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Information on EC 1.17.4.1 - ribonucleoside-diphosphate reductase and Organism(s) Mus musculus and UniProt Accession P11157
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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: Mus musculus
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
-
-
-
-
nucleoside diphosphate reductase
-
-
-
-
reductase, ribonucleoside diphosphate
-
-
-
-
ribonucleoside 5'-diphosphate reductase
-
-
-
-
ribonucleoside diphosphate reductase
-
-
-
-
ribonucleotide diphosphate reductase
-
-
-
-
ribonucleotide reductase
-
-
-
-
UDP reductase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
2'-deoxyribonucleoside 5'-diphosphate + thioredoxin disulfide + H2O = ribonucleoside 5'-diphosphate + thioredoxin
2'-deoxyribonucleoside 5'-diphosphate + thioredoxin disulfide + H2O = ribonucleoside 5'-diphosphate + thioredoxin
proposed mechanism
-
2'-deoxyribonucleoside 5'-diphosphate + thioredoxin disulfide + H2O = ribonucleoside 5'-diphosphate + thioredoxin
postulated mechanism, radical cation intermediates
-
2'-deoxyribonucleoside 5'-diphosphate + thioredoxin disulfide + H2O = ribonucleoside 5'-diphosphate + thioredoxin
allosteric regulation of the catalytic activity of subunit R1
-
2'-deoxyribonucleoside 5'-diphosphate + thioredoxin disulfide + H2O = ribonucleoside 5'-diphosphate + thioredoxin
kinetics and mechanism of formation of the tyrosyl radical and micro-oxo-diiron cluster in the R2 subunit
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
-
-
-
-
oxidation
-
-
-
-
reduction
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-
-
-
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
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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
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
-
ir
ADP + reduced thioredoxin
2'-deoxy-ADP + oxidized thioredoxin + H2O
-
-
-
ir
CDP + reduced thioredoxin
2'-deoxy-CDP + oxidized thioredoxin + H2O
-
-
-
ir
GDP + reduced thioredoxin
2'-deoxy-GDP + oxidized thioredoxin + H2O
-
-
-
ir
nucleoside 5'-diphosphate + glutaredoxin
2'-deoxynucleoside 5'-diphosphate + glutaredoxin disulfide + H2O
-
class I RNRs
-
-
?
nucleoside 5'-diphosphate + NrdH-redoxin
2'-deoxynucleoside 5'-diphosphate + NrdH-redoxin disulfide + H2O
-
only class Ib RNRs
-
-
?
nucleoside 5'-diphosphate + thioredoxin
2'-deoxynucleoside 5'-diphosphate + thioredoxin disulfide + H2O
-
class I and class II RNRs
-
-
?
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
UDP + reduced thioredoxin
2'-deoxy-UDP + 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
-
-
-
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
-
-
-
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
-
-
-
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
-
-
-
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
-
-
-
ir
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
-
CDP, ADP and GDP are reduced very poorly in the absence of allosteric effectors
ir
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
CDP is the only substrate that is reduced with a significant activity even in the absence of allosteric effectors
-
?
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
enzyme catalyzes the first unique step in DNA synthesis
-
?
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
enzyme catalyzes the first unique step in DNA synthesis
-
?
additional information
?
-
-
no substrate activity for L-ribofuranosyl-adenine 5'-diphosphate
-
-
?
additional information
?
-
-
class Ia and Ib RNRs convert nucleoside diphosphates into 2'-deoxynucleoside diphosphates using glutaredoxin or thioredoxin as cofactor. Class II RNRs catalyze the same reaction but also convert nucleoside triphosphates to the correspondent 2'deoxy products, EC 1.17.4.2, overview
-
-
?
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 I RNRs
-
-
?
nucleoside 5'-diphosphate + NrdH-redoxin
2'-deoxynucleoside 5'-diphosphate + NrdH-redoxin disulfide + H2O
-
only class Ib RNRs
-
-
?
nucleoside 5'-diphosphate + thioredoxin
2'-deoxynucleoside 5'-diphosphate + thioredoxin disulfide + H2O
-
class I and class II RNRs
-
-
?
