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Information on EC 3.1.4.1 - phosphodiesterase I and Organism(s) Homo sapiens and UniProt Accession Q9Y2M0
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3.1.4.1 phosphodiesterase IIUBMB Comments
Hydrolyses both ribonucleotides and deoxyribonucleotides. Has low activity towards polynucleotides. A 3'-phosphate terminus on the substrate inhibits hydrolysis.
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Word Map
- 3.1.4.1
- camp
- phosphodiesterases
- calcification
- arterial
-
topoisomerase
- rolipram
- monophosphate
-
camp-specific
-
infancy
- osteoblast
-
hypophosphatemic
- rickets
- camptothecin
-
pseudoxanthoma
-
ectoenzyme
- topotecan
-
5'-nucleotide
- elasticum
- ibmx
- ankylosis
- 3'-phosphate
- zaprinast
-
top1-dna
- camp-pde
-
tcf7l2
- milrinone
-
tissue-nonspecific
-
cgmp-inhibited
-
cgmp-stimulated
-
pyrophosphohydrolase
- cilomilast
-
cementum
- 3-isobutyl-1-methylxanthine
-
rolipram-sensitive
- vinpocetine
-
cardiotonic
- pharmacology
- medicine
- synthesis
- drug development
- biotechnology
- analysis
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
enpp1, pde4a, phosphodiesterase i, pde i, tyrosyl-dna phosphodiesterase 1, ectonucleotide pyrophosphatase/phosphodiesterase 1, nucleotide phosphodiesterase, cpsf-73, 5'-phosphodiesterase, ectonucleotide pyrophosphatase phosphodiesterase 1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
5'-exonuclease
-
-
-
-
5'-nucleotide phosphodiesterase
-
-
-
-
5'-phosphodiesterase
-
-
-
-
orthophosphoric diester phosphohydrolase
-
-
-
-
PC-1
TDP1
tyrosyl-DNA phosphodiesterase 1
tyrosyl-DNA phosphodiesterase I
additional information
-
the enzyme belongs to a family of enzymes with nucleoside triphosphate pyrophophohydrolase, NTPPPH, activity
PC-1
-
PC-1, plasma-cell differentiation antigen-1, membrane glycoprotein, has 5'-nucleotide phosphodiesterase and nucleotide pyrophosphatase activity
TDP1
-
-
tyrosyl-DNA phosphodiesterase 1
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
[nucleotide]n + H2O = [nucleotide]m + nucleotide
the enzyme may be able to recognize nucleoside 5'-monophosphates in the substrates and nick them even if the phosphodiester bonds are closed covalently, although the mode of action of this enzyme on oligo- or polynucleotides is typically exonucleolytic
-
[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
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoric ester hydrolysis
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
oligonucleotide 5'-nucleotidohydrolase
Hydrolyses both ribonucleotides and deoxyribonucleotides. Has low activity towards polynucleotides. A 3'-phosphate terminus on the substrate inhibits hydrolysis.
CAS REGISTRY NUMBER
COMMENTARY
9025-82-5
-
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
10-hydroxydecyl-oligonucleotide + H2O
?
-
different sequences of the oligonucleotides, overview. The enzyme catalyzes the cleavage of the synthetic analogue of the apurinic/apyrimidinic site
-
-
?
3'-phosphohistidyl-linked tyrosyl-DNA phosphodiesterase I-DNA complex + H2O
?
tyrosyl-DNA phosphodiesterase I hydrolyzes the 3'phospho-histidyl bond formed between tyrosyl-DNA phosphodiesterase I and DNA
-
-
?
3'-phosphotyrosyl-linked topoisomerase I-DNA complex + H2O
?
tyrosyl-DNA phosphodiesterase I hydrolyzes the 3'phospho-tyrosyl bond formed between DNA topoisomerase I and DNA
-
-
?
3-hydroxy-2(hydroxymethyl)-tetrahydrofuran-oligonucleotide + H2O
?
-
different sequences of the oligonucleotides, overview. The enzyme catalyzes the cleavage of the synthetic analogue of the apurinic/apyrimidinic site. In the case of tetrahydrofuran, the enzyme generates break with the 5'-tetrahydrofuran and the 3'-phosphate termini
the enzyme generates a non-phosphorylated 5'-THF-terminus by the cleavage of 3-hydroxy-2(hydroxymethyl)-tetrahydrofuran-containing DNA
-
?
4-nitrophenyl phenyl phosphonate + H2O
4-nitrophenol + phenyl phosphonate
-
-
-
-
?
4-nitrophenyl phosphocholine + H2O
4-nitrophenol + phosphocholine
secreted recombinant human SMPDL3A hydrolyzes 4-nitrophenyl phosphorylcholine, a synthetic analogue of the phosphorylcholine headgroup of lipids such as sphingomyelin and phosphatidylcholine
-
-
?
5'-p-nitrophenyl deoxythymidine 5'-phosphate + H2O
5'-dTMP + p-nitrophenol
-
-
-
-
?
5'-phosphotyrosyl-linked topoisomerase II-DNA complex + H2O
?
tyrosyl-DNA phosphodiesterase I hydrolyzes the 5'phospho-tyrosyl bond formed between DNA topoisomerase II and DNA
-
-
?
bis-ethylene glycolyl-oligonucleotide + H2O
?
-
different sequences of the oligonucleotides, overview. The enzyme catalyzes the cleavage of the synthetic analogue of the apurinic/apyrimidinic site
-
-
?
cAMP + H2O
?
-
incubated with or without 0.2 mM CaCl2, 10 mU calmodulin, and PDE1 inhibitor vinpocetin, 30°C, pH 7.5
-
-
?
dinucleoside monophosphates + H2O
mononucleoside 5'-phosphate
-
3'-5' linkage
-
?
p-nitrophenyl phenylphosphonate + H2O
p-nitrophenol + benzenephosphonic acid
-
-
-
-
?
p-nitrophenylthymidine 5'-phosphate + H2O
5'-TMP + p-nitrophenol
-
-
-
-
?
P1,P4-bis(5'-uridyl) tetraphosphate + H2O
UMP + uridine 5'-triphosphate
-
-
-
?
thymidine 5'-monophosphate p-nitrophenylester + H2O
? + phosphate
-
-
-
?
ADP + H2O
AMP + phosphate
-
ADPase activity, hydrolysis of ADP by human plasma PDEase acts as an inhibitor of platelet aggregation
-
?
cyclic 3',5'-mononucleotides + H2O
mononucleoside 5'-phosphate
-
phosphodiester bonds
-
?
cyclic 3',5'-mononucleotides + H2O
mononucleoside 5'-phosphate
-
phosphodiester bonds
-
-
?
diadenosine polyphosphate + H2O
AMP + adenosine polyphosphate-1
-
phosphodiesterase can be considered as a catabolic enzyme
-
-
?
DNA + H2O
DNA(n-1) + 2'-deoxynucleoside 5'-phosphate
-
enzyme hydolyzes single-stranded DNA more preferentially than double-stranded DNA, the enzyme also hydrolyzes nicked superhelical covalently closed circular phiX174RFI DNA to yield first open circular DNA and then linear DNA
-
-
?
DNA + H2O
DNA(n-1) + 2'-deoxynucleoside 5'-phosphate
-
enzyme hydrolyzes single-stranded DNA, no activity with double-stranded DNA
-
-
?
oligonucleotides + H2O
oligonucleotides(n-1) + 5'-mononucleotides
-
specific for 3'-5'-direction from the 3'-hydroxyl terminal in a stepwise manner
-
-
?
oligonucleotides + H2O
oligonucleotides(n-1) + 5'-mononucleotides
-
specific for 3'-5'-direction from the 3'-hydroxyl terminal in a stepwise manner
-
?
polynucleotides + H2O
polynucleotides(n-1) + 5'-mononucleotides
-
specific for 3'-5'-direction from the 3'-hydroxyl terminal in a stepwise manner
-
?
additional information
?
-
-
no activity with p-nitrophenylthymidine 3'-phosphate
-
-
?
additional information
?
-
-
no activity with p-nitrophenylthymidine 3'-phosphate
-
-
?
additional information
?
-
-
PC-1, PC-1 may take part in purine uptake for metabolic needs of cells
-
-
?
additional information
?
-
-
enzyme might function as a modulating factor of platelet aggregation
-
-
?
additional information
?
-
-
enzyme may be involved in nucleotides metabolism in human plasma
-
-
?
additional information
?
-
-
PC-1 plays a major role in bone and cartilage metabolism by producing diphosphate
-
-
?
additional information
?
-
-
tyrosyl-DNA phosphodiesterase 1 catalyses the hydrolysis of phosphodiester linkages between a DNA 3' phosphate and a tyrosine residue as well as a variety of other DNA 3 substituents, the enzyme shows affinity for the substrate increased as the DNA length
-
-
?
additional information
?
-
-
Tdp1 activity on DNA substrate with 3'-dRP moiety in the single strand break. The 15-mer with 3'-dRP is generated by incubating 10 nM AP-DNA with EndoIII, site cleavage activity of tyrosyl-DNA phosphodiesterase 1, overview
-
-
?
additional information
?
-
-
the active site H263 is covalently bound through a phosphoamide bond to the 3' end of DNA moiety of the substrate
-
-
?
additional information
?
-
SMPDL3A is a functional metallophosphoesterase, and despite having no detectable activity towards sphingomyelin, possesses a nucleotide phosphodiesterase activity, particularly strongly against nucleotide triphosphates
-
-
?
additional information
?
-
-
SMPDL3A is a functional metallophosphoesterase, and despite having no detectable activity towards sphingomyelin, possesses a nucleotide phosphodiesterase activity, particularly strongly against nucleotide triphosphates
-
-
?
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
-
-
?
additional information
?
