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Information on EC 1.17.4.1 - ribonucleoside-diphosphate reductase and Organism(s) Homo sapiens
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1.17.4.1 ribonucleoside-diphosphate reductaseIUBMB Comments
This enzyme is responsible for the de novo conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair. There are three types of this enzyme differing in their cofactors. Class Ia enzymes contain a diiron(III)-tyrosyl radical, class Ib enzymes contain a dimanganese-tyrosyl radical, and class II enzymes contain adenosylcobalamin. In all cases the cofactors are involved in generation of a transient thiyl (sulfanyl) radical on a cysteine residue, which attacks the substrate, forming a ribonucleotide 3'-radical, followed by water loss to form a ketyl (alpha-oxoalkyl) radical. The ketyl radical is reduced to 3'-keto-deoxynucleotide concomitant with formation of a disulfide anion radical between two cysteine residues. A proton-coupled electron-transfer from the disulfide radical to the substrate generates a 3'-deoxynucleotide radical, and the final product is formed when the hydrogen atom that was initially removed from the 3'-position of the nucleotide by the thiyl radical is returned to the same position. The disulfide bridge is reduced by the action of thioredoxin. cf. EC 1.1.98.6, ribonucleoside-triphosphate reductase (formate) and EC 1.17.4.2, ribonucleoside-triphosphate reductase (thioredoxin).
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Word Map
- 1.17.4.1
- deoxyribonucleotides
- hydroxyurea
-
tyrosyl
- reductases
- chlamydia
- trachomatis
-
deoxynucleotides
-
proton-coupled
-
diiron
- deoxycytidine
-
diferric
-
thiyl
- dntps
- dcdp
- thiosemicarbazone
-
diferric-tyrosyl
-
nrdabs
-
hydroxyurea-resistant
- medicine
-
nrdef
-
heterodinuclear
- drug development
-
antiferromagnetically
- pharmacology
- molecular biology
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
Reaction Schemes
Synonyms
ribonucleoside diphosphate reductase, cdp reductase, class i rnr, class i ribonucleotide reductase, class ia rnr, ribonucleoside-diphosphate reductase, class ia ribonucleotide reductase, adp reductase, p53-inducible ribonucleotide reductase, class ic ribonucleotide reductase, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
2'-deoxyribonucleoside-diphosphate:oxidized-thioredoxin 2'-oxidoreductase
-
-
-
-
ADP reductase
-
-
-
-
CDP reductase
-
-
-
-
class I ribonucleotide reductase
nucleoside diphosphate reductase
-
-
-
-
reductase, ribonucleoside diphosphate
-
-
-
-
ribonucleoside 5'-diphosphate reductase
-
-
-
-
ribonucleoside diphosphate reductase
-
-
-
-
ribonucleotide diphosphate reductase
-
-
-
-
ribonucleotide reductase
UDP reductase
-
-
-
-
ribonucleotide reductase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
2'-deoxyribonucleoside 5'-diphosphate + thioredoxin disulfide + H2O = ribonucleoside 5'-diphosphate + thioredoxin
proposed mechanism
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
oxidation
-
-
-
-
redox reaction
-
-
-
-
reduction
-
-
-
-
PATHWAY SOURCE
PATHWAYS
KEGG
-
-, -, -, -, -, -, -, -, -
SYSTEMATIC NAME
IUBMB Comments
2'-deoxyribonucleoside-5'-diphosphate:thioredoxin-disulfide 2'-oxidoreductase
This enzyme is responsible for the de novo conversion of ribonucleoside diphosphates into deoxyribonucleoside diphosphates, which are essential for DNA synthesis and repair. There are three types of this enzyme differing in their cofactors. Class Ia enzymes contain a diiron(III)-tyrosyl radical, class Ib enzymes contain a dimanganese-tyrosyl radical, and class II enzymes contain adenosylcobalamin. In all cases the cofactors are involved in generation of a transient thiyl (sulfanyl) radical on a cysteine residue, which attacks the substrate, forming a ribonucleotide 3'-radical, followed by water loss to form a ketyl (alpha-oxoalkyl) radical. The ketyl radical is reduced to 3'-keto-deoxynucleotide concomitant with formation of a disulfide anion radical between two cysteine residues. A proton-coupled electron-transfer from the disulfide radical to the substrate generates a 3'-deoxynucleotide radical, and the final product is formed when the hydrogen atom that was initially removed from the 3'-position of the nucleotide by the thiyl radical is returned to the same position. The disulfide bridge is reduced by the action of thioredoxin. cf. EC 1.1.98.6, ribonucleoside-triphosphate reductase (formate) and EC 1.17.4.2, ribonucleoside-triphosphate reductase (thioredoxin).
CAS REGISTRY NUMBER
COMMENTARY
9047-64-7
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
GDP + thioredoxin
2'-dGDP + thioredoxin disulfide + H2O
-
-
-
?
nucleoside 5'-diphosphate + glutaredoxin
2'-deoxynucleoside 5'-diphosphate + glutaredoxin disulfide + H2O
-
class Ia RNRs
-
-
?
nucleoside 5'-diphosphate + thioredoxin
2'-deoxynucleoside 5'-diphosphate + thioredoxin disulfide + H2O
-
class Ia RNRs
-
-
?
ribonucleoside 5'-diphosphate + thioredoxin
2'-deoxyribonuleoside 5'-diphosphate + thioredoxin disulfide + H2O
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
UDP + thioredoxin
2'-dUDP + thioredoxin disulfide + H2O
-
-
-
?
ADP + thioredoxin
2'-dADP + thioredoxin disulfide + H2O
-
-
-
?
CDP + thioredoxin
2'-dCDP + thioredoxin disulfide + H2O
-
-
-
?
