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Information on EC 1.17.4.1 - ribonucleoside-diphosphate reductase and Organism(s) Chlamydia trachomatis and UniProt Accession O84835
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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
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proton-coupled
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diiron
- deoxycytidine
-
diferric
-
thiyl
- dntps
- dcdp
- thiosemicarbazone
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diferric-tyrosyl
-
nrdabs
-
hydroxyurea-resistant
- medicine
-
nrdef
-
heterodinuclear
- drug development
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antiferromagnetically
- pharmacology
- molecular biology
The taxonomic range for the selected organisms is: Chlamydia trachomatis
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
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ADP reductase
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CDP reductase
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nucleoside diphosphate reductase
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reductase, ribonucleoside diphosphate
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ribonucleoside 5'-diphosphate reductase
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ribonucleoside diphosphate reductase
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ribonucleotide diphosphate reductase
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ribonucleotide reductase
UDP reductase
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additional information
ribonucleotide reductase
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
2'-deoxyribonucleoside 5'-diphosphate + thioredoxin disulfide + H2O = ribonucleoside 5'-diphosphate + thioredoxin
catalytic mechanism
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
redox reaction
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oxidation
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reduction
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PATHWAY SOURCE
PATHWAYS
KEGG
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-, -, -, -, -, -, -, -, -
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
CDP + thioredoxin
2'-deoxyCDP + thioredoxin disulfide + H2O
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?
ribonucleoside diphosphate + reduced thioredoxin
2'-deoxyribonucleoside diphosphate + oxidized thioredoxin + H2O
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ir
ribonucleoside diphosphate + thioredoxin
2'-deoxyribonucleoside diphosphate + thioredoxin disulfide + H2O
ribonucleoside diphosphate + thioredoxin
2'-deoxyribonucleoside diphosphate + thioredoxin disulfide + H2O
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?
ribonucleoside diphosphate + thioredoxin
2'-deoxyribonucleoside diphosphate + thioredoxin disulfide + H2O
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the catalytic reaction in class I RNR involves a long-range electron transfer, coupled to proton transfer, between the substrate binding site in protein R1 and the iron/radical site in protein R2
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?
additional information
?
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ribonucleotide reductases catalyze the reduction of ribonucleotides to deoxyribonucleotides for DNA synthesis
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?
additional information
?
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ribonucleotide reductases catalyze the reduction of ribonucleotides to deoxyribonucleotides for DNA synthesis
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?
additional information
?
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the RNR reaction involves replacement by hydrogen of the hydroxyl group on the 2'-carbon of the nucleoside diphosphate substrate. This chemically difficult replacement occurs by a free-radical mechanism. The enzyme employs a heterobinuclear MnIV/FeIII cluster for radical initiation. In essence, the MnIV ion of the cluster functionally replaces the Y radical of the conventional class I RNR. The Ct beta2 protein also autoactivates by reaction of its reduced MnII/FeII metal cluster with O2. In this reaction, an unprecedented MnIV/FeIV intermediate accumulates almost stoichiometrically and decays by one-electron reduction of the FeIV site. This reduction is mediated by the near-surface residue, Y222, overview
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?
additional information
?
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the RNR reaction involves replacement by hydrogen of the hydroxyl group on the 2'-carbon of the nucleoside diphosphate substrate. This chemically difficult replacement occurs by a free-radical mechanism. The enzyme employs a heterobinuclear MnIV/FeIII cluster for radical initiation. In essence, the MnIV ion of the cluster functionally replaces the Y radical of the conventional class I RNR. The Ct beta2 protein also autoactivates by reaction of its reduced MnII/FeII metal cluster with O2. In this reaction, an unprecedented MnIV/FeIV intermediate accumulates almost stoichiometrically and decays by one-electron reduction of the FeIV site. This reduction is mediated by the near-surface residue, Y222, overview
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?
additional information
?
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substrate is CDP, R2 is the catalytic subunit
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?
additional information
?
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catalysis by a class I RNR begins when a cysteine residue in the alpha2 subunit is oxidized to a thiyl radical by a cofactor about 35 A away in the beta2 subunit. In a class Ia or Ib RNR, a stable tyrosyl radical is the C oxidant, whereas a MnIV/FeIII cluster serves this function in the class Ic enzyme from Chlamydia trachomatis
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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
CDP + thioredoxin
2'-deoxyCDP + thioredoxin disulfide + H2O
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?
ribonucleoside diphosphate + thioredoxin
2'-deoxyribonucleoside diphosphate + thioredoxin disulfide + H2O
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?
additional information
?
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ribonucleotide reductases catalyze the reduction of ribonucleotides to deoxyribonucleotides for DNA synthesis
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?
additional information
?
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ribonucleotide reductases catalyze the reduction of ribonucleotides to deoxyribonucleotides for DNA synthesis
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?
additional information
?