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
additional information
?
-
-
class Ia and Ib RNRs convert nucleoside diphosphates into 2'-deoxynucleoside diphosphates using glutaredoxin or thioredoxin as cofactor. Class II RNRs catalyze the same reaction but also convert nucleoside triphosphates to the correspondent 2'deoxy products, EC 1.17.4.2, overview
-
-
?
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
enzyme catalyzes the first unique step in DNA synthesis
-
?
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
-
enzyme catalyzes the first unique step in DNA synthesis
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
-
cofactor specificity and binding, role in reaction, overview
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Iron
additional information
additional information
-
the essential metallo-cofactor is a micro-oxo-micro-carboxylato-diiron cluster adjacent to a stable tyrosyl radical
additional information
-
model of enzyme regulation by nucleoside 5'-triphosphates
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
2',3'-dideoxy-ATP
-
less potent inhibitor than dATP, 0.1 mM, 50% inhibition of CDP reduction
2,3,4-trihydroxybenzohydroxamic acid
-
0.012 mM, 50% inhibition, hydroxyurea-resistant cells
bathophenanthroline sulfonate
-
5 mM, almost complete inhibition of CDP and GDP reduction
ethyleneglycol-bis-(2-aminoethylether)-N,N,N',N'-tetraacetic acid
-
trivial name EGTA
Fmoc(NCH3)PhgLDChaDF
-
inhibitor identified by competition with inhibitor N-AcFTLDADF and inhibition of enzyme activity
FmocWFDF
-
inhibitor identified by competition with inhibitor N-AcFTLDADF and inhibition of enzyme activity
FmocWVFF
-
inhibitor identified by competition with inhibitor N-AcFTLDADF and inhibition of enzyme activity
gamma-L-Glutaminyl-4-hydroxybenzene
-
naturally occuring quinol from spores of Agaricus bisporus, 0.76 mM, 50% inhibition
L-ADP
-
inhibition of D-ADP reduction, competitive inhibition of dGTP-dependent D-ADP reductase
monoclonal antibody raised against yeast tubulin
-
CDP reductase activity is inhibited to a greater extent than ADP, UDP or GDP reductase activity, antibody recognizes a specific sequence in the C-terminal region on the R2 subunit
-
N-ethylmaleimide
-
0.1 mM, 50% inhibition of intact enzyme, 0.05 mM, 50% inhibition of effector-binding subunit, 0.3 mM, 50% inhibition of non-heme iron subunit
N-[[(3S,5S,7S,7aS)-7-([[3-(9H-fluoren-9-yl)propanoyl]oxy]methyl)-3-hydroxy-5-(2-methylpropoxy)hexahydropyrano[3,4-b]pyrrol-1(2H)-yl]acetyl]-L-alpha-aspartyl-L-phenylalanine
-
50% inhibition at 0.04-0.05 mM, bicyclic scaffold is necessary to maintain inhibitory activity
NSFTLDADF
-
inhibition of CDP reductase activity, peptide corresponds to the C-terminal region of the R2 subunit and competes with binding of R2 to the R1 subunit
o-ClBzocFc[ELDK]DF
-
inhibitor identified by competition with inhibitor N-AcFTLDADF and inhibition of enzyme activity
p-chloromercuribenzoate
-
0.35 mM, 50% inhibition of intact enzyme, 0.15 mM, 50% inhibition of effector-binding subunit, 1.5 mM, 50% inhibition of non-heme iron subunit
sodium arsenite
-
0.025 mM, almost complete inhibition of CDP reduction, 86% inhibition of GDP reduction
[FeCl4] 2-acetylpyridine N,N-dimethylthiosemicarbazone
-
Ga(III) and Fe(III) complexes destroy the tyrosyl radical of the presumed target ribonucleotide reductase
[GalCl2] 2-acetylpyridine N,N-dimethylthiosemicarbazone
-
Ga(III) and Fe(III) complexes destroy the tyrosyl radical of the presumed target ribonucleotide reductase
1-Formylisoquinoline thiosemicarbazone
-
0.0006 mM, 81% inhibition, 0.1 mM desferal reverses inhibition
3,5-diamino-1H-1,2,4-triazole
-
2 mM, 41% inhibition, presence of 0.1 mM desferal potentiates inhibition
4-Methyl-5-amino isoquinoline-1-carboxaldehyde thiosemicarbazone
-
inhibits the non-heme iron subunit
4-Methyl-5-amino-1-formylisoquinoline thiosemicarbazone
-
0.0003 mM, 93% inhibition, 0.1 mM desferal reverses inhibition
dATP
-
strong inhibition of the ATP activated enzyme, complete inhibition of GDP reduction, inhibition of ADP reduction
