Information on EC 1.17.4.2 - ribonucleoside-triphosphate reductase

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The enzyme appears in viruses and cellular organisms

EC NUMBER
COMMENTARY hide
1.17.4.2
-
RECOMMENDED NAME
GeneOntology No.
ribonucleoside-triphosphate reductase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
2'-deoxyribonucleoside triphosphate + thioredoxin disulfide + H2O = ribonucleoside triphosphate + thioredoxin
show the reaction diagram
requires a cobamide coenzyme and ATP
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
redox reaction
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
adenosine deoxyribonucleotides de novo biosynthesis II
-
-
guanosine deoxyribonucleotides de novo biosynthesis II
-
-
Metabolic pathways
-
-
purine metabolism
-
-
Purine metabolism
-
-
pyrimidine deoxyribonucleotides de novo biosynthesis II
-
-
Pyrimidine metabolism
-
-
superpathway of pyrimidine deoxyribonucleotides de novo biosynthesis (E. coli)
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-
SYSTEMATIC NAME
IUBMB Comments
2'-deoxyribonucleoside-triphosphate:thioredoxin-disulfide 2'-oxidoreductase
Requires a cobamide coenzyme and ATP.
CAS REGISTRY NUMBER
COMMENTARY hide
9068-66-0
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
-
-
Manually annotated by BRENDA team
strain 7119
-
-
Manually annotated by BRENDA team
Astasia sp.
euglenoid flagellate
-
-
Manually annotated by BRENDA team
strain KM
-
-
Manually annotated by BRENDA team
strain KM
-
-
Manually annotated by BRENDA team
J-10-fl (ATCC 29366)
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
strain R1, ATCC 13939
-
-
Manually annotated by BRENDA team
JM109
-
-
Manually annotated by BRENDA team
strain Z
-
-
Manually annotated by BRENDA team
strain Z
-
-
Manually annotated by BRENDA team
Euglena sp.
euglenoid flagellate
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
-
-
-
Manually annotated by BRENDA team
industrial strain BMK
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-
Manually annotated by BRENDA team
strain MSB8 (DSM3109)
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-
Manually annotated by BRENDA team
strain X1
-
-
Manually annotated by BRENDA team
strain YT-1
-
-
Manually annotated by BRENDA team
X-1
-
-
Manually annotated by BRENDA team
X-1
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
-
RNR is the rate-limiting enzyme in deoxyribonucleoside triphosphate, dNTP, biosynthesis
physiological function
additional information
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
2'-deoxyribonucleoside triphosphate + oxidized thioredoxin + H2O
ribonucleoside triphosphate + reduced thioredoxin
show the reaction diagram
-
-
-
-
r
ADP + reduced thioredoxin
dADP + oxidized thioredoxin + H2O
show the reaction diagram
ATP + reduced thioredoxin
dATP + oxidized thioredoxin + H2O
show the reaction diagram
CDP + reduced dithiothreitol
dCDP + oxidized dithiothreitol + H2O
show the reaction diagram
CDP + reduced thioredoxin
dCDP + oxidized thioredoxin + H2O
show the reaction diagram
CMP + reduced thioredoxin
dCMP + oxidized thioredoxin + H2O
show the reaction diagram
CTP + adenosylcobalamin
?
show the reaction diagram
-
-
-
-
?
CTP + reduced thioredoxin
dCTP + oxidized thioredoxin + H2O
show the reaction diagram
CTP + reduced thioredoxin
dCTP + thioredoxin disulfide + H2O
show the reaction diagram
dATP + adenosylcobalamin
?
show the reaction diagram
-
-
-
-
?
GDP + reduced thioredoxin
dGDP + oxidized thioredoxin + H2O
show the reaction diagram
GTP + reduced thioredoxin
dGTP + oxidized thioredoxin + H2O
show the reaction diagram
IDP + reduced thioredoxin
dIDP + oxidized thioredoxin
show the reaction diagram
-
-
-
-
?