-
-
the enzyme catalyzes the hydrolysis of 3' phosphotyrosyl linkers and other 3'-end blocking lesions. When Top1 nicks double-stranded DNA, a covalent cleavage complex is formed that can be repaired by the enzyme, the mechanism involves the following steps: first, as Lys265 and Lys495 residues in the catalytic site coordinate the oxygen atoms of the phosphate group, His263 attacks the phosphorus atom linked to the oxygen of the Top1 catalytic residue, Tyr723, at the 3' end of DNA. Second, the TDP1-DNA covalent intermediate formed is hydrolyzed by a His493-activated water molecule, leading to the generation of a DNA product with a 3' phosphate
-
-
?
additional information
?
-
-
the enzyme cleaves the apurinic/apyrimidinic site in DNA by hydrolysis of the phosphodiester bond between the substituent and 5' adjacent phosphate. The product of enzyme cleavage in the case of the apurinic/apyrimidinic site is unstable and is hydrolyzed with the formation of 3'- and 5'-margin phosphates. The following repair demands the ordered action of polynucleotide kinase phosphorylase, with XRCC1, DNA polymerase beta, and DNA ligase, mechanism, overview
-
-
?
additional information
?
-
-
tyrosyl-DNA phosphodiesterase 1 catalyzes the hydrolysis of the phosphodiester linkage between the DNA 3'-phosphate and a tyrosine residue as well as a variety of other DNA 30 damaged termini. The enzyme can liberate the 3'-DNA phosphate termini from apurinic/apyrimidinic sites. The enzyme is more active in the cleavage of the apurinic/apyrimidinic sites inside bubble-DNA structure in comparison to ssDNA containing apurinic/apyrimidinic site, it hydrolyzes apurinic/apyrimidinic sites opposite to bulky fluorescein adduct faster than apurinic/apyrimidinic sites located in dsDNA, specificity of the apurinic/apyrimidinic site cleavage activity
-
-
?
additional information
?
-
-
tyrosyl-DNA phosphodiesterase I specifically catalyzes the hydrolysis of the phosphodiester bond between the catalytic Tyr723 of Top1 and DNA-3'-phosphate, then polynucleotide kinase phosphatase hydrolyzes the resulting 3'-phosphate end and catalyzes the phosphorylation of the 5'-hydroxyl end of the broken DNA strand. This results in a broken DNA strand with termini consisting of a 5'-phosphate and 3'-hydroxyl for DNA repair. DNA polymerase beta replaces the missing DNA segment, and finally DNA ligase III reseals the broken DNA
-
-
?
additional information
?
-
-
efficiency of apurinic/apyrimidinic site hydrolysis catalyzed by the enzyme decreases in the order: dsAP-DNA/bubble > ssAP-DNA > dsAP-DNA/Flu >> dsAP-DNA, the enzyme shows preference for 3'-substituent located on the termini of DNA compared to nicks
-
-
?
additional information
?
-
-
isozymes NPP1 and NPP3 can hydrolyze ATP, as well as inhibitor molecule 4, they also show very low activity with inhibitors 1 and 2, 1-4% compared to the activit with ATP
-
-
?
additional information
?
-
-
recombinant human enzyme processes 5'-phosphotyrosyl DNA ends when they mimic the 5'-overhangs of topoisomerase II-DNA cleavage complexes and 3'-deoxyribose phosphates generated from hydrolysis of abasic sites
-
-
?
additional information
?
-
SMPDL3A is not an acid sphingomyelinase, but unexpectedly is active against nucleotide diphosphate and triphosphate substrates at acidic and neutral pH
-
-
?
additional information
?
-
-
SMPDL3A is not an acid sphingomyelinase, but unexpectedly is active against nucleotide diphosphate and triphosphate substrates at acidic and neutral pH
-
-
?
additional information
?
-
-
substrate is 5'-[32P]-labeled single-stranded DNA oligonucleotide containing a 3'-phosphotyrosine (N14Y)
-
-
?
additional information
?
-
-
substrate is a 5'-[32P]-labeled single-stranded DNA oligonucleotide containing a 3' phosphotyrosine (N14Y)
-
-
?
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
-
-
?
additional information
?
-
-
the enzyme is also able to effectively cleave non-nucleotide insertions in DNA, decanediol and diethyleneglycol moieties by the same mechanism as in the case of tetrahydrofuran cleavage, it catalyzes the hydrolysis of decanediol- and bis-ethylene glycol-containing DNA even more effectively than tetrahydrofuran-containing DNA particularly in the case of decanediol-containing DNA. Repair of 5'-tetrahydrofuran and other apurinic/apyrimidinic site analogues can be processed by the long-patch base excision repair pathway, overview.The efficiency of enzyme-catalyzed hydrolysis of apurinic/apyrimidinic-site analogues correlates with the DNA helix distortion induced by the substituent
-
-
?
additional information
?
-
the enzyme cleaves the 3'-diester bond between tyrosine and DNA as well as removes other lesions, producing a 3'-phosphate that can be removed by polynucleotide kinase/phosphatase
-
-
?
additional information
?
-
the enzyme hydrolyzes the phosphodiester bond between a catalytic tyrosine Tyr723 (human) of topoisomerase 1 and DNA 3'-phosphate
-
-
?
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'-phosphohistidyl-linked tyrosyl-DNA phosphodiesterase I-DNA complex + H2O
?
tyrosyl-DNA phosphodiesterase I hydrolyzes the 3'phospho-histidyl bond formed between tyrosyl-DNA phosphodiesterase I and DNA
-
-
?
3'-phosphotyrosyl-linked topoisomerase I-DNA complex + H2O
?
tyrosyl-DNA phosphodiesterase I hydrolyzes the 3'phospho-tyrosyl bond formed between DNA topoisomerase I and DNA
-
-
?
5'-phosphotyrosyl-linked topoisomerase II-DNA complex + H2O
?
tyrosyl-DNA phosphodiesterase I hydrolyzes the 5'phospho-tyrosyl bond formed between DNA topoisomerase II and DNA
-
-
?
diadenosine polyphosphate + H2O
AMP + adenosine polyphosphate-1
-
phosphodiesterase can be considered as a catabolic enzyme
-
-
?
additional information
?
-
-
PC-1, PC-1 may take part in purine uptake for metabolic needs of cells
-
-
?
additional information
?
-
-
enzyme might function as a modulating factor of platelet aggregation
-
-
?
additional information
?
-
-
enzyme may be involved in nucleotides metabolism in human plasma
-
-
?
additional information
?
-
-
PC-1 plays a major role in bone and cartilage metabolism by producing diphosphate
-
-
?
additional information
?
-
-
tyrosyl-DNA phosphodiesterase 1 catalyses the hydrolysis of phosphodiester linkages between a DNA 3' phosphate and a tyrosine residue as well as a variety of other DNA 3 substituents, the enzyme shows affinity for the substrate increased as the DNA length
-
-
?
additional information
?
-
SMPDL3A is a functional metallophosphoesterase, and despite having no detectable activity towards sphingomyelin, possesses a nucleotide phosphodiesterase activity, particularly strongly against nucleotide triphosphates
-
-
?
additional information
?
-
-
SMPDL3A is a functional metallophosphoesterase, and despite having no detectable activity towards sphingomyelin, possesses a nucleotide phosphodiesterase activity, particularly strongly against nucleotide triphosphates
-
-
?
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
-
-
?
additional information
?
-
-
the enzyme catalyzes the hydrolysis of 3' phosphotyrosyl linkers and other 3'-end blocking lesions. When Top1 nicks double-stranded DNA, a covalent cleavage complex is formed that can be repaired by the enzyme, the mechanism involves the following steps: first, as Lys265 and Lys495 residues in the catalytic site coordinate the oxygen atoms of the phosphate group, His263 attacks the phosphorus atom linked to the oxygen of the Top1 catalytic residue, Tyr723, at the 3' end of DNA. Second, the TDP1-DNA covalent intermediate formed is hydrolyzed by a His493-activated water molecule, leading to the generation of a DNA product with a 3' phosphate
-
-
?
additional information
?
-
-
the enzyme cleaves the apurinic/apyrimidinic site in DNA by hydrolysis of the phosphodiester bond between the substituent and 5' adjacent phosphate. The product of enzyme cleavage in the case of the apurinic/apyrimidinic site is unstable and is hydrolyzed with the formation of 3'- and 5'-margin phosphates. The following repair demands the ordered action of polynucleotide kinase phosphorylase, with XRCC1, DNA polymerase beta, and DNA ligase, mechanism, overview
-
-
?
additional information
?
-
-
tyrosyl-DNA phosphodiesterase 1 catalyzes the hydrolysis of the phosphodiester linkage between the DNA 3'-phosphate and a tyrosine residue as well as a variety of other DNA 30 damaged termini. The enzyme can liberate the 3'-DNA phosphate termini from apurinic/apyrimidinic sites. The enzyme is more active in the cleavage of the apurinic/apyrimidinic sites inside bubble-DNA structure in comparison to ssDNA containing apurinic/apyrimidinic site, it hydrolyzes apurinic/apyrimidinic sites opposite to bulky fluorescein adduct faster than apurinic/apyrimidinic sites located in dsDNA, specificity of the apurinic/apyrimidinic site cleavage activity
-
-
?
additional information
?
-
-
tyrosyl-DNA phosphodiesterase I specifically catalyzes the hydrolysis of the phosphodiester bond between the catalytic Tyr723 of Top1 and DNA-3'-phosphate, then polynucleotide kinase phosphatase hydrolyzes the resulting 3'-phosphate end and catalyzes the phosphorylation of the 5'-hydroxyl end of the broken DNA strand. This results in a broken DNA strand with termini consisting of a 5'-phosphate and 3'-hydroxyl for DNA repair. DNA polymerase beta replaces the missing DNA segment, and finally DNA ligase III reseals the broken DNA
-
-
?
additional information
?
-
the enzyme cleaves the 3'-diester bond between tyrosine and DNA as well as removes other lesions, producing a 3'-phosphate that can be removed by polynucleotide kinase/phosphatase
-
-
?
additional information
?