CDP + thioredoxin
2'-dCDP + thioredoxin disulfide + H2O
for ATP-bound enzyme CDP is the favored substrate
-
-
?
ribonucleoside 5'-diphosphate + thioredoxin
2'-deoxyribonuleoside 5'-diphosphate + thioredoxin disulfide + H2O
-
-
-
-
?
ribonucleoside 5'-diphosphate + thioredoxin
2'-deoxyribonuleoside 5'-diphosphate + thioredoxin disulfide + H2O
-
the essential enzyme catalyzes the rate-limiting step in dNTP production for DNA synthesis
-
-
?
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
-
-
ir
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
-
-
ir
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
-
-
ir
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
-
-
ir
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
enzyme catalyzes the first unique step in DNA synthesis
-
?
additional information
?
-
-
human p53R2 is a 351-residue p53-inducible ribonucleotide reductase small subunit, hp53R2 supplies dNTPs for DNA repair to cells in G0-G1 in a p53-dependent fashion, rather than exhibiting cyclic dNTP synthesis. Hp53R2 structure-function relationship determination and analysis, overview
-
-
?
additional information
?
-
-
CDP as substrate resulting information of product dCDP
-
-
?
additional information
?
-
-
class Ia RNRs convert nucleoside diphosphates into 2'-deoxynucleoside diphosphates using glutaredoxin or thioredoxin as cofactor
-
-
?
additional information
?
-
-
the class I RNR active-site disulfide bridge between Cys225 and Cys462 must be reduced for a complete turnover. The electron required for this reduction is provided by a redox network, which involves a cysteine pair at the C-terminus of the R1 subunit, the thioredoxin or glutaredoxin system, and NADPH. For in vitro experiments, the disulfide bridge can be reduced by small thiol compounds such as DTT
-
-
?
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
nucleoside 5'-diphosphate + glutaredoxin
2'-deoxynucleoside 5'-diphosphate + glutaredoxin disulfide + H2O
-
class Ia RNRs
-
-
?
nucleoside 5'-diphosphate + thioredoxin
2'-deoxynucleoside 5'-diphosphate + thioredoxin disulfide + H2O
-
class Ia RNRs
-
-
?
ribonucleoside 5'-diphosphate + thioredoxin
2'-deoxyribonuleoside 5'-diphosphate + thioredoxin disulfide + H2O
-
the essential enzyme catalyzes the rate-limiting step in dNTP production for DNA synthesis
-
-
?
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
enzyme catalyzes the first unique step in DNA synthesis
-
?
additional information
?
-
-
human p53R2 is a 351-residue p53-inducible ribonucleotide reductase small subunit, hp53R2 supplies dNTPs for DNA repair to cells in G0-G1 in a p53-dependent fashion, rather than exhibiting cyclic dNTP synthesis. Hp53R2 structure-function relationship determination and analysis, overview
-
-
?
additional information
?
-
-
class Ia RNRs convert nucleoside diphosphates into 2'-deoxynucleoside diphosphates using glutaredoxin or thioredoxin as cofactor
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
cofactor specificity and binding, role in reaction, overview
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
-
monomers A and B exhibit mono- and binuclear iron occupancy, the active site iron coordination environment, involving E131, H134, D100, E194, E228, and H231, is different between monomers A and B, binding structure, overview. Mobility and accessibility of the radical iron center, and radical transfer pathway, overview
Fe3+
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
(-)-epicatechin
-
interacts with the R2 protein, leading to a loss of the tyrosyl radical EPR signal. Proliferation of cells exposed to (-)-epicatechin is downregulated, and deoxyribonucleotide levels are significantly diminished
(2E)-2-(anthracen-9-ylmethylidene)-N-hydroxyhydrazinecarboximidamide
-
i.e. ABNM-13, application leads to significant alterations of deoxyribonucleoside triphosphate pool balance and a highly significant decrease of incorporation of radiolabeled cytidine into DNA of HL-60 cells. Diminished ribonucleotide reductase activity causes replication stress which is consistent with activation of Chk1 and Chk2, resulting in downregulation/degradation of Cdc25A. Cdc25B is upregulated, leading to dephosphorylation and activation of Cdk1. The combined disregulation of Cdc25A and Cdc25B is the most likely cause for ABNM-13 induced S-phase arrest
2-(diphenylmethylidene)-N,N-dimethylhydrazinecarbothioamide
-
metal chelator, significantly decreases ribonucleotide reductase activity, whereas the NADPH/NADP+ total ratio is not reduced
2-acetylpyridine N-pyrrolidinylthiosemicarbazonato-N,N,S-dichlorogallium(III)
-
-
2-[di(pyridin-2-yl)methylidene]-N,N-dimethylhydrazinecarbothioamide
-
metal chelator, significantly decreases ribonucleotide reductase activity, whereas the NADPH/NADP+ total ratio is not reduced
3-aminopyridine-2-carboxaldehyde-thiosemicarbazone
-
i.e. 3-AP, phase I study in combination with high dose cytarabine in patients with advanced myeloid leukemia, resulting in enhanced cytarabine cytotoxicity with possible methemoglobinemia, overview
5'-O-valproyl-3'-C-methyladenosine
inhibits ribonucleotide reductase activity by competing with ATP as an allosteric effector and concomitantlyreduces the intracellular deoxyribonucleoside triphosphate pools. In contrast to previously used ribonucleotide reductase nucleoside analogs does not require intracellular kinases for its activity and therefore holds promise against drug resistant tumors with downregulated nucleoside kinases
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6-chloro-9H-(3-C-methyl-2,3-di-O-acetyl-5-O-benzoyl-beta-D-ribofuranosyl)purine
-
-
clofarabine
-
an adenosine analogue is used in the treatment of refractory leukemias. Its mode of cytotoxicity is associated in part with the triphosphate functioning as an allosteric reversible inhibitor of hRNR, rapid inactivation