dATP
-
0.0033 mM, 50% inhibition of CDP reduction, 0.0036 mM, 50% inhibition of GDP reduction
dATP
-
0.1 mM, 96% inhibition of CDP reductase activity in dextran sulfate-treated cells, 85% inhibition of GDP reductase activity
dGTP
-
0.08 mM, 50% inhibition of CDP reduction, 0.19 mM, 50% inhibition of GDP reduction
EDTA
-
reversible stimulation of GDP reduction, irreversible inhibition of CDP reduction
Hydroxyurea
-
2 mM, 93% inhibition, presence of 0.1 mM desferal potentiates inhibition
pyrazoloimidazol
-
2 mM, 79% inhibition, presence of 0.1 mM desferal potentiates inhibition, inhibits the non-heme iron subunit
Thenoyltrifluoroacetone
-
5 mM, almost complete inhibition of CDP and GDP reduction
additional information
-
inhibition of reductase by hydroxyurea, guanazole and pyrazolo-imidazole is potentiated by iron-chelating agents e.g. EDTA, desferrioxamine mesylate and 8-hydroxyquinoline, inhibition by 4-methyl-5-amino-1-formylisoquinoline thiosemicarbazone and 1-formylisoquinoline thiosemicarbazone is reversed by iron chelating agents
-
additional information
-
overview: naturally occuring inhibitors e.g. proteins and nucleotides
-
additional information
-
L1210 cells with resistance to specific nucleotide reductase inhibitors
-
additional information
-
comprehensive and quantitative model for allosteric control of mRR enzymatic activity based on molecular mass, ligand binding and enzyme activity studies
-
additional information
-
synthesis, characterization, and interaction with ribonucleotide reductase subunit R2 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
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
EDTA
-
reversible stimulation of GDP reduction, irreversible inhibition of CDP reduction
adenyl-5'-yl-imidodiphosphate
-
can replace ATP as activator of CDP and UDP reduction
dATP
-
0.2-0.4 mM, induces formation of dimers and tetramers of subunit R1, 1-2 mM, induces formation of hexamers of subunit R1
additional information
-
enzyme of cells first treated with 2,6-dichlorophenolindophenol has a complete dependence on NADPH which can also be met by dithiothreitol or dihydrolipoic acid
-
additional information
-
subunit R1 has 2 effector-binding sites per polypeptide chain: one activity site for dATP and ATP, with dATP-inhibiting and ATP-stimulating catalytic activity and a second specificity site for dATP, ATP, dTTP and dGTP directing substrate specificity
-
additional information
-
overview: nucleoside 5'-diphosphates as effectors of mammalian ribonucleotide reductase
-
additional information
-
comprehensive and quantitative model for allosteric control of mRR enzymatic activity based on molecular mass, ligand binding and enzyme activity studies
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
extracts from hydroxyurea resistant cell line HU-7 exhibit a 13fold higher ADP reductase activity and a 5fold higher CDP reductase activity when compared to wild-type
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
-
-
cell line
-
L1210 cells resistant to specific ribonucleotide reductase inhibitors
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
-
the reaction of class I RNRs involves tyrosyl or cysteinyl radicals and requires aerobic conditions, while for class II RNRs the reaction involves deoxyadenosyl or cysteinyl radicals and is independent of oxygen
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). RIR2_MOUSE
390
0
45096
Swiss-Prot
other Location (Reliability: 3)
PDB
SCOP
CATH
UNIPROT
ORGANISM
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
additional information
additional information
-
nucleotide binding to the specificity site drives formation of an active R1,2R2,2 dimer, ATP or dATP binding to the adenine-specific site results in formation of an inactive tetramer and ATP binding to the hexamerization site drives formation of an active R1,6R2,6 hexamer which is probably the major active form in mammalian cells
additional information
-