ITP + reduced thioredoxin
dITP + oxidized thioredoxin
show the reaction diagram
-
-
-
-
?
nucleoside 5'-triphosphate + formate
2'-deoxynucleoside 5'-triphosphate + H2O
show the reaction diagram
nucleoside 5'-triphosphate + thioredoxin
2'-deoxynucleoside 5'-triphosphate + thioredoxin disulfide + H2O
show the reaction diagram
ribonucleoside triphosphate + 2-hydroxyethyl disulfide
2'-deoxyribonucleoside triphosphate + 2-mercaptoethanol + H2O
show the reaction diagram
-
-
-
-
?
ribonucleoside triphosphate + dihydrolipoate
2'-deoxyribonucleoside triphosphate + lipoate + H2O
show the reaction diagram
ribonucleoside triphosphate + dithioerythritol
2'-deoxyribonucleoside triphosphate + ? + H2O
show the reaction diagram
ribonucleoside triphosphate + dithiothreitol
2'-deoxyribonucleoside triphosphate + ? + H2O
show the reaction diagram
ribonucleoside triphosphate + GSSG
2'-deoxyribonucleoside triphosphate + GSH + H2O
show the reaction diagram
ribonucleoside triphosphate + NADP+
2'-deoxyribonucleoside triphosphate + NADPH + H2O
show the reaction diagram
-
-
-
-
?
ribonucleoside triphosphate + R(SH)2
deoxyribonucleoside triphosphate + RS2 + H2O
show the reaction diagram
ribonucleoside triphosphate + reduced thioredoxin
2'-deoxyribonucleoside triphosphate + oxidized thioredoxin + H2O
show the reaction diagram
ribonucleoside triphosphate + reduced thioredoxin + H2O
2'-deoxyribonucleoside triphosphate + oxidized thioredoxin + H2O
show the reaction diagram
ribonucleoside triphosphate + thioredoxin
2'-deoxyribonucleoside triphosphate + thioredoxin disulfide + H2O
show the reaction diagram
-
-
-
-
?
UDP + reduced thioredoxin
dUDP + oxidized thioredoxin + H2O
show the reaction diagram
UMP + reduced thioredoxin
dUMP + oxidized thioredoxin + H2O
show the reaction diagram
-
-
-
-
?
UTP + reduced thioredoxin
dUTP + oxidized thioredoxin + H2O
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
2'-deoxyribonucleoside triphosphate + oxidized thioredoxin + H2O
ribonucleoside triphosphate + reduced thioredoxin
show the reaction diagram
-
-
-
-
r
nucleoside 5'-triphosphate + formate
2'-deoxynucleoside 5'-triphosphate + H2O
show the reaction diagram
nucleoside 5'-triphosphate + thioredoxin
2'-deoxynucleoside 5'-triphosphate + thioredoxin disulfide + H2O
show the reaction diagram
ribonucleoside triphosphate + reduced thioredoxin + H2O
2'-deoxyribonucleoside triphosphate + oxidized thioredoxin + H2O
show the reaction diagram
ribonucleoside triphosphate + thioredoxin
2'-deoxyribonucleoside triphosphate + thioredoxin disulfide + H2O
show the reaction diagram
-
-
-
-
?