clofarabine diphosphate
-
ClFDP, a C-site slow-binding, reversible inhibitor, mechanism of inhibition via altering the quaternary structure of the large subunit of RNR, overview. Binds also mutant D57N-alpha subunit. CDP protects against inhibition
clofarabine triphosphate
-
ClFTP, an A-site rapidly binding reversible inhibitor, mechanism of inhibition via altering the quaternary structure of the large subunit of RNR, overview. Neither CDP (C site) nor dGTP (A site) had any effect on inhibition by ClFTP
dATP
-
inhibition of ADP reduction; inhibition of CDP reduction; inhibition of GDP reduction
IRBIT
IRBIT is a conserved metazoan protein implicated in diverse functions. IRBIT consists of a putative enzymatic domain that has similarity to S-adenosylhomocysteine hydrolase and an essential N-terminal domain of 104 amino acids. It forms a dATPdependent complex with ribonucleotide reductase, which stabilizes dATP in the activity site of ribonucleotide reductase and thus inhibits the enzyme. Formation of the ribonucleotide reductase-IRBIT complex is regulated through phosphorylation of IRBIT, and ablation of IRBIT expression in HeLa cells causes imbalanced dNTP pools and altered cell cycle progression. Under normal physiological conditions, where ATP levels are high, such inhibition can only be achieved when binding of IRBIT is strengthened by phosphorylation
-
[bis(2-acetylpyridine N,N-dimethylthiosemicarbazonato)-N,N,S-gallium(III)] hexafluorophosphate
-
-
[bis(2-acetylpyridine N,N-dimethylthiosemicarbazonato)-N,N,S-iron(III)] hexafluorophosphate
-
-
[bis(2-acetylpyridine N,N-dimethylthiosemicarbazonato)-N,N,S-iron(III)] tetrachloroferrate(III)
-
-
[bis(2-acetylpyridine N-pyrrolidinylthiosemicarbazonato)-N,N,S-gallium(III)] hexafluorophosphate
-
-
[bis(2-acetylpyridine N-pyrrolidinylthiosemicarbazonato)-N,N,S-iron(III)] hexafluorophosphate
-
-
[bis(2-acetylpyridine N-pyrrolidinylthiosemicarbazonato)-N,N,S-iron(III)] tetrachloroferrate(III)
-
-
[bis(acetylpyrazine N,N-dimethylthiosemicarbazonato)-N,N,S-gallium(III)] hexafluorophosphate
-
-
[bis(acetylpyrazine N,N-dimethylthiosemicarbazonato)-N,N,S-iron(III)] hexafluorophosphate
-
-
[bis(acetylpyrazine N,N-dimethylthiosemicarbazonato)-N,N,S-iron(III)] tetrachloroferrate(III)
-
-
[bis(acetylpyrazine N-piperidinylthiosemicarbazonato)-N,N,S-gallium(III)] hexafluorophosphate
-
-
[bis(acetylpyrazine N-piperidinylthiosemicarbazonato)-N,N,S-iron(III)] hexafluorophosphate
-
-
[bis(acetylpyrazine N-piperidinylthiosemicarbazonato)-N,N,S-iron(III)] tetrachloroferrate(III)
-
-
[bis(acetylpyrazine N-pyrrolidinylthiosemicarbazonato)-N,N,S-gallium(III)] hexafluorophosphate
-
-
[bis(acetylpyrazine N-pyrrolidinylthiosemicarbazonato)-N,N,S-iron(III)] hexafluorophosphate
-
-
[bis(acetylpyrazine N-pyrrolidinylthiosemicarbazonato)-N,N,S-iron(III)] tetrachloroferrate(III)
-
-
3-aminopyridine-2-carboxaldehyde thiosemicarbazone
-
i.e.3-AP or triapine, in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloprol, phase I study, detailed overview, the inhibitor inhibits the M2 subunit, and depletes intracellular deoxyribonculeotide pools, especially dATP
deferoxamine mesylate
-
IC50 for subunit p53R2 is 0.00316 mM, IC50 for hRRM2 subunit is 0.5 mM
Hydroxyurea
-
IC50 for subunit p53R2 is 2.48 mM, IC50 for hRRM2 subunit is 0.991 mM
triapine
-
i.e. 3-AP, triapine enhances the cytotoxicity of gemcitabine and arabinoside cytosine in four non-small-cell-lung-cancer cell lines, e.g. in SW1573 cells, but not in H460 cells, multiple-drug-effect analysis, overview
additional information
-
overview: naturally occuring inhibitors e.g. proteins and nucleotides
-
additional information
-
synthesis, characterization, cytotoxicity in human cell lines, and interaction with ribonucleotide reductase of gallium(III) and iron(III) complexes of alpha-N-heterocyclic thiosemicarbazones, overview, gallium(III) enhances, whereas iron(III) weakens the cytotoxicity of the ligands
-
additional information
-
construction and synthesis of ribose-modified purine nucleosides as ribonucleotide reductase inhibitors. Synthesis, antitumor activity, and molecular modeling of N6-substituted 3-C-methyladenosine derivatives, an unsubstituted N6-amino group is essential for optimal cytotoxicity of 3'-Me-Ado. The anticancer nucleosides act as antimetabolites after metabolic activation by phosphorylation to the corresponding 5'-di- or 5'-triphosphates, overview
-
additional information
-
inhibitory mechanisms of heterocyclic carboxaldehyde thiosemicabazones
-
additional information
-
synthesis and ribonucleotide reductase inhibitory activity of thiosemicarbazones, overview
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
ATP
binding of deoxynucleoside triphosphate effectors (ATP/dATP, dGTP, and dTTP) modulates the specificity of class I ribonucleotide reductase for CDP, UDP, ADP, and GDP substrates. The unprotonated N1 of adenosine is the primary determinant of ATP/dATP-directed specificity for CDP
ATP
binding of deoxynucleoside triphosphate effectors ATP/dATP, dGTP, and dTTP modulates the specificity of class I ribonucleotide reductase for CDP, UDP, ADP, and GDP substrates. dNTP effectors and NDP substrates bind on either side of a flexible nine-amino acid loop. The unprotonated N1 of adenosine is the primary determinant of ATP/dATP-directed specificity for CDP. Interactions with the effector nucleobase alter loop 2 geometry, resulting in changes in specificity among the four NDP substrates of ribonucleotide reductase
dATP
binding of deoxynucleoside triphosphate effectors (ATP/dATP, dGTP, and dTTP) modulates the specificity of class I ribonucleotide reductase for CDP, UDP, ADP, and GDP substrates. The unprotonated N1 of adenosine is the primary determinant of ATP/dATP-directed specificity for CDP
dATP