enzyme in Ehrlich ascites tumor cells consits of two nonidentical subunits: an effector-binding subunit, EB, and a non-heme iron containing subunit, NHI, since their relative levels are not coordinately regulated the stoichiometry of the whole enzyme varies with the cell cycle
additional information
-
composition of the enzyme is not constant, but is altered in presence of effectors
additional information
-
large subunit R1 contains binding sites for substrates and allosteric effectors, smaller subunit R2 contains non-heme iron and a tyrosyl free-radical
additional information
-
large subunit R1 contains binding sites for substrates and allosteric effectors, smaller subunit R2 contains non-heme iron and a tyrosyl free-radical
additional information
-
in presence of dTTP, subunit R1 forms dimers. In presence of dATP or ATP, subunit R1 forms hexamers of 544000 Da, which interact with the subunit R2 dimer to form an enzymatically active protein complex alpha6beta2. The complex can be in activated or inhibited state depending on whether ATP or dATP is bound. Complex alpha6beta2 is the major form of enzyme at physiological levels of subunits and nucleotides
additional information
-
structure comparisons of classI-III RNRs, model for the subunit organization of RNRs, overview
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D57N
R265A
-
mutant in subunit R2, about 10% of wild-type activity. Mutant is able to form stable tyrosyl radicals and bind subunit R1 with similar kinetics as wild-type
R265E
-
mutant in subunit R2, about 40% of wild-type activity. Mutant is able to form stable tyrosyl radicals and bind subunit R1 with similar kinetics as wild-type
R265Q
-
mutant in subunit R2, about 1% of wild-type activity. Mutant is able to form stable tyrosyl radicals and bind subunit R1 with similar kinetics as wild-type
R265Y
-
mutant in subunit R2, about 4% of wild-type activity. Mutant is able to form stable tyrosyl radicals and bind subunit R1 with similar kinetics as wild-type
Y370W
-
mutation in R2 subunit, point mutation does not affect the ability to form a normal diferric iron/tyrosyl radical center, 1.7% of wild-type activity probably due to slow radical transfer
additional information
-
transfection of RRM2 protein-expressing Hep-G2 cells with constructed potent siRNA, NM_009104, inhibitors of ribonucleotide reductase subunit RRM2 reduce cell proliferation in vitro and in vivo, overview
D57N
-
mutation in R1 subunit, in contrast to wild-type dATP stimulates CDP reduction, GDP reduction is inhibited by dGTP, ADP reduction is inhibited by dTTP similar to wild-type, this suggests that the mutant enzyme binds both ATP and dATP to the activity site but does not distinguish between them when it comes to catalysis
D57N
-
mutant of the catalytic subunit mR1 is not inhibited by dATP because of a block in the formation of R1(4b)
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
effector-binding subunit of mammalia is more sensitive to proteolysis by chymotrypsin, to heating at 55°C and to sulfhydryl reagents e.g. p-chloromercuribenzoate and N-ethylmaleimide, than the nonheme iron subunit, the latter is more sensitive to trypsin treatment
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
chimeric R2 genes in which C-terminal sequences in Escherichia coli subunit R2 are replaced by C-terminal sequences from the mouse subunit R2
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of M1 mutant cDNA containing a G to A transition at codon 57 in chinese hamster ovary cells
nearly full length cDNA of M1 and M2 subunits, expression of M2 subunit in mouse 3T6 cells and monkey COS-7 cells
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
in transgenic mice expressing xanthine oxidase regulatory subunit RRM1, carcinogen-induced lung tumor formation is significantly suppressed. RRM1 transgenic animals repair chemically induced DNA damage with greater efficiency than control animals
medicine
-
ribonucleotide reductase is a therapeutic target for DNA replication-dependent diseases such as cancer in humans
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Kucera, R.; Paulus, H.