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
5'-deoxyadenosylcobalamin
5,6-dimethylbenzimidazolycobamide
-
-
adenosylcobalamin
Coalpha-(aden-9-yl)-Cobeta-adenosylcobamide
-
-
Coalpha-(benzimidazolyl)-Cobeta-adenosylcobamide
-
-
Cobalamin
coenzyme B12
dihydrolipoate
-
-
NADPH
-
can utilize NADPH as hydrogen donor for ribonucleotide reduction
S-adenosyl-L-methionine
thioredoxin
additional information
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Cs+
-
activating effect
K+
-
activating effect
Li+
-
activating effect
Mn2+
-
stimulates enzyme activity
Na+
-
activating effect
NH4+
-
activating effect
Rb+
-
activating effect
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2',2'-difluoro-2'-deoxycytidine 5'-triphosphate
2'-chloro-2'-deoxy-UTP
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-
2'-deoxyadenosylcobalamin
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-
3,3',4,4',5,5'-hexahydroxy-trans-stilbene
-
i.e. M8, a resveratrol analogue, inhibits the enzyme and causes an imbalance of intracellular dNTP pools, the dATP pool is eliminated, while the dCTP and dTTP pools are enlarged. M8 leads to complete growth inhibition of HT-29 cells at 0.015 mM within 7 days, overview
3-aminopyridine-2-carboxaldehyde thiosemicarbazone
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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
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
3-isoadenosylcobalamin
-
-
-
adenosylcobalamin
-
-
caracemide
chlorambucil
cisplatin
cob(II)alamin
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-
cyanocobalamin
-
-
gallic acid
-
inhibition of enzyme activity and induction of dose-dependent apoptosis and attenuated progression from G0/G1 to S phase of cells cycle. Highly synergistic effects of simultaneous treatment of cells with gallic acid and enzyme inhibitor N',3,4,5-tetrahydroxybenzenecarboximidamide
gemcitabine
Hydroxyurea
isopropylideneadenosylcobalamin
-
-
Mg2+
-
strongly inhibitory in absence of ATP
N',3,4,5-tetrahydroxybenzenecarboximidamide
-
i.e. trimidox, highly synergistic effects of simultaneous treatment of cells with inhibitors gallic acid and trimidox
N-hydroxy-N'-(3,4,5-trimethoxyphenyl)-3,4,5-trimethoxybenzamidine
-
a resveratrol analogue, inhibits the enzyme in HL-60 cells showing synergistic effects with arabinofuranosylcytosine in antitumor activity, overview
nebularylcobalamin
-
-
signalosome protein complex COP9
i.e. CSN, is a negative regulator of RNR2 activity in Arabidopsis thaliana. The pleiotropic regulator of plant development and contains eight-subunits, RNR2 binds to the C-terminus of subunit 7, CSN7; i.e. CSN, is a negative regulator of RNR2 activity in Arabidopsis thaliana. The pleiotropic regulator of plant development and contains eight-subunits, RNR2 binds to the C-terminus of subunit 7, CSN7
-
triapine
tubercidylcobalamin
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-
[3-(adenosin-5'-O-yl)propyl]cobalamin
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[4-(adenosin-5'-O-yl)butyl]cobalamin
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-
[5-(adenosin-5'-O-yl)pentyl]cobalamin
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-
[6-(adenosin-5'-O-yl)hexyl]cobalamin
-
-
[7-(adenosin-5'-O-yl)heptyl]cobalamin
-
-
[omega-(adenosin-5'-O-yl)alkyl]cobalamin
-
-
additional information
-
no enzyme inhibition by arabinoside cytosine
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2',5'-dideoxyadenosylcobalamin anilide
-
-
2-mercaptoethanol
-
-
5'-deoxy-5'-adenosylcobalamin
-
-
5'-deoxyadenosylcobalamin
5'-deoxyadenosylcobalamin anilide
-
-
5'-deoxyuridylcobalamin
-
-
cyanocobalamin
-
-
cyanocobalamin anilide
-
-
cyanocobalamin dibasic acid
-
-
-
cyanocobalamin ethylamide
-
-
-
cyanocobalamin monobasic acid
-
-
-
ethyl cobalamin
-
-
hydroxocobalamin
-
-
hydroxocobalamin methylamide
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-
methyl cobalamin
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NADPH
-
stimulates reductase activity in crude extracts
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0003 - 0.06
adenosylcobalamin
0.08