binding of deoxynucleoside triphosphate effectors ATP/dATP, dGTP, and dTTP modulates the specificity of class I ribonucleotide reductase for CDP, UDP, ADP, and GDP substrates. dNTP effectors and NDP substrates bind on either side of a flexible nine-amino acid loop.. The unprotonated N1 of adenosine is the primary determinant of ATP/dATP-directed specificity for CDP. Interactions with the effector nucleobase alter loop 2 geometry, resulting in changes in specificity among the four NDP substrates of ribonucleotide reductase
dGTP
binding of deoxynucleoside triphosphate effectors (ATP/dATP, dGTP, and dTTP) modulates the specificity of class I ribonucleotide reductase for CDP, UDP, ADP, and GDP substrates. The O6 and protonated N1 of dGTP direct specificity for ADP
dGTP
binding of deoxynucleoside triphosphate effectors ATP/dATP, dGTP, and dTTP modulates the specificity of class I ribonucleotide reductase for CDP, UDP, ADP, and GDP substrates. dNTP effectors and NDP substrates bind on either side of a flexible nine-amino acid loop. The O6 and protonated N1 of dGTP direct specificity for ADP. Interactions with the effector nucleobase alter loop 2 geometry, resulting in changes in specificity among the four NDP substrates of ribonucleotide reductase
dTTP
binding of deoxynucleoside triphosphate effectors (ATP/dATP, dGTP, and dTTP) modulates the specificity of class I ribonucleotide reductase for CDP, UDP, ADP, and GDP substrates. The 5-methyl, O4, and N3 groups of dTTP contributes to specificity for GDP
dTTP
binding of deoxynucleoside triphosphate effectors ATP/dATP, dGTP, and dTTP modulates the specificity of class I ribonucleotide reductase for CDP, UDP, ADP, and GDP substrates. dNTP effectors and NDP substrates bind on either side of a flexible nine-amino acid loop. Interactions with the effector nucleobase alter loop 2 geometry, resulting in changes in specificity among the four NDP substrates of ribonucleotide reductase
additional information
-
TTP, dATP, TTP/GDP, TTP/ATP, and TTP/dATP, 1. TTP bound at the S-site, 2. dATP bound at the S-site, 3. TTP bound at the S-site and GDP at the C-site, 4. TTP bound at the S-site and ATP at the A-site, and 5. TTP bound at the S-site and dATP at the A-site
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.4
5'-O-valproyl-3'-C-methyladenosine
pH and temperature not specified in the publication
-
0.00004
clofarabine
-
pH not specified in the publication, temperature not specified in the publication
additional information
additional information
-
inhibition kinetics of clofarabine di- and triphosphates, overview
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.011
(2E)-2-(anthracen-9-ylmethylidene)-N-hydroxyhydrazinecarboximidamide
Homo sapiens
-
pH not specified in the publication, temperature not specified in the publication
0.5
2-furan-3-ylbenzaldehyde N-(4-hydroxyphenyl)thiosemicarbazone
Homo sapiens
-
above, pH 7.2, 37°C
0.5
2-hydroxybenzaldehyde N-(4-chlorophenyl)thiosemicarbazone
Homo sapiens
-
above, pH 7.2, 37°C
0.5
2-thiophen-2-ylbenzaldehyde N-(4-chlorophenyl)thiosemicarbazone
Homo sapiens
-
above, pH 7.2, 37°C
0.5
4-hydroxy-3-methoxybenzaldehyde N-(4-chlorophenyl)thiosemicarbazone
Homo sapiens
-
above, pH 7.2, 37°C
0.5
4-hydroxy-3-methoxybenzaldehyde N-phenylthiosemicarbazone
Homo sapiens
-
above, pH 7.2, 37°C
0.042
4-hydroxybenzaldehyde N-(2-methoxyphenyl)thiosemicarbazone
Homo sapiens
-
above, pH 7.2, 37°C
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7.2
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
37
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
adults with refractory acute leukemias and aggressive myeloproliferative disorders, MPD
-
-
P23921: ribonucleoside-diphosphate reductase large subunit RRM1, P31350: ribonucleoside-diphosphate reductase subunit RRM2
SwissProt
ribonucleoside-diphosphate reductase large subunit
Uniprot
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
additional information
-
RNR expression in small cell lung cancer cell lines, overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
metabolism
physiological function
additional information
metabolism
constitutive ribonucleotide reductase activity ensures stable and balanced dNTP production, which is essential for de novo DNA synthesis. The enzyme is responsible for the rate-limiting step of de novo DNA synthesis
metabolism
constitutive RNR activity ensures stable and balanced dNTP production, which is essential for de novo DNA synthesis. The enzyme is responsible for the rate-limiting step of de novo DNA synthesis
metabolism
provides the precursors necessary for DNA synthesis. Constitutive ribonucleotide reductase activity ensures stable and balanced dNTP production, which is essential for de novo DNA synthesis. The enzyme is responsible for the rate-limiting step of de novo DNA synthesis
metabolism
the enzyme maintains balanced pools of deoxyribonucleotide substrates for DNA replication by converting ribonucleoside diphosphates to 2'-deoxyribonucleoside diphosphates
physiological function
-
hp53R2 possibly plays a regulatory role in iron assimilation
physiological function
-
the enzyme is involved in DNA replication and damage repair, respectively
physiological function
a conserved cluster of charged residues, including Lys95, Glu98, Glu-05, and Glu174, at the interface may function as an ionic lock for small subunit M2 homodimer. The transfection of the wild-type small subunit M2 but not the K95E mutant rescues theG1/S phase cell cycle arrest and cell growth inhibition caused by the siRNA knockdown of M2
physiological function
in nontransformed cells only during quiescence, isoform p53R2 is required for maintenance of mitochondrial DNA and for optimal DNA repair after UV damage
additional information
-
RR is regulated transcriptionally and allosterically. RR activity is also controlled by subunit RR2 levels
additional information
-