Studies on ribonucleoside-diphosphate reductase in permeable animal cells. II. Catalytic and regulatory properties of the enzyme in mouse L cells
Arch. Biochem. Biophys.
214
114-123
1982
Mus musculus
Kjoller Larsen, I.; Sjberg, B.M.; Thelander, L.
Characterization of the active site of ribonucleotide reductase of Escherichia coli, bacteriophage T4 and mammalian cells by inhibition studies with hydroxyurea analogues
Eur. J. Biochem.
125
75-81
1982
Tequatrovirus T4, Bos taurus, Escherichia coli, Mus musculus
Cory, J.G.; Sato, A.; Lasater, L.
Specific inhibition of the subunits of ribonucleotide reductase as a new approach to combination chemotherapy
Adv. Enzyme Regul.
19
139-150
1981
Mus musculus
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
-
Sato, A.; Bacon, P.E.; Cory, J.G.
Studies on the differential mechanisms of inhibition of ribonucleotide reductase by specific inhibitors of the non-heme iron subunit
Adv. Enzyme Regul.
22
231-241
1984
Mus musculus
carter, G.L.; Cory, J.G.
Selective resistance of L1210 cell lines to inhibitors directed at the subunits of ribonucleotide reductase
Adv. Enzyme Regul.
29
123-139
1989
Mus musculus
Cory, J.G.; Sato, A.; Brown, N.C.
Protein properties of the subunits of ribonucleotide reductase and the specificity of the allosteric site(s)
Adv. Enzyme Regul.
25
3-19
1986
Mus musculus
Cory, J.G.; Rey, D.A.; Carter, G.L.; Bacon, P.E.
Nucleoside 5'-diphosphates as effectors of mammalian ribonucleotide reductase
J. Biol. Chem.
260
12001-12007
1985
Mus musculus
Sato, A.; Cory, J.G.
Differential sensitivities of the subunits of mammalian ribonucleotide reductase to proteases, sulfhydryl reagents, and heat
Arch. Biochem. Biophys.
244
572-579
1986
Mus musculus
Stubbe, J.
Ribonucleotide reductases
Adv. Enzymol. Relat. Areas Mol. Biol.
63
349-419
1990
Escherichia coli, Herpes simplex virus, Mus musculus
Thelander, M.; Thelander, L.
Molecular cloning and expression of the functional gene encoding the M2 subunit of mouse ribonucleotide reductase: a new dominant marker gene
EMBO J.
8
2475-2479
1989
Mus musculus (P11157)
Caras, I.W.; Martin, D.W.
Molecular cloning of the cDNA for a mutant mouse ribonucleotide reductase M1 that produces a dominant mutator phenotype in mammalian cells
Mol. Cell. Biol.
8
2698-2704
1988
Mus musculus
Thelander, L.; Berg, P.
Isolation and characterization of expressible cDNA clones encoding the M1 and M2 subunits of mouse ribonucleotide reductase
Mol. Cell. Biol.
6
3433-3442
1986
Mus musculus
Fitzgerald, G.B.; Rosowsky, A.; Wick, M.M.
Inhibition of ribonucleotide reductase by naturally occurring quinols from spores of Agaricus bisporus
Biochem. Biophys. Res. Commun.
120
1008-1014
1984
Mus musculus
Engstrm, Y.; Rozell, B.; Hansson, H.A.; Stemme, S.; Thelander, L.
Localization of ribonucleotide reductase in mammalian cells
EMBO J.
3
863-867
1984
Mus musculus, Rattus norvegicus
Kucera, R.; Paulus, H.
Studied on ribonucleoside-diphosphate reductase in permeable animal cells. I. Reversible permeabilization of mouse L cells with dextran sulfate
Arch. Biochem. Biophys.
214
102-113
1982
Mus musculus
Cory, J.G.; Fleischer, A.E.
The molecular weight of Ehrlich tumor cell ribonucleotide reductase and its subunits: effector-induced changes
Arch. Biochem. Biophys.