-
the enzyme hydrolyzes the phosphodiester bond between a catalytic tyrosine Tyr723 (human) of topoisomerase 1 and DNA 3'-phosphate
-
-
?
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Ca2+
divalent cations
Mg2+
Zn2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(2R,4R,4aR,7R,8aS)-4,7-dimethyl-2-(5-aminothiophen-2-yl)octahydro-2H-chromen-4-ol
-
(2R,4S,4aR,7R,8aS)-4,7-dimethyl-2-(5-aminothiophen-2-yl)octahydro-2H-chromen-4-ol
-
(6-methyl-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]-isoquinolin-3-yl)carbamic acid
-
-
(S)-3-(4-hydroxy-3-methoxyphenyl)propane-1,2-diol-2-beta-D-(6'-O-galloyl) glucopyranoside
-
2,2,2-trifluoro-N-(5-((2R,4R,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)acetamide
-
2,2,2-trifluoro-N-(5-((2R,4S,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)acetamide
-
2,2,2-trifluoro-N-(8-(trifluoromethyl)benzo[f][1,2,3,4,5]pentathiepin-6-yl)acetamide
-
2-((6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5H-indeno-[1,2-c]isoquinolin-3-yl)amino)acetic acid
-
-
2-(2,6-dimethylhept-5-en-1-yl)-5,7-dimethyl-1,3-diazatricyclo[3.3.1.1(3,7)]decan-6-one
-
2-(3-(dimethylamino)propoxy)-3-methoxy-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione
-
-
2-(3-(ethylamino)propoxy)-3-methoxy-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione
-
-
2-(3-aminopropoxy)-3-methoxy-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione
-
-
2-(dibutylamino)-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)acetamide
-
2-(piperidin-1-yl)-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)acetamide
-
2-(pyrrolidin-1-yl)-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)acetamide
-
2-morpholino-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)acetamide
-
3-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one
-
3-(((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one
-
3-((3,4,5-trimethoxybenzyl)oxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one
-
3-(2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one
-
3-(4-hydroxy-3-methoxyphenyl)propane-1,2-diol 2-beta-D-(6'-O-galloyl)glucopyranoside
-
3-(piperidin-1-yl)-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)propanamide
-
3-(pyrrolidin-1-yl)-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)propanamide
-
3-amino-6-(3-aminopropyl)-5,6-dihydro-9-methoxy-5,11-dioxo-11H-indeno[1,2-c]isoquinoline dihydrochloride
-
-
3-cyano-6,11-dihydro-5,11-dioxo-6-[3-(dimethylaminopropyl)-5H-indeno[1,2-c]isoquinoline]
-
-
3-iodo-9-methoxy-6-(3-(dimethylamino)propyl)-5H-indeno-[1,2-c]isoquinoline-5,11(6H)-dione
-
-
3-methoxy-6-(3-morpholinopropyl)-2-(3-(piperidin-1-yl)-propoxy)-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione
-
-
3-methoxy-6-(3-morpholinopropyl)-2-(3-(pyrrolidin-1-yl)-propoxy)-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione
-
-
3-morpholino-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)propanamide
-
4-[(6-(3-((tert-butoxycarbonyl)amino)propyl)-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl)amino]-4-oxobutanoic acid
-
-
6,6'-[(1R,2R,3S,4S)-2,4-bis(4-hydroxyphenyl)cyclobutane-1,3-diyl]di(2H-pyran-2-one)
-
6,6'-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis(5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione)
-
-
6-(3-(1H-imidazol-1-yl)propyl)-8-methoxy-3-nitro-5Hindeno[1,2-c]isoquinoline-5,11(6H)-dione
-
-
6-(3-aminopropyl)-3-(methylamino)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
-
-
6-(3-aminopropyl)-5,6-dihydro-8-methoxy-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
-
-
6-(3-aminopropyl)-5,6-dihydro-9-methoxy-3-iodo-5,11-dioxo-11H-indeno[1,2-c]isoquinoline
-
-
6-(3-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
-
-
6-(3-aminopropyl)-7-methoxy-3-nitro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
-
-
6-(3-aminopropyl)-8-hydroxy-3-nitro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
-
6-(3-aminopropyl)-9-methoxy-3-nitro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
-
-
6-[(6-(3-((tert-butoxycarbonyl)amino)propyl)-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl)amino]-6-oxohexanoic acid
-
-
7-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-2,3-dihydrocyclopenta[c]chromen-4(1H)-one
-
7-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-4-methyl-2H-chromen-2-one
-
7-(((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-2,3-dihydrocyclopenta[c]chromen-4(1H)-one
-
7-(((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-4-methyl-2H-chromen-2-one
-
7-((3,4,5-trimethoxybenzyl)oxy)-2,3-dihydrocyclopenta[c]chromen-4(1H)-one
-
7-(2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethoxy)-2,3-dihydrocyclopenta[c]chromen-4(1H)-one
-
7-[[(1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methoxy]-2,3-dihydrobenzo[b]cyclopenta[d]pyran-4(1H)-one
-
alpha,beta-methylene-adenosine triphosphate
-
inhibition in decreasing order: alpha,beta-methyl-adenosine triphosphate, ATP, UTP, GTP, CTP
CTP
-
inhibition in decreasing order: alpha,beta-methylene-adenosine triphosphate, ATP, UTP, GTP, CTP
ethyl 2-[(6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5Hindeno[1,2-c]isoquinolin-3-yl)amino]acetate
-
-
methyl 2-[(6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5Hindeno[1,2-c]isoquinolin-3-yl)amino]-2-oxoacetate
-
-
methyl 3-[(6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5Hindeno[1,2-c]isoquinolin-3-yl)amino]-3-oxopropanoate
-
-
methyl 4-[(6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5Hindeno[1,2-c]isoquinolin-3-yl)amino]-4-oxobutanoate
-
-
methyl 5-[(6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5Hindeno[1,2-c]isoquinolin-3-yl)amino]-5-oxopentanoate
-
-
methyl 6-[(6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5Hindeno[1,2-c]isoquinolin-3-yl)amino]-6-oxohexanoate
-
-
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
N-(2-[1-[2-(2-methyl-1H-imidazol-1-yl)pyrimidin-4-yl]piperidin-4-yl]ethyl)sulfuric diamide
-
-
N-(2-[1-[6-(2-methyl-1H-imidazol-1-yl)pyrimidin-4-yl]piperidin-4-yl]ethyl)sulfuric diamide
-
-
N-(5-((2R,4R,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)acetamide
-
N-(5-((2R,4R,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)benzamide
-
N-(5-((2R,4R,4aR,7R,8aS)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)adamantane-1-carboxamide
-
N-(5-((2R,4S,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)acetamide
-
N-(5-((2R,4S,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2yl)benzamide
-
N-(5-((2R,4S,4aR,7R,8aS)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)adamantane-1-carboxamide
-
N-[2-(1-[6,7-dimethoxy-2-[(E)-2-(pyridin-3-yl)ethenyl]quinazolin-4-yl]piperidin-4-yl)ethyl]sulfuric diamide
-
-
N-[2-[1-(2-ethyl-6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl]sulfuric diamide
-
-
N-[2-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl]sulfuric diamide
-
enzyme binding, structure modelling, overview
N-[6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl]acetamide
-
-
N2,N2-dibutyl-N-[8-(trifluoromethyl)-1,2,3,4,5-benzopentathiepin-6-yl]glycinamide
-
UTP
-
inhibition in decreasing order: alpha,beta-methylene-adenosine triphosphate, ATP, UTP, GTP, CTP
vinpocetin
-
10 mU, surpresses the increase of activity, caused by the addition of 0.2 mM Ca2+
AMP
-
5'-AMP, but 2'-AMP, 3'-AMP, 3': 5'cAMP and 2': 3'cAMP has no inhibiting effects; competitive; product inhibition
ATP
-
inhibition in decreasing order: alpha,beta-methylene-adenosine triphosphate, ATP, UTP, GTP, CTP
GTP
-
inhibition in decreasing order: alpha,beta-methylene-adenosine triphosphate, ATP, UTP, GTP, CTP
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
additional information
-
no inhibition by adenosine, inosine, phenylalanine and caffeine
-
additional information
-
not inhibitory: 3-isobutyl-1methylxanthine, Ro 20-1724, 13-dipropyl-8-p-sulfophenylxanthine
-
additional information
-
expression of PC-1 is down-regulated during adipocyte maturation
-
additional information
-
the enzyme is not inhibited by bis(1,3,4-oxadiazol-2-methyl)-5-thione, 5-[4-pyridyl]-1,3,4-oxadiazole-2(3H)-thione, 5-[3-hydroxyphenyl]-1,3,4-oxadiazole-2(3H)-thione, 5-[4-benzyloxyphenyl]-3-octyl-1,3,4-oxadiazole-2(3H)-thione, and 5-[4-(t-butyldimethylsilyloxy)-phenyl]-1,3,4-thiadiazole-2 (3H)-thione
-
additional information
-
