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Literature summary extracted from

  • Comeaux, E.Q.; van Waardenburg, R.C.
    Tyrosyl-DNA phosphodiesterase I resolves both naturally and chemically induced DNA adducts and its potential as a therapeutic target (2014), Drug Metab. Rev., 46, 494-507.
    View publication on PubMed

Activating Compound

EC Number Activating Compound Comment Organism Structure
3.1.4.1 additional information etoposide and doxorubicin trigger a series of events that eventually lead to an enhanced DNA-linkage of topo I, which then is acted upon by the enzyme TDP1 Mus musculus
3.1.4.1 additional information etoposide and doxorubicin trigger a series of events that eventually lead to an enhanced DNA-linkage of topo I, which then is acted upon by the enzyme TDP1 Rattus norvegicus
3.1.4.1 additional information etoposide and doxorubicin trigger a series of events that eventually lead to an enhanced DNA-linkage of topo I, which then is acted upon by the enzyme TDP1 Canis lupus familiaris
3.1.4.1 additional information etoposide and doxorubicin trigger a series of events that eventually lead to an enhanced DNA-linkage of topo I, which then is acted upon by the enzyme TDP1 Gallus gallus
3.1.4.1 additional information etoposide and doxorubicin trigger a series of events that eventually lead to an enhanced DNA-linkage of topo I, which then is acted upon by the enzyme TDP1 Drosophila melanogaster
3.1.4.1 additional information the Topo2 inhibitors etoposide and doxorubicin, and analogues topotecan and irinotecan, trigger a series of events that eventually lead to an enhanced DNA-linkage of topo I, which then is acted upon by the enzyme TDP1, overview Saccharomyces cerevisiae
3.1.4.1 additional information the Topo2 inhibitors etoposide, i.e. VP16, and doxorubicin, and analogues topotecan and irinotecan, trigger a series of events that eventually lead to an enhanced DNA-linkage of topo I, which then is acted upon by the enzyme TDP1, overview Homo sapiens

Application

EC Number Application Comment Organism
3.1.4.1 drug development the enzyme is a a therapeutic target. It is of growing interesting in cancer treatment for its role in the repair of a variety of DNA adducts that are induced by chemotherapeutics Homo sapiens

Cloned(Commentary)

EC Number Cloned (Comment) Organism
3.1.4.1 overexpression of the enzyme in HEK293 cells and CHL cells leads to increase resistance to camptothecin-induced DNA damage Homo sapiens

Protein Variants

EC Number Protein Variants Comment Organism
3.1.4.1 H182F catalytically inactive mutant, expression of this Tdp1H182F protein does not reveal an enhanced Topo1-dependent toxicity or an increased CPT sensitivity, suggesting that sequestering of the DNA-adduct does not hinder repair by alternative pathways Saccharomyces cerevisiae

Inhibitors

EC Number Inhibitors Comment Organism Structure
3.1.4.1 methyl-3,4-dephostatin a dephostatin derivative, structure-activity relationship analogues of this active compound that have a chemical substitution at a single position show a dramatic decrease in inhibition activity Homo sapiens
3.1.4.1 additional information docking simulations suggest that enzyme inhibitors bind within the catalytic pocket to prevent docking of endogenous substrates Homo sapiens
3.1.4.1 NSC88915 a deoxycorticosterone derivative of progesterone coupled to methyl-p-toluene-sulfonate, structure-activity relationship analogues of this active compound that have a chemical substitution at a single position show a dramatic decrease in inhibition activity Homo sapiens

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
3.1.4.1 additional information Mus musculus substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues ?
-
?
3.1.4.1 additional information Rattus norvegicus substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues ?
-
?
3.1.4.1 additional information Canis lupus familiaris substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues ?
-
?
3.1.4.1 additional information Gallus gallus substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues ?
-
?
3.1.4.1 additional information Drosophila melanogaster substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues ?
-
?
3.1.4.1 additional information Saccharomyces cerevisiae substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues, substrates vary in size and complexity ?
-
?
3.1.4.1 additional information Homo sapiens substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues, substrates vary in size and complexity ?
-
?
3.1.4.1 additional information Saccharomyces cerevisiae ATCC 204508 substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues, substrates vary in size and complexity ?
-
?