structural basis for substrate selection, RR activity is lowest at high dATP concentrations when the hexamer population is high, egulation of RR by dATPinduced oligomerization, overview. RR is regulated transcriptionally and allosterically. RR is further regulated by subunit localization and by its protein inhibitor Sml1
additional information
-
the reaction of class Ia RNRs involves tyrosyl or cysteinyl radicals and requires aerobic conditions
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). RIR2B_HUMAN
351
1
40737
Swiss-Prot
other Location (Reliability: 1)
RIR1_HUMAN
792
0
90070
Swiss-Prot
other Location (Reliability: 3)
RIR2_HUMAN
389
0
44878
Swiss-Prot
other Location (Reliability: 2)
Q9UKM0_HUMAN
33
0
3616
TrEMBL
other Location (Reliability: 2)
B4E0I8_HUMAN
695
0
79230
TrEMBL
other Location (Reliability: 1)
B3KS26_HUMAN
297
1
34556
TrEMBL
other Location (Reliability: 2)
B4DNN4_HUMAN
762
0
86452
TrEMBL
other Location (Reliability: 2)
Q53GZ5_HUMAN
792
0
89972
TrEMBL
other Location (Reliability: 3)
H0YCY7_HUMAN
130
1
14123
TrEMBL
other Location (Reliability: 3)
B4DS95_HUMAN
683
0
77626
TrEMBL
other Location (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
160000
-
2 * 160000, subunit R1, + 2 * 78000, subunit R2, the catalytic active enzyme forms a dimer of homodimers
78000
-
2 * 160000, subunit R1, + 2 * 78000, subunit R2, the catalytic active enzyme forms a dimer of homodimers
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
multimer
-
alphanbetan multi-subunit protein complex consisting of subunit types RR1 and RR2, the alpha or RR1 subunit contains the catalytic C site and two allosteric sites, while the beta or RR2 subunit houses a stable tyrosyl free radical that is transferred some 35 A to the catalytic site to initiate radical-based chemistry on the substrate
oligomer
-
RNRs are composed of alpha- and beta-subunits that form active (alpha)n(beta)m, with n or m being 2 or 6, complexes. Subunit alpha binds NDP substrates, i.e. CDP, UDP, ADP, and GDP, C site, as well as ATP and dNTPs, i.e. dATP, dGTP, TTP, allosteric effectors that control enzyme activity (A site) and substrate specificity, S site
tetramer
additional information
tetramer
-
2 * 160000, subunit R1, + 2 * 78000, subunit R2, the catalytic active enzyme forms a dimer of homodimers
tetramer
-
RNR is a tetramer consisting of two non-identical homodimers. The two identical M2 subunits regulate the substrate specificity of the enzyme, while the other two identical M1 subunits are responsible for the activity by binding the ribonucleotides and allosteric effectors
tetramer
-
the enzyme consists of M1, M2, and p53R2 subunits in an alphabeta2gamma constellation
additional information
ribonucleoside-diphosphate reductase subunit M2 B may substitute for small enzyme subunit hRRM2 to form a functional holoenzyme with large subunit hRRM1. The holoenzyme with subunit M2 B can only achieve 40-75% kinetic activity of that with hRRM2. Both small subunits share the same binding site on large subunit hRRM1. The effectors ATP or dATP can regulate holoenzyme activity independent of the small subunit
additional information
-
one monomer can swivel between two conformations and impose significant influences on helix D and helix B of the opposite monomer. This change ultimately affects the orientation of D100 and, thus, the integrity of the binuclear iron environment. Structural basis of B helix disorder and the N-terminal swivel region, overview
additional information
-
dATP-induced oligomerization, overview, modeling of the holo-complex
additional information
-
structure comparisons of classI-III RNRs, model for the subunit organization of RNRs, overview
additional information
in hypoxic conditions the small subunit of the ribonucleotide reductase enzyme is switched from RRM2 to RRM2B in order to facilitate nucleotide production and ongoing replication. Specific residues within RRM2B are identified that are responsible for maintaining activity in hypoxia
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified recombinant His6-tagged hp53R2, sitting drop vapor diffusion method, at 25°C, 0.002 ml of 4.5 mg/ml protein in 20 mM Tris, pH 7.5, are mixed with 150 mM NaCl and 0.002 ml of precipitant solution containing 0.1 M sodium citrate, pH 6.45, 1.3 M Li2SO4, and 0.5 M (NH4)2SO4, reservoir volume is 0.250 ml, 7-14 days, addition of ferrous ammonium sulfate of 5 mM 1 h prior to harvesting, X-ray diffraction structure determination and analysis at 2.6 A resolution
-
subunit RR1 in complex with TTP, dATP, TTP/GDP, TTP/ATP, and TTP/dATP, 1. TTP bound at the S-site, 2. dATP bound at the S-site, 3. TTP bound at the S-site and GDP at the C-site, 4. TTP bound at the S-site and ATP at the A-site, and 5. TTP bound at the S-site and dATP at the A-site, X-ray diffraction structure determination and analysis at resolutions of 2.4 A, 2.3 A, 3.2 A, 3.1 A, and 3.1 A, respectively
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D16R
-
site-directed mutagenesis, the mutant retains 55% of wild-type activity for CDP reduction, and 67% for ADP reduction, it is not inhibited and does not form hexamers at physiologically relevant dATP concentrations
D287A
D57N
H2E
-
site-directed mutagenesis, the mutant retains 56% of wild-type activity for CDP reduction, and 56% for ADP reduction
K95E
mutation in small subunit M2, results in dimer disassembly and enzyme activity inhibition. Mutant is capable of generating the diiron and tyrosyl radical cofactor, but the disassembly of the M2 dimer reduces its interaction with the large subunit M1. The transfection of the wild-type M2 but not the K95E mutant rescues theG1/S phase cell cycle arrest and cell growth inhibition caused by the siRNA knockdown of M2
K95E/E98K
charge-exchanging double mutation, recovers the dimerization and activity lost in mutant K95E
additional information
-