design, synthesis, and evaluation of new indenoisoquinolines that are dual inhibitors of both tyrosyl-DNA phosphodiesterase I and topoisomerase 1, structure-activity relationships and cytotoxicity, overview. No inhibition by methyl 2-[(6-methyl-5,11-dioxo-6,11-dihydro-5H-indeno-[1,2-c]isoquinolin-3-yl)amino]-2-oxoacetate, methyl 3-[(6-methyl-5,11-dioxo-6,11-dihydro-5H-indeno-[1,2-c]isoquinolin-3-yl)amino]-3-oxopropanoate, methyl 4-[(6-methyl-5,11-dioxo-6,11-dihydro-5H-indeno-[1,2-c]isoquinolin-3-yl)amino]-4-oxobutanoate, methyl 5-[(6-methyl-5,11-dioxo-6,11-dihydro-5H-indeno-[1,2-c]isoquinolin-3-yl)amino]-5-oxopentanoate, methyl 6-[(6-methyl-5,11-dioxo-6,11-dihydro-5H-indeno-[1,2-c]isoquinolin-3-yl)amino]-6-oxohexanoate, 3-[(6-methyl-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]-isoquinolin-3-yl)amino]-3-oxopropanoic acid, methyl 3-[(6-(3-((tert-butoxycarbonyl)amino)propyl)-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl)amino]-3-oxopropanoate, methyl 4-[(6-(3-((tert-butoxycarbonyl)amino)propyl)-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl)amino]-4-oxobutanoate, methyl 5-[(6-(3-((tert-butoxycarbonyl)amino)propyl)-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl)amino]-5-oxopentanoate, 5-[(6-(3-((tert-butoxycarbonyl)amino)propyl)-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl)amino]-5-oxopentanoic acid, 2-[(6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5H-indeno-[1,2-c]isoquinolin-3-yl)amino]-2-oxoacetic acid, 3-[(6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5H-indeno-[1,2-c]isoquinolin-3-yl)amino]-3-oxopropanoic acid, 4-[(6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5H-indeno-[1,2-c]isoquinolin-3-yl)amino]-4-oxobutanoic acid, 5-[(6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5H-indeno-[1,2-c]isoquinolin-3-yl)amino]-5-oxopentanoic acid, 6-[(6-(3-aminopropyl)-5,11-dioxo-6,11-dihydro-5H-indeno-[1,2-c]isoquinolin-3-yl)amino]-6-oxohexanoic acid, ethyl 2-[(6-Methyl-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl)amino]acetate, 2-[(6-methyl-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]-isoquinolin-3-yl)amino]acetic acid, 2-((6-(3-((tert-butoxycarbonyl)amino)propyl)-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl)amino)acetic acid, 6-(3-bromopropyl)-5,6-dihydro-8-methoxy-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline, 6-(3-azidopropyl)-5,6-dihydro-8-methoxy-3-nitro-5,11-dioxo-11H-indeno[1,2-c]isoquinoline, 8-methoxy-6-(3-morpholinopropyl)-3-nitro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione, N-[5,11-dioxo-6-[3-(2l5-triaz-1-en-2-yn-1-yl)propyl]-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl]acetamide, N-[6-(3-hydroxypropyl)-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl]acetamide, N-[6-(3-aminopropyl)-11-hydroxy-5-oxo-6,11-dihydro-5H-indeno[1,2-c]isoquinolin-3-yl]acetamide, 6-(3-hydroxypropyl)-3-nitro-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione, 3-cyano-5,11-dihydro-6-[3-(1H-imidazolyl)propyl]-5,11-dioxo-6,11-dihydro-5H-indeno[1,2-c]isoquinoline, 3-cyano-6,11-dihydro-5,11-dioxo-6-(3-morpholinylpropyl)-5H-indeno[1,2-c]isoquinoline, and 3-cyano-5,11-dihydro-6-[3-(dimethylamino)propyl]-5,11-dioxoindeno[1,2-c]isquinoline. Molecular modeling of the enzyme based on crystal structure PDB 1RFF
-
additional information
docking simulations suggest that enzyme inhibitors bind within the catalytic pocket to prevent docking of endogenous substrates
-
additional information
-
synthesis and evaluation of dual tyrosyl-DNA phosphodiesterase I-topoisomerase I inhibitors based on the indenoisoquinoline chemotype, structure-activity relationship studies, overview
-
additional information
-
structure-based drug design, synthesis, and biological evaluation of O-2-modified indenoisoquinolines as dual topoisomerase I-tyrosyl-DNA phosphodiesterase I inhibitors, structure-activity relationships, molecular docking studies, and molecular modeling, overview. No inhibition by 2-(allyloxy)-3-methoxy-6-(3-morpholinopropyl)-5H-[1,3]-dioxolo[4',5':5,6]indeno [1,2-c]isoquinoline-5,12(6H)-dione, 3-methoxy-2-(3-morpholinopropoxy)-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]isoquinoline-5,12(6H)-dione, 3-methoxy-2-(3-(4-methylpiperazin-1-yl)propoxy)-6-(3-morpholinopropyl)-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]-isoquinoline-5,12(6H)-dione, methyl 2-((3-methoxy-6-(3-morpholinopropyl)-5,12-dioxo-6,12-dihydro-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]-isoquinolin-2-yl)oxy)acetate, and 2-((12-hydroxy-3-methoxy-6-(3-morpholinopropyl)-5-oxo-6,12-dihydro-5H-[1,3]dioxolo[4',5':5,6]indeno[1,2-c]-isoquinolin-2-yl)oxy)acetohydrazide. Antiproliferative potencies of selected O-2-modified indenoisoquinolines, overview
-
additional information
-
design and synthesis of highly potent and selective ectonucleotide pyrophosphatase/phosphodiesterase I inhibitors based on an adenosine 5-(alpha or gamma)-thio-(alpha,beta- or beta,gamma)-methylenetriphosphate scaffold, compound configurations analsis by NMR spectroscopy, overview. Analogue 4 is not a good inhibitor. The thiophosphate groups are designed to chelate the tentative Zn2+ ions. Docking od 1-3 into the NPP1 model suggests that activity correlates with the number of H-bonds with binding site residues, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
nicotinamide
-
patients with neurofibromatosis, induction of alkaline phosphodiesterase I
additional information
-
insulin levels do not appear to regulate PC-1 levels in humans, PC-1 is overexpressed in patients with insulin resistance
-
additional information
-
processing by the proteasome is required for TDP1 cleavage in vivo
-
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
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
kinetics of enzyme cleavage activity on different apurinic/apyrimidinic-DNA substrates., overview
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000685
(RP)-adenosine 5'-(alpha-thio-beta,gamma-dichloromethylene)triphosphate
-
pH 8.5, 37°C, enzyme NPP1
0.0045
(RP)-adenosine 5'-(alpha-thio-beta,gamma-methylene)triphosphate
-
pH 8.5, 37°C, enzyme NPP1
0.0152
(SP)-adenosine 5'-(alpha-thio-beta,gamma-dichloromethylene)triphosphate
-
pH 8.5, 37°C, enzyme NPP1
0.0013
(SP)-adenosine 5'-(alpha-thio-beta,gamma-methylene)triphosphate
-
pH 8.5, 37°C, enzyme NPP1
0.36
5-[3-benzyloxyphenyl]-1,3,4-oxadiazole-2(3H)-thione
-
in 20 mM Tris-HCl, pH 8.0, 0.5 M NaCl and 1 mM CaCl2, at 37°C
0.36
5-[4-(t-butyldimethylsilyloxy)-phenyl]-1,3,4-oxadiazole-2(3H)-thione
-
in 20 mM Tris-HCl, pH 8.0, 0.5 M NaCl and 1 mM CaCl2, at 37°C
0.85
5-[4-benzyloxyphenyl]-1,3,4-oxadiazole-2(3H)-thione
-
in 20 mM Tris-HCl, pH 8.0, 0.5 M NaCl and 1 mM CaCl2, at 37°C
0.85
5-[4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione
-
in 20 mM Tris-HCl, pH 8.0, 0.5 M NaCl and 1 mM CaCl2, at 37°C
0.00002
adenosine 5'-(gamma-thio-beta,gamma-methylene)triphosphate
-
pH 8.5, 37°C, enzyme NPP1
0.15
bis(1,3,4-oxadiazol-2-propyl)-5-thione
-
in 20 mM Tris-HCl, pH 8.0, 0.5 M NaCl and 1 mM CaCl2, at 37°C
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.015
(2R,4R,4aR,7R,8aS)-4,7-dimethyl-2-(5-aminothiophen-2-yl)octahydro-2H-chromen-4-ol
Homo sapiens
at pH 8.0 and 26°C
0.015
(2R,4S,4aR,7R,8aS)-4,7-dimethyl-2-(5-aminothiophen-2-yl)octahydro-2H-chromen-4-ol
Homo sapiens
at pH 8.0 and 26°C
0.0006
(RP)-adenosine 5'-(alpha-thio-beta,gamma-dichloromethylene)triphosphate
Homo sapiens
-
pH 8.5, 37°C, enzyme NPP1
0.0163
(RP)-adenosine 5'-(alpha-thio-beta,gamma-methylene)triphosphate
Homo sapiens
-
pH 8.5, 37°C, enzyme NPP1
0.0312
(SP)-adenosine 5'-(alpha-thio-beta,gamma-dichloromethylene)triphosphate
Homo sapiens
-
pH 8.5, 37°C, enzyme NPP1
0.0187
(SP)-adenosine 5'-(alpha-thio-beta,gamma-methylene)triphosphate
Homo sapiens
-
pH 8.5, 37°C, enzyme NPP1
0.004
2,2,2-trifluoro-N-(5-((2R,4R,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)acetamide
Homo sapiens
at pH 8.0 and 26°C
0.0014
2,2,2-trifluoro-N-(5-((2R,4S,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)acetamide
Homo sapiens
at pH 8.0 and 26°C
0.01
2,2,2-trifluoro-N-(8-(trifluoromethyl)benzo[f][1,2,3,4,5]pentathiepin-6-yl)acetamide
Homo sapiens
IC50 above 0.1 mM, at pH 8.0 and 26°C
0.00022
2-(dibutylamino)-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)acetamide
Homo sapiens
at pH 8.0 and 26°C
0.00128
2-(piperidin-1-yl)-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)acetamide
Homo sapiens
at pH 8.0 and 26°C
0.0037
2-(pyrrolidin-1-yl)-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)acetamide
Homo sapiens
at pH 8.0 and 26°C
0.00162
2-morpholino-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)acetamide
Homo sapiens
at pH 8.0 and 26°C
0.00123
3-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one
Homo sapiens
pH and temperature not specified in the publication
0.0012
3-(((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one
Homo sapiens
pH and temperature not specified in the publication
0.01
3-((3,4,5-trimethoxybenzyl)oxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one
Homo sapiens
IC50 above 0.01 mM, pH and temperature not specified in the publication
0.00493
3-((3-methoxybenzyl)oxy)-7,8,9,10-tetrahydro-6Hbenzo[c]chromen-6-one
Homo sapiens
pH and temperature not specified in the publication
0.00145