ADP
-
in presence of effector dGTP
0.015 - 2.3
ATP
0.11
CDP
-
presence of effector dATP
0.01 - 9.5
CTP
0.09 - 0.99
GTP
0.01
UTP
-
immobilized enzyme
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0145
ATP
Lactobacillus leichmannii
-
-
0.00367 - 0.03
CTP
0.0158
UTP
Lactobacillus leichmannii
-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0143 - 0.0208
cob(II)alamin
0.0426
cyanocobalamin
-
-
0.0558
[3-(adenosin-5'-O-yl)propyl]cobalamin
-
-
0.0189
[4-(adenosin-5'-O-yl)butyl]cobalamin
-
-
0.0077
[5-(adenosin-5'-O-yl)pentyl]cobalamin
-
-
0.0246
[6-(adenosin-5'-O-yl)hexyl]cobalamin
-
-
0.0128
[7-(adenosin-5'-O-yl)heptyl]cobalamin
-
-
additional information
additional information
-
inhibition kinetics with gemcitabine
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SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
77.25
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-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.8 - 8.4
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-
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
20 - 80
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SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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fibroblast cell, non-dividing cells expressing enzyme subunit p53R2, but not sunit R2 protein, have reduced dNTP levels if exposed to the enzyme--specific inhibitor hydroxyurea. After DNA damage, a slow, up to 4fold increase in p53R2 expression leads to 3fold increase in dNTP pools in G0/G1 cells
Manually annotated by BRENDA team
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significant induction of subunit R2 following blood feeding
Manually annotated by BRENDA team
-
isozymes R2 and p53R2
Manually annotated by BRENDA team
subunit R2 isoforms TSO2 and RNR2A
Manually annotated by BRENDA team
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colon cancer cell. Cell line expresses subunit R2 in excess resulting in protection against DNA damage and replication stress
Manually annotated by BRENDA team
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oropharyngeal epidermal carcinoma cell line. At G1/S phase transition, level of p53-dependent small enzyme subunit M2B increases to maximum levles, and decreases with DNA synthesis. In response to DNA replication, subunit M2B redistributes from the cytoplasm to the nucleus earlier than small subunit M2
Manually annotated by BRENDA team
cauline leaf, subunit R2 isoforms TSO2 and RNR2A
Manually annotated by BRENDA team
-
higest expression of subunit R2 in ovary of blood-fed or sugar-fed animals. Significant induction following blood feeding
Manually annotated by BRENDA team
subunit R2 isoform TSO2
Manually annotated by BRENDA team
subunit R2 isoforms TSO2 and RNR2A
Manually annotated by BRENDA team
subunit R2 isoforms TSO2 and RNR2A
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
PDB
SCOP
CATH
ORGANISM
UNIPROT
Thermotoga maritima (strain ATCC 43589 / MSB8 / DSM 3109 / JCM 10099)
Thermotoga maritima (strain ATCC 43589 / MSB8 / DSM 3109 / JCM 10099)
Thermotoga maritima (strain ATCC 43589 / MSB8 / DSM 3109 / JCM 10099)
Thermotoga maritima (strain ATCC 43589 / MSB8 / DSM 3109 / JCM 10099)
Thermotoga maritima (strain ATCC 43589 / MSB8 / DSM 3109 / JCM 10099)
Thermotoga maritima (strain ATCC 43589 / MSB8 / DSM 3109 / JCM 10099)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
69300
-
enzyme in 6 M guanidine-HCl, 0.1 M dithiothreitol, equilibrium ultracentrifugation
72000
-
gel filtration
72500
-
native enzyme in 0.1 M glycine buffer, pH 9.1, equilibrium ultracentrifugation
72600
-
maleated enzyme in 0.05 M phosphate buffer, equilibrium ultracentrifugation
74500
-
enzyme in 6 M guanidine-HCl, 0.1 M dithiothreitol, heated for 20 min at 60C, equilibrium ultracentrifugation
75300
-
native enzyme in 0.05 M phosphate buffer, pH 7.0, sedimentation equilibrium method
80000
-
gel filtration
81800
-
MALDI-TOF mass spectrometry
81850
-
predicted molecular weight based on the predicted amino acid sequence from the sequenced gene
100000
-
size exclusion chromatography, SDS-PAGE
107000
-
