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Information on EC 3.1.4.1 - phosphodiesterase I and Organism(s) Saccharomyces cerevisiae and UniProt Accession P38319
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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: Saccharomyces cerevisiae
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
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-
-
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5'-nucleotide phosphodiesterase
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-
-
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5'-phosphodiesterase
-
-
-
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orthophosphoric diester phosphohydrolase
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-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
hydrolytically removes 5'-nucleotides successively from the 3'-hydroxy termini of 3'-hydroxy-terminated oligonucleotides
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
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoric ester hydrolysis
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-
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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
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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
(5'-GATCTAAAAGACTT-3')-phosphotyrosine + H2O
(5'-GATCTAAAAGACTT-3')-phosphate + L-tyrosine
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-
-
?
additional information
?
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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
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-
?
additional information
?
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the enzyme hydrolyzes the covalent bond between the tyrosyl residue of topoisomerase 1 and the 3'-phosphate group in DNA. The enzyme is able to initiate the cleavage of internal apurinic/apyrimidinic sites or 3-hydroxy-2-hydroxymethyl tetrahydrofuran in DNA and its subsequent repair
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-
?
additional information
?
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-
the enzyme hydrolyzes the covalent bond between the tyrosyl residue of topoisomerase 1 and the 3'-phosphate group in DNA. The enzyme is able to initiate the cleavage of internal apurinic/apyrimidinic sites or 3-hydroxy-2-hydroxymethyl tetrahydrofuran in DNA and its subsequent repair
-
-
?
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
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 hydrolyzes the covalent bond between the tyrosyl residue of topoisomerase 1 and the 3'-phosphate group in DNA. The enzyme is able to initiate the cleavage of internal apurinic/apyrimidinic sites or 3-hydroxy-2-hydroxymethyl tetrahydrofuran in DNA and its subsequent repair
-
-
?
additional information
?
-
-
the enzyme hydrolyzes the covalent bond between the tyrosyl residue of topoisomerase 1 and the 3'-phosphate group in DNA. The enzyme is able to initiate the cleavage of internal apurinic/apyrimidinic sites or 3-hydroxy-2-hydroxymethyl tetrahydrofuran in DNA and its subsequent repair
-
-
?
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
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
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.0011
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
wild type enzyme, at pH 7.5 and 30°C
0.0026
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
mutant enzyme H432N, at pH 7.5 and 30°C
0.0034
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
mutant enzyme H182A, at pH 7.5 and 30°C
0.0048
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
mutant enzyme H432R, at pH 7.5 and 30°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.003
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
mutant enzyme H182A, at pH 7.5 and 30°C
0.007
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
mutant enzyme H432R, at pH 7.5 and 30°C
0.012
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
mutant enzyme H432N, at pH 7.5 and 30°C
0.28
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
wild type enzyme, at pH 7.5 and 30°C
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.9
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
mutant enzyme H182A, at pH 7.5 and 30°C
1.5
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
mutant enzyme H432R, at pH 7.5 and 30°C
4.7
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
mutant enzyme H432N, at pH 7.5 and 30°C
250
(5'-GATCTAAAAGACTT-3')-phosphotyrosine
wild type enzyme, at pH 7.5 and 30°C
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
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
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
physiological function
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
physiological function
the enzyme catalyzes the repair of 3'-DNA adducts, such as the 3'-phosphotyrosyl linkage of DNA topoisomerase I to DNA
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
H182A
the mutant shows strongly reduced catalytic efficiency compared to the wild type enzyme, potentiates the cytotoxicity of the Hisgab mutants and induces a DNA topoisomerase 1-independent lethal phenotype in combination with the H432N mutant
H182A/H432N
the mutant protein reveals a dramatic (210fold) reduction in catalytic activity compared to the wild type
H182A/H432R
the mutant protein reveals a dramatic (more than 50%) reduction in catalytic activity compared to the wild type
H182F
H432N
the mutant shows strongly reduced catalytic efficiency compared to the wild type enzyme
H432R
the mutant shows strongly reduced catalytic efficiency compared to the wild type enzyme
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
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
SP-Sepharose column chromatography and Flag M2 affinity matrix chromatography
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
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)
Comeaux, E.Q.; Cuya, S.M.; Kojima, K.; Jafari, N.; Wanzeck, K.C.; Mobley, J.A.; Bjornsti, M.A.; van Waardenburg, R.C.
Tyrosyl-DNA phosphodiesterase I catalytic mutants reveal an alternative nucleophile that can catalyze substrate cleavage
J. Biol. Chem.
290
6203-6214
2015
Saccharomyces cerevisiae (P38319), Saccharomyces cerevisiae
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