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catalysis by a class I RNR begins when a cysteine residue in the alpha2 subunit is oxidized to a thiyl radical by a cofactor about 35 A away in the beta2 subunit. In a class Ia or Ib RNR, a stable tyrosyl radical is the C oxidant, whereas a MnIV/FeIII cluster serves this function in the class Ic enzyme from Chlamydia trachomatis
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Mn/Fe redox cofactor
unusual cofactor instead of Fe-Fe cofactor in other RNRs. Assembly, maintenance, and role in catalysis of the MnIV/FeIII cofactor of Ctbeta2 subunit, structure modelling, detailed overview
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Mn-Fe cofactor
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the R2 protein of class I RNR contains a Mn-Fe instead of the standard Fe-Fe cofactor. Ct R2 has a redox-inert phenylalanine replacing the radical-forming tyrosine of classic RNRs, which implies a different mechanism of O2 activation, overview
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MnIV/FeIII cofactor
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electron transfer mechanism and conformational identification, role in reaction and mechanism, detailed overview
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manganese-iron cofactor
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the class Ic RNR from Chlamydia trachomatis uses a Mn(IV)/Fe(III) cofactor, with high specificity for MnIV, which functionally replaces the tyrosyl radical used by conventional class I RNRs to initiate substrate radical production. The intermediate decays by reduction of the Fe site to the active MnIV/FeIII-R2 complex. The reaction of the MnII/FeII-R2 species with H2O2 proceeds in three resolved steps: sequential oxidation to MnIII/FeIII-R2 and Mn(IV)/Fe(IV)-R2, followed by decay of the intermediate to the active Mn(IV)/Fe(III)-R2 product, kinetics and reaction mechanism, overview
manganese-iron cofactor
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the class Ic RNR from Chlamydia trachomatis uses a MnIV/FeIII cofactor, with high specificity for MnIV in place of the tyrosyl radical for radical initiation, R2 is activated when its MnII/FeII form reacts with O2 to generate a MnIV/FeIV intermediate, which decays by reduction of the FeIV site to the active MnIV/FeIII state, the reduction step in this sequence is mediated by residue Y222, overview
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Fe2+
unusual cofactor instead of Fe-Fe cofactor in other RNRs. Assembly, maintenance, and role in catalysis of the MnIV/FeIII cofactor of Ctbeta2 subunit, structure modelling, detailed overview
Mn2+
unusual cofactor instead of Fe-Fe cofactor in other RNRs. Assembly, maintenance, and role in catalysis of the MnIV/FeIII cofactor of Ctbeta2 subunit, structure modelling, detailed overview
Fe2+
Iron
Manganese
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the class Ic RNR from Chlamydia trachomatis uses a Mn(IV)/Fe(III) cofactor, with high specificity for Mn(IV) in place of the Y for radical initiation, R2 is activated when its MnII/FeII form reacts with O2 to generate a MnIV/FeIV intermediate, which decays by reduction of the FeIV site to the active Mn(IV)/Fe(III) state, the reduction step in this sequence is mediated by residue Y222, overview
Mg2+
Mn2+
Fe2+
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the manganese- and iron content of the R2 subunit decides about the enzyme activity, determination of metal contents, overview
Fe2+
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metal content determination of oxidized and reduced subunit R2, electronic features and nuclear geometry of the manganese and iron sites, kinetics, overview. The R2 protein of class I RNR contains a Mn-Fe instead of the standard Fe-Fe cofactor. Ct R2 has a redox-inert phenylalanine replacing the radical-forming tyrosine of classic RNRs, which implies a different mechanism of O2 activation, overview. Structure modelling
Iron
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initiator of catalysis is the paramagnetic Fe(III)Fe(IV) state of the iron cluster. Proposition of reaction scheme of the iron site
Iron
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the class Ic RNR from Chlamydia trachomatis uses a Mn(IV)/Fe(III) cofactor, with high specificity for Mn(IV) in place of the Y for radical initiation, R2 is activated when its MnII/FeII form reacts with O2 to generate a MnIV/FeIV intermediate, which decays by reduction of the FeIV site to the active Mn(IV)/Fe(III) state, the reduction step in this sequence is mediated by residue Y222, overview
Mn2+
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the manganese- and iron content of the R2 subunit decides about the enzyme activity, determination of metal contents, overview
Mn2+
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metal content determination of oxidized and reduced subunit R2, electronic features and nuclear geometry of the manganese and iron sites, kinetics, overview. The R2 protein of class I RNR contains a Mn-Fe instead of the standard Fe-Fe cofactor. Ct R2 has a redox-inert phenylalanine replacing the radical-forming tyrosine of classic RNRs, which implies a different mechanism of O2 activation, overview. Structure modelling
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Hydroxyurea
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inhibition of the enzyme by the 1-electron donor hydroxyurea produces the Mn(III)Fe(III) state
Hydroxyurea
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inactivates both Ia/b and Ic beta2 subunits by reducing their C oxidants, reacts with the MnIV/FeIII cofactor to give two distinct products: the homogeneous MnIII/FeIII-beta2 complex, which forms only under turnover conditions, in the presence of alpha2 and the substrate, and a distinct, diamagnetic Mn/Fe cluster, which forms about 900fold less rapidly as a second phase in the reaction under turnover conditions and as the sole outcome in the reaction of MnIV/FeIII-beta2 only