3-(2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethoxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one
Homo sapiens
pH and temperature not specified in the publication
0.00562
3-(benzyloxy)-7,8,9,10-tetrahydro-6H-benzo[c]chromen-6-one
Homo sapiens
pH and temperature not specified in the publication
0.00366
3-(piperidin-1-yl)-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)propanamide
Homo sapiens
at pH 8.0 and 26°C
0.00603
3-(pyrrolidin-1-yl)-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)propanamide
Homo sapiens
at pH 8.0 and 26°C
0.0013
3-morpholino-N-(8-(trifluoromethyl)benzo[f]-[1,2,3,4,5]pentathiepin-6-yl)propanamide
Homo sapiens
at pH 8.0 and 26°C
0.01
4-methyl-7-((3,4,5-trimethoxybenzyl)oxy)-2H-chromen-2-one
Homo sapiens
IC50 above 0.01 mM, pH and temperature not specified in the publication
0.494
5-[3-benzyloxyphenyl]-1,3,4-oxadiazole-2(3H)-thione
Homo sapiens
-
in 20 mM Tris-HCl, pH 8.0, 0.5 M NaCl and 1 mM CaCl2, at 37°C
0.368
5-[4-(t-butyldimethylsilyloxy)-phenyl]-1,3,4-oxadiazole-2(3H)-thione
Homo sapiens
-
in 20 mM Tris-HCl, pH 8.0, 0.5 M NaCl and 1 mM CaCl2, at 37°C
0.628
5-[4-benzyloxyphenyl]-1,3,4-oxadiazole-2(3H)-thione
Homo sapiens
-
in 20 mM Tris-HCl, pH 8.0, 0.5 M NaCl and 1 mM CaCl2, at 37°C
0.9
5-[4-hydroxyphenyl]-1,3,4-thiadiazole-2(3H)-thione
Homo sapiens
-
in 20 mM Tris-HCl, pH 8.0, 0.5 M NaCl and 1 mM CaCl2, at 37°C
0.998
5-[4-pyridyl]-1,3,4-thiadiazole-2(3H)-thione
Homo sapiens
-
in 20 mM Tris-HCl, pH 8.0, 0.5 M NaCl and 1 mM CaCl2, at 37°C
0.001
6,6'-[(1R,2R,3S,4S)-2,4-bis(4-hydroxyphenyl)cyclobutane-1,3-diyl]di(2H-pyran-2-one)
Homo sapiens
at pH 8.0 and 26°C
0.00152
6,6'-[propane-1,3-diylbis(iminopropane-3,1-diyl)]bis(5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione)
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.014
6-(10-aminodecyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.0128
6-(11-aminoundecyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.0151
6-(12-aminododecyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.0553
6-(2-aminoethyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.0295
6-(3-aminopropyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.0223
6-(4-aminobutyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.0175
6-(5-aminopentyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.025
6-(6-aminohexyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.0288
6-(7-aminoheptyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.048
6-(8-aminooctyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.047
6-(9-aminononyl)-5H-indeno[1,2-c]isoquinoline-5,11(6H)-dione
Homo sapiens
-
pH 7.5, 25°C, recombinant enzyme
0.00137
7-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-2,3-dihydrocyclopenta[c]chromen-4(1H)-one
Homo sapiens
pH and temperature not specified in the publication
0.00156
7-(((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-4-methyl-2H-chromen-2-one
Homo sapiens
pH and temperature not specified in the publication
0.000675
7-(((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-2,3-dihydrocyclopenta[c]chromen-4(1H)-one
Homo sapiens
pH and temperature not specified in the publication
0.00431
7-(((1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)methoxy)-4-methyl-2H-chromen-2-one
Homo sapiens
pH and temperature not specified in the publication
0.01
7-((3,4,5-trimethoxybenzyl)oxy)-2,3-dihydrocyclopenta[c]chromen-4(1H)-one
Homo sapiens
IC50 above 0.01 mM, pH and temperature not specified in the publication
0.01
7-((3-methoxybenzyl) oxy)-4-methyl-2H-chromen-2-one
Homo sapiens
IC50 above 0.01 mM, pH and temperature not specified in the publication
0.01
7-((3-methoxybenzyl)oxy)-2,3-dihydrocyclopenta[c]chromen-4(1H)-one
Homo sapiens
IC50 above 0.01 mM, pH and temperature not specified in the publication
0.00109
7-(2-((1R,5S)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethoxy)-2,3-dihydrocyclopenta[c]chromen-4(1H)-one
Homo sapiens
pH and temperature not specified in the publication
0.00917
7-(benzyloxy)-2,3-dihydrocyclopenta[c]chromen-4(1H)-one
Homo sapiens
pH and temperature not specified in the publication
0.00528
7-(benzyloxy)-4-methyl-2H-chromen-2-one
Homo sapiens
pH and temperature not specified in the publication
0.0000675
7-[[(1S,5R)-6,6-dimethylbicyclo[3.1.1]hept-2-en-2-yl]methoxy]-2,3-dihydrobenzo[b]cyclopenta[d]pyran-4(1H)-one
Homo sapiens
at pH 8.0 and 26°C
0.00039
adenosine 5'-(gamma-thio-beta,gamma-methylene)triphosphate
Homo sapiens
-
pH 8.5, 37°C, enzyme NPP1
0.467
bis(1,3,4-oxadiazol-2-propyl)-5-thione
Homo sapiens
-
in 20 mM Tris-HCl, pH 8.0, 0.5 M NaCl and 1 mM CaCl2, at 37°C
0.0004
methyl-3,4-dephostatin
Homo sapiens
pH and temperature not specified in the publication
0.00245
N-(2-[1-[2-(2-methyl-1H-imidazol-1-yl)pyrimidin-4-yl]piperidin-4-yl]ethyl)sulfuric diamide
Homo sapiens
-
-
0.0006
N-(2-[1-[6-(2-methyl-1H-imidazol-1-yl)pyrimidin-4-yl]piperidin-4-yl]ethyl)sulfuric diamide
Homo sapiens
-
-
0.0035
N-(3,7-dimethyloct-6-en-1-yl)tricyclo[3.3.1.1(3,7)]decan-2-amine
Homo sapiens
at pH 8.0 and 26°C
0.0029
N-(5-((2R,4R,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)acetamide
Homo sapiens
at pH 8.0 and 26°C
0.0033
N-(5-((2R,4R,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)benzamide
Homo sapiens
at pH 8.0 and 26°C
0.0028
N-(5-((2R,4R,4aR,7R,8aS)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)adamantane-1-carboxamide
Homo sapiens
at pH 8.0 and 26°C
0.0058
N-(5-((2R,4S,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)acetamide
Homo sapiens
at pH 8.0 and 26°C
0.005
N-(5-((2R,4S,4aR,7R,8aR)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2yl)benzamide
Homo sapiens
at pH 8.0 and 26°C
0.00124
N-(5-((2R,4S,4aR,7R,8aS)-4-hydroxy-4,7-dimethyloctahydro-2H-chromen-2-yl)thiophen-2-yl)adamantane-1-carboxamide
Homo sapiens
at pH 8.0 and 26°C
0.01
N-phenyl-2-(piperidin-1-yl)acetamide
Homo sapiens
IC50 above 0.1 mM, at pH 8.0 and 26°C
0.01
N-phenyl-2-(pyrrolidin-1-yl)acetamide
Homo sapiens
IC50 above 0.1 mM, at pH 8.0 and 26°C
0.000035
N-[2-(1-[6,7-dimethoxy-2-[(E)-2-(pyridin-3-yl)ethenyl]quinazolin-4-yl]piperidin-4-yl)ethyl]sulfuric diamide
Homo sapiens
-
-
0.000214
N-[2-[1-(2-ethyl-6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl]sulfuric diamide
Homo sapiens
-
-
0.000036
N-[2-[1-(6,7-dimethoxyquinazolin-4-yl)piperidin-4-yl]ethyl]sulfuric diamide
Homo sapiens
-
-
0.00598
N-[2-[1-(6-chloroquinazolin-4-yl)piperidin-4-yl]ethyl]sulfuric diamide
Homo sapiens
-
-
0.01
N-[2-[1-(7-chloroquinazolin-4-yl)piperidin-4-yl]ethyl]sulfuric diamide
Homo sapiens
-
above
0.000187
N-[2-[1-(7-methoxyquinazolin-4-yl)piperidin-4-yl]ethyl]sulfuric diamide
Homo sapiens
-
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
208356, 208358, 208367, 208383, 649302, 697554, 697620, 699172, 699286, 707668, 709235, 710877, 711445, 714101, 714113, 715042, 716301, 716603, 728098, 729329, 729624
-
-
fetal, origin of the fetal serum PDEase might be a soluble form of human PC-1, a plasma cell membrane glycoprotein, with a molecular weight of 130000 Da, which possesses alkaline phosphodiesterase I and nucleotide pyrophosphatase activity
-
-
patients with neurofibromatosis: over-expression of alkaline phosphodiesterase I
-
-
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
PC-1 is either overexpressed or overactive in adipose tissue of insulin-resistant individuals both nondiabetic and diabetic
-
PC-1 is either overexpressed or overactive in muscle of insulin-resistant individuals both nondiabetic and diabetic
-
tumor-derived and normal fibroblasts, patients with neurofibromatosis
-
dermal fibroblasts, PC-1 is either overexpressed or overactive in fibroblasts of insulin-resistant individuals both nondiabetic and diabetic
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
PC-1, active site of plasma-membrane-associated PC-1 appears to be located extracellularly
-
the enzyme is secreted, secretion of SMPDL3A is increased by cholesterol, synthetic regulated by liver X receptor ligands, and cyclic AMP in primary macrophages
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
malfunction
metabolism
physiological function
additional information
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
evolution
the enzyme is a member of the metallophosphoesterase enzyme family, the molecular mass of secreted SMPDL3A is tissue and/or species dependent
evolution
-
the enzyme is a member of the phospholipase D superfamily of enzymes that catalyze the hydrolysis of a variety of phosphodiester bonds in many different substrates
evolution
-
the enzymes belongs to the ectonucleotide pyrophosphatase/phosphodiesterase (NPP) family
evolution
-
tyrosyl-DNA phosphodiesterase I is a member of the phospholipase D superfamily of enzymes
malfunction
-