Organism

EC Number Organism UniProt Comment Textmining
3.1.4.1 Canis lupus familiaris E2REL5
-
-
3.1.4.1 Drosophila melanogaster Q9VQM4
-
-
3.1.4.1 Gallus gallus F1NSQ5
-
-
3.1.4.1 Homo sapiens Q9NUW8
-
-
3.1.4.1 Mus musculus Q8BJ37
-
-
3.1.4.1 Rattus norvegicus Q4G056
-
-
3.1.4.1 Saccharomyces cerevisiae P38319
-
-
3.1.4.1 Saccharomyces cerevisiae ATCC 204508 P38319
-
-

Posttranslational Modification

EC Number Posttranslational Modification Comment Organism
3.1.4.1 phosphoprotein the N-terminal region is posttranslationally modified by phosphorylation of Ser81. Enzyme phosphorylation appears to be mediated by ATM (Ataxia telangiectasia mutated) and DNA-PK (DNA-dependent protein kinase) and is increased upon cellular treatment with camptothecin. Phosphorylation of Ser81 regulates hTdp1 targeting to sites of DNA damage and stabilizes its interaction with X-ray repair cross-complementing protein 1 (XRCC1) and/or DNA ligase III similar to how ATM-mediated phosphorylation of PNKP promotes its activity at DNA lesions Homo sapiens
3.1.4.1 poly(ADP-ribosyl)ation the N-terminal region is posttranslationally modified by parylation, i.e. addition of polyadenosylribose units at an undefined site. Parylation of the enzyme stimulates Tdp1 translocation to sites of DNA damage, not only increases Tdp1 protein stability but also facilitates Tdp1 interaction/complex formation with XRCC1 Homo sapiens
3.1.4.1 sumoylation the N-terminal region is posttranslationally modified by sumoylation, i.e. addition of small ubiquitin-like protein to Lys111, the sumoylation may be involved in regulating Tdp1 recruitment to DNA lesions. The enzyme is conjugated to all three SUMO isoforms, SUMO-1, SUMO-2 and SUMO-3 Homo sapiens

Reaction

EC Number Reaction Comment Organism Reaction ID
3.1.4.1 [nucleotide]n + H2O = [nucleotide]m + nucleotide catalytic mechanism, the enzyme has a unique catalytic cycle, structure-function analysis overview Mus musculus
3.1.4.1 [nucleotide]n + H2O = [nucleotide]m + nucleotide catalytic mechanism, the enzyme has a unique catalytic cycle, structure-function analysis overview Rattus norvegicus
3.1.4.1 [nucleotide]n + H2O = [nucleotide]m + nucleotide catalytic mechanism, the enzyme has a unique catalytic cycle, structure-function analysis overview Canis lupus familiaris
3.1.4.1 [nucleotide]n + H2O = [nucleotide]m + nucleotide catalytic mechanism, the enzyme has a unique catalytic cycle, structure-function analysis overview Gallus gallus
3.1.4.1 [nucleotide]n + H2O = [nucleotide]m + nucleotide catalytic mechanism, the enzyme has a unique catalytic cycle, structure-function analysis overview Drosophila melanogaster
3.1.4.1 [nucleotide]n + H2O = [nucleotide]m + nucleotide catalytic mechanism, the enzyme has a unique catalytic cycle, structure-function analysis overview. The enzyme's N-terminal catalytic His182 functions as a nucleophile (Hisnuc) to attack the 3'-phospho-tyrosyl linkage. This results in dissociation of the tyrosine (and by extension Topo1) from the DNA end and the formation of a enzyme-DNA covalent reaction intermediate via a 3'-phospho-histidyl linkage Saccharomyces cerevisiae
3.1.4.1 [nucleotide]n + H2O = [nucleotide]m + nucleotide catalytic mechanism, the enzyme has a unique catalytic cycle, structure-function analysis overview. The enzyme's N-terminal catalytic His263 functions as a nucleophile (Hisnuc) to attack the 3'-phospho-tyrosyl linkage. This results in dissociation of the tyrosine (and by extension Topo1) from the DNA end and the formation of a enzyme-DNA covalent reaction intermediate via a 3'-phospho-histidyl linkage Homo sapiens

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
3.1.4.1 additional information substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues Mus musculus ?
-
?
3.1.4.1 additional information substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues Rattus norvegicus ?
-
?
3.1.4.1 additional information substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues Canis lupus familiaris ?
-
?
3.1.4.1 additional information substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues Gallus gallus ?
-
?
3.1.4.1 additional information substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues Drosophila melanogaster ?
-
?
3.1.4.1 additional information substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues, substrates vary in size and complexity Saccharomyces cerevisiae ?
-
?
3.1.4.1 additional information substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues, substrates vary in size and complexity Homo sapiens ?
-
?
3.1.4.1 additional information the enzyme is able to act as a limited 3'-exonuclease by removing a single RNA or DNA nucleotide from the 3'-end of the DNA, but only if it bears a 3'-hydroxyl-group rather than a 3'-phosphoryl-group. The latter restriction prevents the enzyme from acting as a classic endonuclease to degrade the products of its own catalysis Homo sapiens ?
-
?
3.1.4.1 additional information substrates are protein-DNA adducts, such as camptothecin stabilized Topo1-DNA adducts, and modified nucleotides, including oxidized nucleotides and chain terminating nucleoside analogues, substrates vary in size and complexity Saccharomyces cerevisiae ATCC 204508 ?
-
?

