed in Escherichia coli Rosetta2(DE3) pLysS
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
-
human Machado-Joseph disease patients' brain samples show a significant accumulation of DNA strand breaks. PNKP stably associates with ataxin-3, a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3, i.e. Machado-Joseph disease
pharmacology
-
PNKP, similar to several other DNA repair proteins, is of increasing clinical interest owing to the identification of small molecule inhibitors of these enzymes that sensitize cells to IR or chemotherapeutic agents
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Jilani, A.; Ramotar, D.; Slack, C.; Ong, C.; Yang, X.M.; Scherer, S.W.; Lasko, D.D.
Molecular cloning of the human gene, PNKP, encoding a polynucleotide kinase 3-phosphatase and evidence for its role in repair of DNA strand breaks caused by oxidative damage
J. Biol. Chem.
274
24176-24186
1999
Homo sapiens (Q96T60), Homo sapiens
Murphy, G.; Sansbury, L.S.; Bergen, A.W.; Wang, Z.; Schatzkin, A.; Lehman, T.; Kalidindi, A.; Modali, R.; Lanza, E.
Polynucleotide kinase 3' phosphatase variant, dietary variables and risk of adenoma recurrence in the Polyp Prevention Trial
Eur. J. Cancer Prev.
17
287-290
2008
Homo sapiens (Q96T60)
Freschauf, G.K.; Karimi-Busheri, F.; Ulaczyk-Lesanko, A.; Mereniuk, T.R.; Ahrens, A.; Koshy, J.M.; Rasouli-Nia, A.; Pasarj, P.; Holmes, C.F.; Rininsland, F.; Hall, D.G.; Weinfeld, M.
Identification of a small molecule inhibitor of the human DNA repair enzyme polynucleotide kinase/phosphatase
Cancer Res.
69
7739-7746
2009
Homo sapiens, Mus musculus, Schizosaccharomyces pombe
Freschauf, G.K.; Mani, R.S.; Mereniuk, T.R.; Fanta, M.; Virgen, C.A.; Dianov, G.L.; Grassot, J.M.; Hall, D.G.; Weinfeld, M.
Mechanism of action of an imido-piperidine inhibitor of human polynucleotide kinase/phosphatase
J. Biol. Chem.
285
2351-2360
2010
Homo sapiens
Shen, J.; Gilmore, E.C.; Marshall, C.A.; Haddadin, M.; Reynolds, J.J.; Eyaid, W.; Bodell, A.; Barry, B.; Gleason, D.; Allen, K.; Ganesh, V.S.; Chang, B.S.; Grix, A.; Hill, R.S.; Topcu, M.; Caldecott, K.W.; Barkovich, A.J.; Walsh, C.A.
Mutations in PNKP cause microcephaly, seizures and defects in DNA repair
Nat. Genet.
42
245-249
2010
Homo sapiens
Ali, A.A.; Jukes, R.M.; Pearl, L.H.; Oliver, A.W.
Specific recognition of a multiply phosphorylated motif in the DNA repair scaffold XRCC1 by the FHA domain of human PNK
Nucleic Acids Res.
37
1701-1712
2009
Homo sapiens (Q96T60)
Weinfeld, M.; Mani, R.S.; Abdou, I.; Aceytuno, R.D.; Glover, J.N.
Tidying up loose ends: the role of polynucleotide kinase/phosphatase in DNA strand break repair
Trends Biochem. Sci.
36
262-271
2011
Homo sapiens, Mus musculus
Tahbaz, N.; Subedi, S.; Weinfeld, M.
Role of polynucleotide kinase/phosphatase in mitochondrial DNA repair
Nucleic Acids Res.
40
3484-3495
2012
Homo sapiens
Della-Maria, J.; Hegde, M.L.; McNeill, D.R.; Matsumoto, Y.; Tsai, M.S.; Ellenberger, T.; Wilson, D.M.; Mitra, S.; Tomkinson, A.E.
The interaction between polynucleotide kinase phosphatase and the DNA repair protein XRCC1 is critical for repair of DNA alkylation damage and stable association at DNA damage sites
J. Biol. Chem.
287
39233-39244
2012
Homo sapiens
Shirodkar, P.; Fenton, A.L.; Meng, L.; Koch, C.A.
Identification and functional characterization of a Ku-binding motif in aprataxin polynucleotide kinase/phosphatase-like factor (APLF)
J. Biol. Chem.
288
19604-19613
2013
Homo sapiens
Chatterjee, A.; Saha, S.; Chakraborty, A.; Silva-Fernandes, A.; Mandal, S.M.; Neves-Carvalho, A.; Liu, Y.; Pandita, R.K.; Hegde, M.L.; Hegde, P.M.; Boldogh, I.; Ashizawa, T.; Koeppen, A.H.; Pandita, T.K.; Maciel, P.; Sarkar, P.S.; Hazra, T.K.
The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3-phosphatase in spinocerebellar ataxia type 3 pathogenesis
PLoS Genet.
11
e1004749
2015
Homo sapiens, Mus musculus (Q9JLV6), Mus musculus
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