PC-1 is the major source of the elevated phosphate levels in chondrocytes and fibroblasts of patients with familial calcium pyrophosphate dehydrate deposition disease, CPPD. CPPD crystals may be a hallmark of the pathology of osteoarthritis
malfunction
-
mutations of the Tdp1 gene are involved in the disease spinocerebellar ataxia with axonal neuropathy
malfunction
-
aberrant nucleotide pyrophosphatase/phosphodiesterase-1 (NPP1) activity is associated with chondrocalcinosis, osteoarthritis, and type 2 diabetes
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
malfunction
-
whilst the enzyme mutants H493R (SCAN1) and H263A retain the ability to bind an apurinic/apyrimidinic site-containing DNA, both mutants do not reveal endonuclease activity
malfunction
enzyme knockdown cells are hypersensitive to etoposide. Late, but not early double-stranded break signaling response is altered in human cells lacking the enzyme. Enzyme knockdown impairs the repair of topoisomerase II-induced DNA double-stranded breaks
metabolism
-
TDP1 knockdown does not produce a change in sensitivity to camptothecin, whereas co-silencing of other pathways cooperating with TDP1 in cell response to topoisomerase I poisons indicates that XRCC1 and BRCA1 are major regulators of sensitivity
metabolism
-
the tyrosyl-DNA phosphodiesterase I hydrolyzes the phosphotyrosyl linkage between degraded Top1 and DNA, then polynucleotide kinase phosphatase hydrolyzes the resulting 3'-phosphate end and catalyzes the phosphorylation of the 5'-hydroxyl end of the broken DNA strand. This results in a broken DNA strand with termini consisting of a 5'-phosphate and 3'-hydroxyl for DNA repair. DNA polymerase beta replaces the missing DNA segment, and finally DNA ligase III reseals the broken DNA. Tyrosyl-DNA phosphodiesterase I is the only enzyme that specifically catalyzes the hydrolysis of the phosphodiester bond between the catalytic Tyr723 of Top1 and DNA-3'-phosphate
physiological function
-
PC-1 is an enzymatic generator of diphosphate and a critical regulator of tissue mineralization
physiological function
-
role of Tdp1 in the new APE-independent base excision repair pathway in mammals
physiological function
-
tyrosyl-DNA phosphodiesterase 1 catalyses the hydrolysis of phosphodiester linkages between a DNA 3' phosphate and a tyrosine residue as well as a variety of other DNA 3 substituents, and is implicated in the repair of covalent complexes involving eukaryotic type IB topoisomerases. Processing by the proteasome is required for TDP1 cleavage in vivo
physiological function
-
tyrosyl-DNA phosphodiesterase 1 is a key enzyme that hydrolyzes the phosphodiester bond between tyrosine of topoisomerase and 3'-phosphate of DNA and repairs topoisomerase-mediated DNA damage during chromosome metabolism
physiological function
-
tyrosyl-DNA phosphodiesterase 1 is an enzyme vital to the repair of covalent DNA-topoisomerase adducts, e.g. induced by the mycotoxin alternariol, it affects alternariol-mediated genotoxicity. TDP1 plays an important role in the repair of topoisomerase-mediated DNA damage. The repair enzyme TDP1 is a factor for the modulation of AOH-mediated DNA damage in human cells. TDP1 is also involved in the repair of topoisomerase II-induced DNA damage
physiological function
-
tyrosyl-DNA phosphodiesterase 1 plays a unique function as it catalyzes the repair of topoisomerase I-mediated DNA damage. TDP1 alone can account for mild levels of camptothecin resistance, repair of topoisomerase I-mediated DNA damage likely occurs through redundant pathways mainly implicating BRCA1 and XRCC1, but not RAD17 and PARP1
physiological function
-
human tyrosyl-DNA phosphodiesterase 1 catalyzes the apurinic/apyrimidinic site cleavage reaction to generate breaks with the 3'- and 5'-phosphate termini. The enzyme activity can contribute to the repair of apurinic/apyrimidinic sites particularly in DNA structures containing ssDNA region or apurinic/apyrimidinic sites in the context of clustered DNA lesions
physiological function
SMPDL3A is the major nucleotide phosphodiesterase secreted by human THP-1 macrophages after LXR stimulation, it may play a novel role in the pathobiology of atherosclerosis. SMPDL3A is a major source of nucleotide phosphodiesterase activity secreted by LXR-stimulated human macrophages, enzyme expression and secretion is regulated by intracellular cAMP, and is regulated by liver X receptor, LXR,. The CREs in the promoter region of SMPDL3A may play a functional role in primary human macrophages. The enzyme is capable of hydrolyzing sphingomyelin in oxidized LDL particles, transforming them into a more aggregation prone form which is more readily retained by arterial proteoglycans. But SMPDL3A is not an acid sphingomyelinase, but unexpectedly is active against nucleotide diphosphate and triphosphate substrates at acidic and neutral pH
physiological function
-
the enzyme plays a critical role in the cellular repair of topoisomerase 1-mediated DNA damage
physiological function
-
the enzyme plays a key role in the repair of damaged DNA resulting from the topoisomerase I inhibitor camptothecin and a variety of other DNA-damaging anticancer agents
physiological function
-
tyrosyl-DNA phosphodiesterase 1 repairs topoisomerase I cleavage complexes by hydrolyzing their 3'-phosphotyrosyl DNA bonds and repairs bleomycin-induced DNA damage by hydrolyzing 3'-phosphoglycolates
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
physiological function
the enzyme plays a key role in the removal of DNA damage resulting from Topo1 inhibition or caused by other anticancer drugs, e.g., temozolomide, bleomycin, etoposide, etc.
physiological function
tyrosyl-DNA-phosphodiesterase 1 is a DNA repair enzyme that removes irreversible protein-linked 3'-DNA complexes, 3'-phosphoglycolates, alkylation damage-induced DNA breaks, and 3'-deoxyribose nucleosides. The enzyme plays an active role in the repair of topoisomerase II-induced DNA damage
additional information
-
knockdown of the enzyme TDP1 in U2-OS cells does not increase sensitivity to gimatecan
additional information
-
Tdp1 is known to interact stably with BER proteins: DNA polymerase beta, XRCC1, PARP1 and DNA ligase III
additional information
-
the enzyme is composed of two domains related by a pseudo-twofold axis of symmetry. Each domain contributes a histidine and a lysine residue to form an active site that is centrally located at the symmetry axis. Four additional residues N283, Q294, N516, and E538 are also positioned near the active site
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). ENPP1_HUMAN
925
1
104924
Swiss-Prot
other Location (Reliability: 1)
ENPP3_HUMAN
875
1
100124
Swiss-Prot
other Location (Reliability: 4)
FAN1_HUMAN
1017
0
114225
Swiss-Prot
other Location (Reliability: 2)
D9MXF4_HUMAN
1017
0
114373
TrEMBL
other Location (Reliability: 2)
A0A590UKC0_HUMAN
587
0
66337
TrEMBL
other Location (Reliability: 2)
X5DRB9_HUMAN
531
0
59136
TrEMBL
other Location (Reliability: 2)
A0A590UJF5_HUMAN
318
0
35697
TrEMBL
other Location (Reliability: 1)
A0A590UK78_HUMAN
298
0
34102
TrEMBL
other Location (Reliability: 2)
H3BQ24_HUMAN
430
0
48017
TrEMBL
other Location (Reliability: 2)
A0A590UJL5_HUMAN
573
0
63609
TrEMBL
other Location (Reliability: 2)
H3BUK3_HUMAN
103
0
11611
TrEMBL
other Location (Reliability: 2)
X5D9F0_HUMAN
531
0
59048
TrEMBL
other Location (Reliability: 2)
Q9UNI4_HUMAN
26
0
2953
TrEMBL
other Location (Reliability: 1)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
16000
-
x * 66000 + x * 45000 + x * 16000, enzyme has a complex structure, which is composed of subunits of different size, stoichiometry of the complex is still uncertain, SDS-PAGE
45000
51260
x * 52000-54000, SDS-PAGE, x * 51260, sequence calculation, x * 45000, about, deglycosylated recombinant enzyme, SDS-PAGE
66000
-
x * 66000 + x * 45000 + x * 16000, enzyme has a complex structure, which is composed of subunits of different size, stoichiometry of the complex is still uncertain, SDS-PAGE
additional information
45000
-
x * 66000 + x * 45000 + x * 16000, enzyme has a complex structure, which is composed of subunits of different size, stoichiometry of the complex is still uncertain, SDS-PAGE
45000
x * 52000-54000, SDS-PAGE, x * 51260, sequence calculation, x * 45000, about, deglycosylated recombinant enzyme, SDS-PAGE
additional information
molecular mass of secreted SMPDL3A is tissue and/or species dependent
additional information
-
molecular mass of secreted SMPDL3A is tissue and/or species dependent
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
the enzyme is composed of two domains related by a pseudo-twofold axis of symmetry. Each domain contributes a histidine and a lysine residue to form an active site that is centrally located at the symmetry axis
?