217
546-551
1982
Mus musculus
Gudas, L.; Eriksson, S.; Ullman, B.; Martin, D.
Purification of a mutant ribonucleotide reductase from cultured mouse T-lymphoma cells
Adv. Enzyme Regul.
19
129-137
1981
Mus musculus
Cory, J.G.; Cory, A.H.; Downes, D.L.
Differential substrate properties of mammalian ribonucleotide reductase
Purine and pyrimidine metabolism in man VIII ed. (Sahota A. and Taylor M. ed.)
631-635
1995
Mus musculus
-
Hamann, C.S.; Lentainge, S.; Li, L.S.; Salem, J.S.; Yang, F.D.; Cooperman, B.S.
Chimeric small subunit inhibitors of mammalian ribonucleotide reductase: a dual function for the R2 C-terminus?
Protein Eng.
11
219-224
1998
Escherichia coli, Mus musculus
Rova, U.; Adrait, A.; Potsch, S.; Graslund, A.; Thelander, L.
Evidence by mutagenesis that Tyr370 of the mouse ribonucleotide reductase R2 protein is the connecting link in the intersubunit radical transfer pathway
J. Biol. Chem.
274
23746-23751
1999
Mus musculus
Reichard, P.; Eliasson, R.; Ingemarson, R.; Thelander, L.
Cross-talk between the allosteric effector-binding sites in mouse ribonucleotide reductase
J. Biol. Chem.
275
33021-33026
2000
Mus musculus
Yun, D.; Krebs, C.; Gupta, G.P.; Iwig, D.F.; Huynh, B.H.; Bollinger, J.M., Jr.
Facile electron transfer during formation of cluster x and kinetic competence of x for tyrosyl radical production in protein R2 of ribonucleotide reductase from mouse
Biochemistry
41
981-990
2002
Mus musculus
Kashlan, O.B.; Scott, C.P.; Lear, J.D.; Cooperman, B.S.
A comprehensive model for the allosteric regulation of mammalian ribonucleotide reductase. Functional consequences of ATP- and dATP-induced oligomerization of the large subunit
Biochemistry
41
462-474
2002
Mus musculus
Cooperman, B.S.; Kashlan, O.B.
A comprehensive model for the allosteric regulation of class Ia ribonucleotide reductases
Adv. Enzyme Regul.
43
167-182
2003
Mus musculus
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
He, J.; Roy, B.; Perigaud, C.; Kashlan, O.B.; Cooperman, B.S.
The enantioselectivities of the active and allosteric sites of mammalian ribonucleotide reductase
FEBS J.
272
1236-1242
2005
Mus musculus
Cooperman, B.S.; Gao, Y.; Tan, C.; Kashlan, O.B.; Kaur, J.
Peptide inhibitors of mammalian ribonucleotide reductase
Adv. Enzyme Regul.
45
112-125
2005
Mus musculus
Fuertes, M.J.; Kaur, J.; Deb, P.; Cooperman, B.S.; Smith, A.B.
Design, synthesis, and evaluation of octahydropyranopyrrole-based inhibitors of mammalian ribonucleotide reductase
Bioorg. Med. Chem. Lett.
15
5146-5149
2005
Mus musculus
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)
Narvaez, A.J.; Voevodskaya, N.; Thelander, L.; Graeslund, A.
The involvement of Arg265 of mouse ribonucleotide reductase R2 protein in proton transfer and catalysis
J. Biol. Chem.
281
26022-26028
2006
Mus musculus
Rofougaran, R.; Vodnala, M.; Hofer, A.
Enzymatically active mammalian ribonucleotide reductase exists primarily as an alpha6beta2 octamer
J. Biol. Chem.
281
27705-27711
2006
Mus musculus
Heidel, J.D.; Liu, J.Y.; Yen, Y.; Zhou, B.; Heale, B.S.; Rossi, J.J.; Bartlett, D.W.; Davis, M.E.
Potent siRNA inhibitors of ribonucleotide reductase subunit RRM2 reduce cell proliferation in vitro and in vivo
Clin. Cancer Res.
13
2207-2215
2007
Mus musculus
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
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