Synonyms

EC Number Synonyms Comment Organism
3.1.4.1 TDP1
-
Saccharomyces cerevisiae
3.1.4.1 TDP1
-
Homo sapiens
3.1.4.1 TDP1
-
Mus musculus
3.1.4.1 TDP1
-
Rattus norvegicus
3.1.4.1 TDP1
-
Canis lupus familiaris
3.1.4.1 TDP1
-
Gallus gallus
3.1.4.1 TDP1
-
Drosophila melanogaster
3.1.4.1 tyrosyl-DNA phosphodiesterase I
-
Saccharomyces cerevisiae
3.1.4.1 tyrosyl-DNA phosphodiesterase I
-
Homo sapiens
3.1.4.1 tyrosyl-DNA phosphodiesterase I
-
Mus musculus
3.1.4.1 tyrosyl-DNA phosphodiesterase I
-
Rattus norvegicus
3.1.4.1 tyrosyl-DNA phosphodiesterase I
-
Canis lupus familiaris
3.1.4.1 tyrosyl-DNA phosphodiesterase I
-
Gallus gallus
3.1.4.1 tyrosyl-DNA phosphodiesterase I
-
Drosophila melanogaster

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
3.1.4.1 0.0004
-
pH and temperature not specified in the publication Homo sapiens methyl-3,4-dephostatin
3.1.4.1 0.009
-
pH and temperature not specified in the publication Homo sapiens NSC88915

General Information

EC Number General Information Comment Organism
3.1.4.1 evolution the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs Mus musculus
3.1.4.1 evolution the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs Rattus norvegicus
3.1.4.1 evolution the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs Canis lupus familiaris
3.1.4.1 evolution the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs Gallus gallus
3.1.4.1 evolution the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs Drosophila melanogaster
3.1.4.1 evolution the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs, three-dimensional structural comparison of four PLD superfamily members, overview Homo sapiens
3.1.4.1 evolution the enzyme belongs to the phospholipase D, PLD, superfamily, which consists of a highly diverse collection of prokaryotic and eukaryotic enzymes, such as bacterial, plant and mammalian PLDs, cardiolipin and phosphatidylserine synthases, Salmonella typhimurium Nuc and mammalian DNase II endonucleases, restriction enzyme BfiI, poxvirus envelope proteins p37K and K4L, and eukaryotic Tdp1, sequence comparison. Family members show the presence of two histidine-lysine-aspartate-asparagine-HKDN-(HxKx4Dx6N; x being any amino acid) motifs, three-dimensional structural comparison of PLD superfamily members, overview Saccharomyces cerevisiae
3.1.4.1 malfunction deletion of the enzyme in budding yeast leads to an increase in Topo1-dependent cytotoxicity either induced by expression of the toxic Topo1T722A mutant enzyme or cells treated with camptothecin Saccharomyces cerevisiae
3.1.4.1 malfunction Tdp1-/- enzyme knockout mice do not show increased sensitivity to etoposide, i.e. VP16 Mus musculus
3.1.4.1 malfunction the mutation H493R forms the molecular basis for the autosomal recessive neurodegenerative disease spinocerebellar ataxia with axonal neuropathy, SCAN1, and results in an increased stability of its Tdp1-DNA reaction intermediate, overview. Enzyme inhibition might potentiate camptothecin-based chemotherapy, overview Homo sapiens
3.1.4.1 physiological function tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA Rattus norvegicus
3.1.4.1 physiological function tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA Canis lupus familiaris
3.1.4.1 physiological function tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA Gallus gallus
3.1.4.1 physiological function tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA Drosophila melanogaster
3.1.4.1 physiological function tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA. Phosphorylation of Ser81 regulates hTdp1 targeting to sites of DNA damage and stabilizes its interaction with X-ray repair cross-complementing protein 1 (XRCC1) and/or DNA ligase III similar to how ATM-mediated phosphorylation of PNKP promotes its activity at DNA lesions. The human enzyme expressed in DT40 chicken B-lymphoblast cells plays a protective role against etoposide Homo sapiens
3.1.4.1 physiological function tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA. The enzyme may play a role in chemo-resistance to pharmacologic inhibitors of topoisomerase I Saccharomyces cerevisiae
3.1.4.1 physiological function tyrosyl-DNA phosphodiesterase I is a eukaryotic DNA repair enzyme that catalyzes the removal of covalent 3'-DNA adducts, the enzyme hydrolyzes the 3'-phospho-tyrosyl that in the cell covalently links DNA topoisomerase I and DNA. The enzyme plays a role in suppressing etoposide-induced DNA damage Mus musculus