expression of subunit R2 siRNA 1284, targeting the AA(N19) sequence motif, inhibits R2 expression and active enzyme complex formation in different cell lines, it also inhibits cell growth and proloferation in vitro by blocking in the S-phase of the cell cycle, overview
D287A
the mutant enzyme (mutation in the ribonucleoside-diphosphate reductase large subunit RRM1) is deficient in allosteric regulation by dGTP and dTTP, but not ATP/dATP
D287A
the mutant enzyme is deficient in allosteric regulation by dGTP and dTTP, but not ATP/dATP
D57N
-
site-directed mutagenesis, binding kinetics to clofarabine di- and triphosphate inhibitors compared to the wild-type enzyme, overview
D57N
-
site-directed mutagenesis, the mutant is not inhibited and does not form hexamers at physiologically relevant dATP concentrations, the mutation of Asp 57 to Asn abolishes the salt-bridge and change the electrostatic environment of the A-site, resulting in loss of allosteric regulation by dATP
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
in hypoxic conditions the small subunit of the ribonucleotide reductase enzyme is switched from RRM2 to RRM2B in order to facilitate nucleotide production and ongoing replication. Specific residues within RRM2B are identified that are responsible for maintaining activity in hypoxia. RRM2B retains activity in hypoxic conditions and is the favored ribonucleotide reductase subunit in hypoxia. Loss of RRM2B has detrimental consequences for cell fate, specifically in hypoxia
745759
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant His6-tagged enzyme from Escherichia coli strain BL21(DE3) by nickel affinity chromatography and gel filtration
-
recombinant His6-tagged subunits hRRM1 and hRRM2 from Escherichia coli strain BL21(DE3)
-
recombinant His6-tagged subunits M2, p53R2, and M1 from Escherichia coli strain BL21(DE3) by nickel affinity chromatography
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of His-tagged alpha and beta subunits and of His-tagged mutant alpha-subunit
-
expression of His6-tagged subunits hRRM1 and hRRM2 in Escherichia coli strain BL21(DE3)
-
expression of His6-tagged subunits M2, p53R2, and M1 in Escherichia coli strain BL21(DE3)
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
the thiazolyl hydrazone VG19 lowers the protein levels of ribonucleotide reductase subunits R1 and R2 and significantly diminishes the incorporation of radio-labeled 14C cytidine, being equivalent to an inhibition of DNA synthesis
the thiazolyl hydrazone VG19 lowers the protein levels of ribonucleotide reductase subunits R1 and R2 and significantly diminishes the incorporation of radio-labeled 14Ccytidine, being equivalent to an inhibition of DNA synthesis
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
drug development
medicine
drug development
-
the enzyme is an important therapeutic target for anticancer drugs
drug development
ribonucleotide reductase is a key enzyme in DNA synthesis and cell growth control and represents an excellent target for anticancer therapy. 5'-O-valproyl-3'-C-methyladenosine inhibits ribonucleotide reductase activity by competing with ATP as an allosteric effector and concomitantly reduces the intracellular deoxyribonucleoside triphosphate pools. In contrast to previously used ribonucleotide reductase nucleoside analogs does not require intracellular kinases for its activity and therefore holds promise against drug resistant tumors with downregulated nucleoside kinases
drug development
the thiazolyl hydrazones VG12, VG19, and VG22 plus arabinofuranosylcytosine might be able to improve conventional chemotherapeutic regimens for the treatment of human malignancies such as acute promyelocytic or chronic myelogenous leukemia
medicine
in transgenic human lung and colon cancer lines expressing xanthine oxidase regulatory subunit RRM1, G2 cell cycle arrest, apoptosis, and efficient DNA damage repair are induced
medicine
-
combination of (2E)-2-(anthracen-9-ylmethylidene)-N-hydroxyhydrazinecarboximidamide with the first-line antileukemic agent arabinofuranosylcytosine, Ara-C, synergistically potentiates the antineoplastic effects of Ara-C
medicine
skin fibroblasts isolated from a patient with a lethal homozygous missense mutation of ioform p53R2 grow normally in culture with an unchanged complement of mtDNA. During active growth, the four dNTP pools do not differ in size from normal controls, whereas during quiescence, the dCTP and dGTP pools decrease to 50% of the control. On withdrawal of ethidium bromide depleting cell of mitochondrial DNA, mitochondrial DNA recovers equally well in cycling mutant and control cells, whereas during quiescence, the mutant fibroblasts remain deficient. Addition of deoxynucleosides to the medium increases intracellular dNTP pools and normalizes mtDNA synthesis. Quiescent mutant fibroblasts are also deficient in the repair of UV-induced DNA damage
medicine
-
thiosemicarbazone chelators 2-[di(pyridin-2-yl)methylidene]-N,N-dimethylhydrazinecarbothioamide and 2-(diphenylmethylidene)-N,N-dimethylhydrazinecarbothioamide possess potent and selective antitumor activity and may have an additional mechanism of ribonucleotide reductase inhibition via their effects on major thiol-containing systems
medicine
high expression of ribonucleotide reductase subunit M2 (RRM2) correlates with poor prognosis of hepatocellular carcinoma. High RRM2 protein expression might be a useful marker for predicting early recurrence and may be a marker for poor prognosis of hepatocellular carcinoma after curative hepatectomy
medicine
the thiazolyl hydrazones VG12, VG19, and VG22 plus arabinofuranosylcytosine might be able to improve conventional chemotherapeutic regimens for the treatment of human malignancies such as acute promyelocytic or chronic myelogenous leukemia
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Elford, H.L.; Van't Riet, B.; Wampler, G.L.; Lin, A.L.; Elford, R.M.