-
x * 66000 + x * 45000 + x * 16000, enzyme has a complex structure, which is composed of subunits of different size, stoichiometry of the complex is still uncertain, SDS-PAGE
?
x * 52000-54000, SDS-PAGE, x * 51260, sequence calculation, x * 45000, about, deglycosylated recombinant enzyme, SDS-PAGE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
glycoprotein
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
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
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
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H263A
H493N
the mutant displays reduced in vitro catalytic activity compared to the wild type enzyme
H493R
K121Q
additional information
H263A
-
the enzyme mutant retains the ability to bind an apurinic/apyrimidinic site-containing DNA, but does not reveal endonuclease activity, it fails to hydrolyze the apurinic/apyrimidinic site
H263A
the mutant displays reduced in vitro catalytic activity compared to the wild type enzyme
H493R
-
SCAN1, the enzyme mutant retains the ability to bind an apurinic/apyrimidinic site-containing DNA, but does not reveal endonuclease activity, it fails to hydrolyze the apurinic/apyrimidinic site
H493R
the mutant displays reduced in vitro catalytic activity compared to the wild type enzyme
K121Q
-
the mutation does not reveal evidence for association with type 2 diabetic end-stage renal disease in African-Americans
K121Q
-
the mutation is closely associated with insulin resistance, type 2 diabetes mellitus, and cardio- and nephrovascular diseases, the product of this polymorphism has a 2-3fold increased binding affinity for the insulin receptor and is more potent than the wild type PC-1 protein
K121Q
-
the polymorphism in the ectonucleotide pyrophosphatase/phosphodiesterase-1 gene is associated with insulin resistance, obesity, and hepatitis C viremia and core antigen levels in chronic hepatitis C virus carriers
additional information
-
mutation of the Msx2 DNA binding site, to prevent binding of Msx2 to this site, inhibits PC-1 promoter activity in FGF2 treated MC3T3E1(C4) calvarial pre-osteoblast cells
additional information
-
knocking down TDP1 in cells expressing a dominant negative form of PARP1 and co-silencing of TDP1 and the checkpoint control gene RAD17, overview
additional information
-
overexpression and suppression of the enzyme in HCT116 cells, increased alternariol-mediated rate of DNA strand breaks in TDP1-suppressed HCT116 cells
pH STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
50
-
up to, metal-free enzyme is less heat stable than the native enzyme, the stability of the metal-free enzyme is restored to the level of the native enzyme by Zn2+ or Co2+
60
-
enzyme preincubated with Zn2+, 50% of activity remained at, in the absence of Zn2+, no activity remained at
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
Ni-chelating resin column chromatography and phosphocellulose P11 column chromatography
Ni-chelating resin column chromatography and phosphocellulose P11 column chromatography, and Superdex 200 gel filtration
recombinant His-tagged enzyme by nickel affinity and phosphocellulose adsorption chromatography, to homogeneity
-
recombinant His-tagged enzyme from CHO cell culture medium by nickel affinity chromatography
recombinant His-tagged wild-type and mutant enzymes byy nickel affinity and phosphocellulose adsorption chromatography, and for the wild-type enzyme further by gel filtration and heparin affinity chromatography, to homogeneity
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
both Msx2 and Runx2 are recruited to a conserved core Msx2 binding site within the PC-1 gene promoter upon FGF2 stimulation, promoter analysis, overview
-
expressed in Mus musculus, PC-1 overexpression impairs insulin stimulation of insulin receptor activation and downstream signalling, when PC-1 is overexpressed it inhibits insulin-induced insulin receptor beta-subunit tyrosine kinase activity.
-
expression in HEK-293 cells and HCT116 cells, quantitative real-time RT-PCR expression analysis
-
gene SMPDL3A, quantitative real-time PCR expression analysis, recombinant His-tagged enzyme expression in CHO cells and secretion to the culture medium
overexpression of the enzyme in HEK293 cells and CHL cells leads to increase resistance to camptothecin-induced DNA damage
recombinant expression in and functional complementation of Tdp1-knock-out Gallus gallus DT40 cells. The chicken Tdp1-/- cells complemented with human enzyme show a similar amount of TDP1 protein expression compared with human 293T cells
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
fibroblast growth factor-2, FGF2, specifically induces PC-1 expression in calvarial pre-osteoblasts, which occurs via a transcriptional mechanism involving Runx2. FGF2 promotes Msx2-stimulated PC-1 expression via Frs2/MAPK signaling, Msx2 promotes transcription of the PC-1 gene downstream of FGF2, overview. both Msx2 and Runx2 are recruited to a conserved core Msx2 binding site within the PC-1 gene promoter upon FGF2 stimulation, and that Msx2 and Runx2 function together to induce PC-1 gene expression in osteoblastic cells
-
genomic instability and cellular senescence in vascular smooth muscle cells increase enzyme expression
-
the enzyme encoding gene is upregulated in bladder tumor versus healthy urothelium tissue. The enzyme is induced by cAMP, the up-regulation of enzyme secretion by raised cAMP levels are mediated by a PKA-independent pathway. The enzyme is strongly upregulated by cholesterol loading, increase in SMPDL3A mRNA expression due to cholesterol accumulation and by and synthetic LXR ligands
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
medicine
drug development
-
the enzyme is a possible target for drug design in treatment of calcium pyrophosphate dehydrate deposition disease. PC-1 interferes with insulin receptor signaling, a link between mutations in PC-1 and insulin resistance. PC-1 inhibitors may therefore also have use in treating diabetic patients
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
medicine
-
ectonucleotide pyrophospatase/phosphodiesterase and adenosine deaminase in the platelets and ectonucleotide pyrophospatase/phosphodiesterasein the serum are decreased in patients with uterine cervix neoplasia treated by conization or radiotherapy in relation to the control and non-treated group
medicine
-
single nucleotide polymorphisms of the ENPP1 gene are associated with type 2 diabetic end-stage renal disease in African-Americans
medicine
-
variants on the nucleotide pyrophosphatase/phosphodiesterase-1 gene are associated with obesity and insulin resistance, the ENPP1 rs997509T allele can predispose obese children to metabolic syndrome and mpaired glucose tolerance and this variant may drive the association between the ENPP1 121Q allele and insulin resistance
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Sakura, H.; Nagashima, S.; Nakashima, A.; Maeda, M.
Characterization of fetal serum 5'-nucleotide phosphodiesterase: A novel function as a platelet aggregation inhibitor in fetal circulation
Thromb. Res.
91
83-89
1998
Homo sapiens
Fukazawa, H.; Nishimura, T.; Tanaka, N.; Suzuki, H.
5'-Nucleotide phosphodiesterase and alkaline phosphatase in tumor cells: evidence for existence of novel species in the cytosol
Biochim. Biophys. Acta
966
99-106
1988
Bos taurus, Homo sapiens, Mus musculus
Ito, K.; Yamamoto, T.; Minamiura, N.
Phosphodiesterase I in human urine: purification and characterization of the enzyme
J. Biochem.
102
359-367
1987
Homo sapiens
Razzell, W.E.
Tissue and intracellular distribution of two phophodiesterases
J. Biol. Chem.
236
3028-3030
1961
Homo sapiens, Rattus norvegicus, Sus scrofa
Maruyama, E.; Takashima, S.
Characterization of over-expressed alkaline phosphodiesterase I in tumor-derived fibroblasts from patients with neurofibromatosis
Cell Biochem. Funct.
11
271-277
1993
Homo sapiens
Belli, S.I.; Goding, J.W.
Biochemical characterization of human PC-1, an enzyme possessing alkaline phosphodiesterase I and nucleotide pyrophosphatase activities
Eur. J. Biochem.
226
433-443
1994
Homo sapiens, Mus musculus
Luthje, J.; Ogilvie, A.
Catabolism of Ap3A and Ap4A in human plasma. Purification and characterization of a glycoprotein complex with 5'-nucleotide phosphodiesterase activity
Eur. J. Biochem.
149
119-127
1985
Homo sapiens
Picher, M.; Boucher, R.C.
Biochemical evidence for an ecto alkaline phosphodiesterase I in human airways
Am. J. Respir. Cell Mol. Biol.
23
255-261
2000
Homo sapiens
Acosta Maldonado, P.; de Carvalho Correa, M.; Vargas Becker, L.; Flores, C.; Beatriz Moretto, M.; Morsch, V.; Chitolina Schetinger, M.R.
Ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP) and adenosine Ddaminase (ADA) activities in patients with uterine cervix neoplasia
Clin. Biochem.
46
400-406
2008
Homo sapiens
Keene, K.L.; Mychaleckyj, J.C.; Smith, S.G.; Leak, T.S.; Perlegas, P.S.; Langefeld, C.D.; Freedman, B.I.; Rich, S.S.; Bowden, D.W.; Sale, M.M.
Association of the distal region of the ectonucleotide pyrophosphatase/phosphodiesterase 1 gene with type 2 diabetes in an African-American population enriched for nephropathy
Diabetes
57
1057-1062
2008
Homo sapiens
Goldfine, I.D.; Maddux, B.A.; Youngren, J.F.; Reaven, G.; Accili, D.; Trischitta, V.; Vigneri, R.; Frittitta, L.
The role of membrane glycoprotein plasma cell antigen 1/ectonucleotide pyrophosphatase phosphodiesterase 1 in the pathogenesis of insulin resistance and related abnormalities
Endocr. Rev.
29
62-75
2008
Homo sapiens
Santoro, N.; Cirillo, G.; Lepore, M.G.; Palma, A.; Amato, A.; Savarese, P.; Marzuillo, P.; Grandone, A.; Perrone, L.; Del Giudice, E.M.
Effect of the rs997509 polymorphism on the association between ectonucleotide pyrophosphatase phosphodiesterase 1 and metabolic syndrome and impaired glucose tolerance in childhood obesity
J. Clin. Endocrinol. Metab.
94
300-305
2009
Homo sapiens
Takahama, Y.; Uto, H.; Kanmura, S.; Oketani, M.; Ido, A.; Kusumoto, K.; Hasuike, S.; Nagata, K.; Hayashi, K.; Stuver, S.; Okayama, A.; Tsubouchi, H.
Association of a genetic polymorphism in ectonucleotide pyrophosphatase/phosphodiesterase 1 with hepatitis C virus infection and hepatitis C virus core antigen levels in subjects in a hyperendemic area of Japan
J. Gastroenterol.
43
942-950
2008
Homo sapiens
Patel, S.D.; Habeski, W.M.; Cheng, A.C.; de la Cruz, E.; Loh, C.; Kablaoui, N.M.