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
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the R2 protein of class I RNR contains a Mn-Fe instead of the standard Fe-Fe cofactor. Ct R2 has a redox-inert phenylalanine replacing the radical-forming tyrosine of classic RNRs, which implies a different mechanism of O2 activation, overview
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
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enzyme redox states, overview
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.048
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recombinant DELTA1-248 R1 subunit, CDP reduction in the presence of ATP
additional information
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activities of recombinant wild-type R1/R2 and chimeric wild-type R2 with truncated R1 mutant DELTA1-248
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
PDB
SCOP
CATH
UNIPROT
ORGANISM
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
tetramer
additional information
additional information
interaction of the alpha2 and beta2 subunits during the reaction, comparison to the RNR from Escherichia coli, overview
additional information
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interaction of the alpha2 and beta2 subunits during the reaction, comparison to the RNR from Escherichia coli, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
subunit R2, X-ray diffraction structure determination and analysis at 2.75-2.90 A resolution
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PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
W51F
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site-directed mutagenesis, the decay of the Mn(IV)/Fe(IV) intermediate is slightly affected
Y222F
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the substitution by site-directed mutagenesis retards the intrinsic decay of the Mn(IV)/Fe(IV) intermediate by about 10fold and diminishes the ability of ascorbate to accelerate the decay by about 65fold but has no detectable effect on the catalytic activity of the Mn(IV)/Fe(III)-R2 product
Y338F
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site-directed mutagenesis, substitution of Y338, the cognate of the subunit interfacial R2 residue in the R1 S R2 PCET pathway of the conventional class I RNRs, has almost no effect on decay of the Mn(IV)/Fe(IV) intermediate but abolishes catalytic activity
additional information
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construction of truncated R1 mutant DELTA1-248
OXIDATION STABILITY
ORGANISM
UNIPROT
LITERATURE
the enzyme is not stable to to reactive oxygen and nitrogen species, RO(N)S, produced by the hosts immune system
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685235
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant wild-type R1 and R2 subunits and F127Y, Y129F and F127Y/Y129F R2 mutant subunits
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CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
expression of wild-type and amino terminal deleted DELTA1-248 R1 subunit and wild-type, F127Y, Y129F and F127Y/Y129F mutant R2 subunit in Escherichia coli
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expression of wild-type R2 and R1 and of truncated R1 mutant DELTA1-248 in Escherichia coli
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overexpression of wild-type and mutant R2 subunits in Escherichia coli strain BL21(DE3)
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pharmacology
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inhibition of RNRs is a proven strategy for combating cancer and some viruses
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Roshick, C.; Iliffe-Lee, E.R.; McClarty, G.
Cloning and characterization of ribonucleotide reductase from chlamydia trachomatis
J. Biol. Chem.
275
38111-38119
2000
Chlamydia trachomatis
Voevodskaya, N.; Narvaez, A.J.; Domkin, V.; Torrents, E.; Thelander, L.; Graeslund, A.
Chlamydial ribonucleotide reductase: tyrosyl radical function in catalysis replaced by the FeIII-FeIV cluster
Proc. Natl. Acad. Sci. USA
103
9850-9854
2006
Chlamydia trachomatis
Jiang, W.; Xie, J.; N?rgaard, H.; Bollinger, J.M.; Krebs, C.
Rapid and quantitative activation of Chlamydia trachomatis ribonucleotide reductase by hydrogen peroxide
Biochemistry
47
4477-4483
2008
Chlamydia trachomatis
Jiang, W.; Saleh, L.; Barr, E.W.; Xie, J.; Gardner, M.M.; Krebs, C.; Bollinger, J.M.
Branched activation- and catalysis-specific pathways for electron relay to the manganese/iron cofactor in ribonucleotide reductase from Chlamydia trachomatis
Biochemistry
47
8477-8484
2008
Chlamydia trachomatis
Voevodskaya, N.; Lendzian, F.; Ehrenberg, A.; Graeslund, A.
High catalytic activity achieved with a mixed manganese-iron site in protein R2 of Chlamydia ribonucleotide reductase
FEBS Lett.
581
3351-3355
2007
Chlamydia trachomatis
Jiang, W.; Yun, D.; Saleh, L.; Bollinger, J.M.; Krebs, C.
Formation and function of the manganese(IV)/iron(III) cofactor in Chlamydia trachomatis ribonucleotide reductase
Biochemistry
47
13736-13744
2008
Chlamydia trachomatis (O84835), Chlamydia trachomatis, Escherichia coli (P69924)
Voevodskaya, N.; Lendzian, F.; Sanganas, O.; Grundmeier, A.; Graeslund, A.; Haumann, M.
Redox intermediates of the Mn-Fe Site in subunit R2 of Chlamydia trachomatis ribonucleotide reductase: an X-ray absorption and EPR study
J. Biol. Chem.
284
4555-4566
2009
Chlamydia trachomatis
Jiang, W.; Xie, J.; Varano, P.T.; Krebs, C.; Bollinger, J.M.
Two distinct mechanisms of inactivation of the class Ic ribonucleotide reductase from Chlamydia trachomatis by hydroxyurea: implications for the protein gating of intersubunit electron transfer
Biochemistry
49
5340-5349
2010
Chlamydia trachomatis
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