Regulation of ribonucleotide reductase in mammalian cells by chemotherapeutic agents
Adv. Enzyme Regul.
19
151-168
1981
Homo sapiens
Lammers, M.; Follmann, H.
The ribonucleotide reductases - a unique group of metalloenzymes essential for cell proliferation
Struct. Bonding
54
27-91
1983
Tequatrovirus T4, Tequintavirus T5, Enterobacteria phage T6, Bos taurus, Saccharomyces cerevisiae, Oryctolagus cuniculus, Escherichia coli, Homo sapiens, Mesocricetus auratus, Mus musculus, Rattus norvegicus, Tetradesmus obliquus
-
Holmgren, A.
Regulation of ribonucleotide reductase
Curr. Top. Cell. Regul.
19
47-76
1981
Escherichia phage T2, Tequatrovirus T4, Tequintavirus T5, Enterobacteria phage T6, Bos taurus, Oryctolagus cuniculus, Escherichia coli, Homo sapiens, Rattus norvegicus
Young, P.; Leeds, J.M.; Slabaugh, M.B.; Mathews, C.K.
Ribonucleotide reductase: evidence for specific association with HeLa cell mitochondria
Biochem. Biophys. Res. Commun.
203
46-52
1994
Homo sapiens
Schroeder, P.; Voevodskaya, N.; Klotz, L.O.; Brenneisen, P.; Graslund, A.; Sies, H.
Loss of the tyrosyl radical in mouse ribonucleotide reductase by (-)-epicatechin
Biochem. Biophys. Res. Commun.
326
614-617
2005
Homo sapiens, Mus musculus
Shao, J.; Zhou, B.; Zhu, L.; Bilio, A.J.; Su, L.; Yuan, Y.C.; Ren, S.; Lien, E.J.; Shih, J.; Yen, Y.
Determination of the potency and subunit-selectivity of ribonucleotide reductase inhibitors with a recombinant-holoenzyme-based in vitro assay
Biochem. Pharmacol.
69
627-634
2005
Homo sapiens
Qiu, W.; Zhou, B.; Darwish, D.; Shao, J.; Yen, Y.
Characterization of enzymatic properties of human ribonucleotide reductase holoenzyme reconstituted in vitro from hRRM1, hRRM2, and p53R2 subunits
Biochem. Biophys. Res. Commun.
340
428-434
2006
Homo sapiens (Q7LG56)
Gautam, A.; Bepler, G.
Suppression of lung tumor formation by the regulatory subunit of ribonucleotide reductase
Cancer Res.
66
6497-6502
2006
Mus musculus, Homo sapiens (P23921)
Avolio, T.M.; Lee, Y.; Feng, N.; Xiong, K.; Jin, H.; Wang, M.; Vassilakos, A.; Wright, J.; Young, A.
RNA interference targeting the R2 subunit of ribonucleotide reductase inhibits growth of tumor cells in vitro and in vivo
Anticancer Drugs
18
377-388
2007
Homo sapiens
Sigmond, J.; Kamphuis, J.A.; Laan, A.C.; Hoebe, E.K.; Bergman, A.M.; Peters, G.J.
The synergistic interaction of gemcitabine and cytosine arabinoside with the ribonucleotide reductase inhibitor triapine is schedule dependent
Biochem. Pharmacol.
73
1548-1557
2007
Homo sapiens
Odenike, O.M.; Larson, R.A.; Gajria, D.; Dolan, M.E.; Delaney, S.M.; Karrison, T.G.; Ratain, M.J.; Stock, W.
Phase I study of the ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde-thiosemicarbazone (3-AP) in combination with high dose cytarabine in patients with advanced myeloid leukemia
Invest. New Drugs
26
233-239
2008
Homo sapiens
Kowol, C.R.; Berger, R.; Eichinger, R.; Roller, A.; Jakupec, M.A.; Schmidt, P.P.; Arion, V.B.; Keppler, B.K.
Gallium(III) and iron(III) complexes of alpha-N-heterocyclic thiosemicarbazones: synthesis, characterization, cytotoxicity, and interaction with ribonucleotide reductase
J. Med. Chem.
50
1254-1265
2007
Homo sapiens, Mus musculus
Cappellacci, L.; Franchetti, P.; Vita, P.; Petrelli, R.; Lavecchia, A.; Jayaram, H.N.; Saiko, P.; Graser, G.; Szekeres, T.; Grifantini, M.
Ribose-modified purine nucleosides as ribonucleotide reductase inhibitors. Synthesis, antitumor activity, and molecular modeling of N6-substituted 3-C-methyladenosine derivatives
J. Med. Chem.
51
4260-4269
2008
Homo sapiens
Karp, J.E.; Giles, F.J.; Gojo, I.; Morris, L.; Greer, J.; Johnson, B.; Thein, M.; Sznol, M.; Low, J.
A phase I study of the novel ribonucleotide reductase inhibitor 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) in combination with the nucleoside analog fludarabine for patients with refractory acute leukemias and aggressive myeloprol
Leuk. Res.
32
71-77
2008
Homo sapiens
Zhu, L.; Zhou, B.; Chen, X.; Jiang, H.; Shao, J.; Yen, Y.
Inhibitory mechanisms of heterocyclic carboxaldehyde thiosemicabazones for two forms of human ribonucleotide reductase
Biochem. Pharmacol.