Quinazolin-4-piperidin-4-methyl sulfamide PC-1 inhibitors: alleviating hERG interactions through structure based design
Bioorg. Med. Chem. Lett.
19
3339-3343
2009
Homo sapiens
Li, Y.; Liu, J.; Hudson, M.; Kim, S.; Hatch, N.E.
FGF2 promotes Msx2 stimulated PC-1 expression via Frs2/MAPK signaling
J. Cell. Biochem.
111
1346-1358
2010
Homo sapiens
Shimizu, K.; Murata, T.; Watanabe, Y.; Sato, C.; Morita, H.; Tagawa, T.
Characterization of phosphodiesterase 1 in human malignant melanoma cell lines
Anticancer Res.
29
1119-1122
2009
Homo sapiens
Khan, K.M.; Fatima, N.; Rasheed, M.; Jalil, S.; Ambreen, N.; Perveen, S.; Choudhary, M.I.
1,3,4-Oxadiazole-2(3H)-thione and its analogues: a new class of non-competitive nucleotide pyrophosphatases/phosphodiesterases 1 inhibitors
Bioorg. Med. Chem.
17
7816-7822
2009
Bothrops atrox, Homo sapiens
Interthal, H.; Champoux, J.J.
Effects of DNA and protein size on substrate cleavage by human tyrosyl-DNA phosphodiesterase 1
Biochem. J.
436
559-566
2011
Homo sapiens
Perego, P.; Cossa, G.; Tinelli, S.; Corna, E.; Carenini, N.; Gatti, L.; De Cesare, M.; Ciusani, E.; Zunino, F.; Luison, E.; Canevari, S.; Zaffaroni, N.; Beretta, G.L.
Role of tyrosyl-DNA phosphodiesterase 1 and inter-players in regulation of tumor cell sensitivity to topoisomerase I inhibition
Biochem. Pharmacol.
83
27-36
2011
Homo sapiens
Lebedeva, N.A.; Rechkunova, N.I.; Lavrik, O.I.
AP-site cleavage activity of tyrosyl-DNA phosphodiesterase 1
FEBS Lett.
585
683-686
2011
Homo sapiens
Fehr, M.; Baechler, S.; Kropat, C.; Mielke, C.; Boege, F.; Pahlke, G.; Marko, D.
Repair of DNA damage induced by the mycotoxin alternariol involves tyrosyl-DNA phosphodiesterase 1
Mycotoxin Res.
26
247-256
2010
Homo sapiens
Lee, S.Y.; Kim, H.; Hwang, H.J.; Jeong, Y.M.; Na, S.H.; Woo, J.C.; Kim, S.G.
Identification of tyrosyl-DNA phosphodiesterase as a novel DNA damage repair enzyme in Arabidopsis
Plant Physiol.
154
1460-1469
2010
Homo sapiens, Arabidopsis thaliana (Q8H1D9)
Conda-Sheridan, M.; Reddy, P.V.; Morrell, A.; Cobb, B.T.; Marchand, C.; Agama, K.; Chergui, A.; Renaud, A.; Stephen, A.G.; Bindu, L.K.; Pommier, Y.; Cushman, M.
Synthesis and biological evaluation of indenoisoquinolines that inhibit both tyrosyl-DNA phosphodiesterase I (Tdp1) and topoisomerase I (Top1)
J. Med. Chem.
56
182-200
2013
Homo sapiens
Lebedeva, N.A.; Rechkunova, N.I.; El-Khamisy, S.F.; Lavrik, O.I.
Tyrosyl-DNA phosphodiesterase 1 initiates repair of apurinic/apyrimidinic sites
Biochimie
94
1749-1753
2012
Homo sapiens
Lebedeva, N.A.; Rechkunova, N.I.; Ishchenko, A.A.; Saparbaev, M.; Lavrik, O.I.
The mechanism of human tyrosyl-DNA phosphodiesterase 1 in the cleavage of AP site and its synthetic analogs
DNA Repair
12
1037-1042
2013
Homo sapiens
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
Drug Metab. Rev.
46
494-507
2014
Canis lupus familiaris (E2REL5), Gallus gallus (F1NSQ5), Saccharomyces cerevisiae (P38319), Rattus norvegicus (Q4G056), Mus musculus (Q8BJ37), Homo sapiens (Q9NUW8), Drosophila melanogaster (Q9VQM4), Saccharomyces cerevisiae ATCC 204508 (P38319)
Murai, J.; Huang, S.Y.; Das, B.B.; Dexheimer, T.S.; Takeda, S.; Pommier, Y.
Tyrosyl-DNA phosphodiesterase 1 (TDP1) repairs DNA damage induced by topoisomerases I and II and base alkylation in vertebrate cells
J. Biol. Chem.
287
12848-12857
2012
Gallus gallus, Homo sapiens
Traini, M.; Quinn, C.M.; Sandoval, C.; Johansson, E.; Schroder, K.; Kockx, M.; Meikle, P.J.; Jessup, W.; Kritharides, L.
Sphingomyelin phosphodiesterase-like 3A (SMPDL3A) is a novel nucleotide phosphodiesterase regulated by cholesterol in human macrophages
J. Biol. Chem.
289
32895-32913
2014
Mus musculus (P70158), Homo sapiens (Q92484), Homo sapiens, Mus musculus C57 black (P70158)
Nguyen, T.X.; Morrell, A.; Conda-Sheridan, M.; Marchand, C.; Agama, K.; Bermingham, A.; Bermingam, A.; Stephen, A.G.; Chergui, A.; Naumova, A.; Fisher, R.; OKeefe, B.R.; Pommier, Y.; Cushman, M.
Synthesis and biological evaluation of the first dual tyrosyl-DNA phosphodiesterase I (Tdp1)-topoisomerase I (Top1) inhibitors
J. Med. Chem.
55
4457-4478
2012
Homo sapiens
Lv, P.C.; Agama, K.; Marchand, C.; Pommier, Y.; Cushman, M.
Design, synthesis, and biological evaluation of O-2-modified indenoisoquinolines as dual topoisomerase I-tyrosyl-DNA phosphodiesterase I inhibitors
J. Med. Chem.
57
4324-4336
2014
Homo sapiens
Nadel, Y.; Lecka, J.; Gilad, Y.; Ben-David, G.; Foerster, D.; Reiser, G.; Kenigsberg, S.; Camden, J.; Weisman, G.A.; Senderowitz, H.; Sevigny, J.; Fischer, B.
Highly potent and selective ectonucleotide pyrophosphatase/phosphodiesterase I inhibitors based on an adenosine 5-(alpha or gamma)-thio-(alpha,beta- or beta,gamma)-methylenetriphosphate scaffold
J. Med. Chem.
57
4677-4691
2014
Homo sapiens
Zakharenko, A.; Khomenko, T.; Zhukova, S.; Koval, O.; Zakharova, O.; Anarbaev, R.; Lebedeva, N.; Korchagina, D.; Komarova, N.; Vasiliev, V.; Reynisson, J.; Volcho, K.; Salakhutdinov, N.; Lavrik, O.
Synthesis and biological evaluation of novel tyrosyl-DNA phosphodiesterase 1 inhibitors with a benzopentathiepine moiety
Bioorg. Med. Chem.
23
2044-2052
2015
Homo sapiens (Q9NKW8)
Khomenko, T.; Zakharenko, A.; Odarchenko, T.; Arabshahi, H.J.; Sannikova, V.; Zakharova, O.; Korchagina, D.; Reynisson, J.; Volcho, K.; Salakhutdinov, N.; Lavrik, O.
New inhibitors of tyrosyl-DNA phosphodiesterase I (Tdp 1) combining 7-hydroxycoumarin and monoterpenoid moieties
Bioorg. Med. Chem.
24
5573-5581
2016
Homo sapiens (Q9NUW8)
Bautista Nino, P.K.; Durik, M.; Danser, A.H.; de Vries, R.; Musterd-Bhaggoe, U.M.; Meima, M.E.; Kavousi, M.; Ghanbari, M.; Hoeijmakers, J.H.; O'Donnell, C.J.; Franceschini, N.; Janssen, G.M.; De Mey, J.G.; Liu, Y.; Shanahan, C.M.; Franco, O.H.; Dehghan, A.; Roks, A.J.
Phosphodiesterase 1 regulation is a key mechanism in vascular aging
Clin. Sci.
129
1061-1075
2015
Homo sapiens
Li-Zhulanov, N.S.; Zakharenko, A.L.; Chepanova, A.A.; Patel, J.; Zafar, A.; Volcho, K.P.; Salakhutdinov, N.F.; Reynisson, J.; Leung, I.K.H.; Lavrik, O.I.
A novel class of tyrosyl-DNA phosphodiesterase 1 inhibitors that contains the octahydro-2H-chromen-4-ol scaffold
Molecules
23
E2468
2018
Homo sapiens (Q9NUW8)
Borda, M.A.; Palmitelli, M.; Veron, G.; Gonzalez-Cid, M.; de Campos Nebel, M.
Tyrosyl-DNA-phosphodiesterase I (TDP1) participates in the removal and repair of stabilized-Top2alpha cleavage complexes in human cells
Mutat. Res.
781
37-48
2015
Homo sapiens (Q9NUW8), Homo sapiens
Cuya, S.M.; Comeaux, E.Q.; Wanzeck, K.; Yoon, K.J.; van Waardenburg, R.C.
Dysregulated human tyrosyl-DNA phosphodiesterase I acts as cellular toxin
Oncotarget
7
86660-86674
2016
Homo sapiens (Q9NUW8), Homo sapiens
Nale, S.; Jadhav, V.
Synthesis of tyrosyl-DNA phosphodiesterase I inhibitors
Tetrahedron Lett.
57
2652-2654
2016
Homo sapiens (Q9NUW8)
-
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