78
1178-1185
2009
Homo sapiens
Smith, P.; Zhou, B.; Ho, N.; Yuan, Y.C.; Su, L.; Tsai, S.C.; Yen, Y.
2.6 a X-ray crystal structure of human p53R2, a p53-inducible ribonucleotide reductase
Biochemistry
48
11134-11141
2009
Homo sapiens
Krishnan, K.; Prathiba, K.; Jayaprakash, V.; Basu, A.; Mishra, N.; Zhou, B.; Hu, S.; Yen, Y.
Synthesis and ribonucleotide reductase inhibitory activity of thiosemicarbazones
Bioorg. Med. Chem. Lett.
18
6248-6250
2008
Homo sapiens
Holmgren, A.; Sengupta, R.
The use of thiols by ribonucleotide reductase
Free Radic. Biol. Med.
49
1617-1628
2010
Saccharomyces cerevisiae, Escherichia coli, Homo sapiens, Lactobacillus leichmannii, Mus musculus
Fairman, J.W.; Wijerathna, S.R.; Ahmad, M.F.; Xu, H.; Nakano, R.; Jha, S.; Prendergast, J.; Welin, R.M.; Flodin, S.; Roos, A.; Nordlund, P.; Li, Z.; Walz, T.; Dealwis, C.G.
Structural basis for allosteric regulation of human ribonucleotide reductase by nucleotide-induced oligomerization
Nat. Struct. Mol. Biol.
18
316-322
2011
Homo sapiens
Aye, Y.; Stubbe, J.
Clofarabine 5-di and -triphosphates inhibit human ribonucleotide reductase by altering the quaternary structure of its large subunit
Proc. Natl. Acad. Sci. USA
108
9815-9820
2011
Homo sapiens
Saiko, P.; Graser, G.; Giessrigl, B.; Lackner, A.; Grusch, M.; Krupitza, G.; Basu, A.; Sinha, B.; Jayaprakash, V.; Jaeger, W.; Fritzer-Szekeres, M.; Szekeres, T.
A novel N-hydroxy-N-aminoguanidine derivative inhibits ribonucleotide reductase activity: Effects in human HL-60 promyelocytic leukemia cells and synergism with arabinofuranosylcytosine (Ara-C)
Biochem. Pharmacol.
81
50-59
2011
Homo sapiens
Chen, X.; Xu, Z.; Zhang, L.; Liu, H.; Liu, X.; Lou, M.; Zhu, L.; Huang, B.; Yang, C.G.; Zhu, W.; Shao, J.
The conserved Lys-95 charged residue cluster is critical for the homodimerization and enzyme activity of human ribonucleotide reductase small subunit m2
J. Biol. Chem.
289
909-920
2014
Homo sapiens (P31350)
Yu, Y.; Suryo Rahmanto, Y.; Hawkins, C.L.; Richardson, D.R.
The potent and novel thiosemicarbazone chelators di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone and 2-benzoylpyridine-4,4-dimethyl-3-thiosemicarbazone affect crucial thiol systems required for ribonucleotide reductase activity
Mol. Pharmacol.
79
921-931
2011
Homo sapiens
Pontarin, G.; Ferraro, P.; Bee, L.; Reichard, P.; Bianchi, V.
Mammalian ribonucleotide reductase subunit p53R2 is required for mitochondrial DNA replication and DNA repair in quiescent cells
Proc. Natl. Acad. Sci. USA
109
13302-13307
2012
Homo sapiens (Q7LG56)
Knappenberger, A.J.; Ahmad, M.F.; Viswanathan, R.; Dealwis, C.G.; Harris, M.E.
Nucleoside analogue triphosphates allosterically regulate human ribonucleotide reductase and identify chemical determinants that drive substrate specificity
Biochemistry
55
5884-5896
2016
Saccharomyces cerevisiae, Homo sapiens (P23921), Homo sapiens (P23921 and P31350), Homo sapiens
Petrelli, R.; Meli, M.; Vita, P.; Torquati, I.; Ferro, A.; Vodnala, M.; DAlessandro, N.; Tolomeo, M.; Del Bello, F.; Kusumanchi, P.; Franchetti, P.; Grifantini, M.; Jayaram, H.N.; Hofer, A.; Cappellacci, L.
From the covalent linkage of drugs to novel inhibitors of ribonucleotide reductase synthesis and biological evaluation of valproic esters of 3-C-methyladenosine
Bioorg. Med. Chem. Lett.
24
5304-5309
2014
Homo sapiens (P23921)
Graser-Loescher, G.; Schoenhuber, A.; Ciglenec, C.; Eberl, S.; Krupitza, G.; Mader, R.M.; Jadav, S.S.; Jayaprakash, V.; Fritzer-Szekeres, M.; Szekeres, T.; Saiko, P.
Thiosemicarbazone derivatives, thiazolyl hydrazones, effectively inhibit leukemic tumor cell growth Down-regulation of ribonucleotide reductase activity and synergism with arabinofuranosylcytosine
Food Chem. Toxicol.
108
53-62
2017
Homo sapiens (P23921)
Lee, B.; Ha, S.Y.; Song, D.H.; Lee, H.W.; Cho, S.Y.; Park, C.K.
High expression of ribonucleotide reductase subunit M2 correlates with poor prognosis of hepatocellular carcinoma
Gut and liver
8
662-668
2014
Homo sapiens (P31350)
Foskolou, I.P.; Jorgensen, C.; Leszczynska, K.B.; Olcina, M.M.; Tarhonskaya, H.; Haisma, B.; DAngiolella, V.; Myers, W.K.; Domene, C.; Flashman, E.; Hammond, E.M.
Ribonucleotide reductase requires subunit switching in hypoxia to maintain DNA replication
Mol. Cell
66
206-220.e9
2017
Homo sapiens (Q7LG56)
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