deduced amino acid sequence
110000
-
sedimentation equilibrium analysis
140000 - 150000
-
-
240000 - 278000
-
-
440000
-
gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
monomer or dimer
tetramer
additional information
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
enzyme in complex with dATP, DTTP, dGTP, dTTP-GDP, dGTP-ADP, dATP-CDP or dATP-UDP
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
fairly stable under conditions of storage, losing only about 23% of its activity in 15 months
-
immobilization stabilizes the enzyme substantially, compared with free enzyme, which has an inactivation half-life of less than 1 day, on immobilization the inactivation half-life is about 15 days
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-100C, may be stored as frozen paste for at least 3 months without significant loss of activity
-
-20C, crude extracts relatively unstable, most of the activity disappears within a few weeks
-
-65C, no detectable loss of enzyme has been observed during several years of storage of packed bacteria
-
0-4C, acetone and hydroxylapatite fractions are quite stable, at least 70-80% of their activities remain after 3 months
-
0-4C, crude extracts relatively unstable, most of the activity disappears within a few weeks
-
20C, 0.03 M dimethylglutarate buffer, pH 7.2, remains fully active on storage for 24 h
-
Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
from overexpressing Escherichia coli cells
-
partially
-
recombinant RNR2 from transgenic Arabidopsis thaliana plants by affinity chromatography; recombinant RNR2 from transgenic Arabidopsis thaliana plants by affinity chromatography
wild-type and mutant enzymes
-
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
chromosomal DNA containg RNR gene PCR amplified, gene cloned, completely sequenced and expressed in Escherichia coli
-
cloned by PCR from peptide sequence information
-
cloned by PCR from peptide sequence information, nrdj gene sequenced completely and expressed in Escherichia coli BL21(DE3)
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cloning, sequencing and expression of the protein
-
gene encoding p53R2 genotyping, real-time RT-PCR expression analysis
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high-level overexpression of RNR subunits, Rrm1, Rrm2 and p53R2, separately or in different combinations, in mice, simultaneous expression of two RNR subunits
-
overexpressed in Escherichia coli
-
subunit R2
-
the nrdDG promoter regulates transcriptional expression of the anaerobic ribonucleotide reductase of Escherichia coli, binding of the pleiotropic FNR, fumarate and nitrate reduction, transcriptional regulator to the nrdDG promoter region affects the transcription, the upstream FNR-2 site is essential for anaerobic activation of the nrdDG promoter. Although the FNR-1 site is not absolutely required, it allows maximal expression of this promoter, overview
-
two-hybrid interaction analysis of CSN7 and RNR2 expressing the vectors under control of the 35S promoter in Nicotiana benthamiana cells, transgenic expression of RNR2 in Arabidopsis thaliana plants; two-hybrid interaction analysis of CSN7 and RNR2 expressing the vectors under control of the 35S promoter in Nicotiana benthamiana cells, transgenic expression of RNR2 in Arabidopsis thaliana plants
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
endogenous RNR transcripts are downregulated in response to large increases of mtDNA in mice, which is indicative of nuclear-mitochondrial crosstalk with regard to mtDNA copy number
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
C644A
-
mutant enzyme is devoid of significant activity
C647A
-
mutant enzyme displays 2% of wild-type activity
C662A
-
mutant enzyme is devoid of significant activity
C665A
-
mutant enzyme is devoid of significant activity
C644A
-
mutant enzyme is devoid of significant activity
-
C647A
-
mutant enzyme displays 2% of wild-type activity
-
C662A
-
mutant enzyme is devoid of significant activity
-
C665A
-
mutant enzyme is devoid of significant activity
-
C119S
-
site-directed mutagenesis
C408A
-
only wild-type enzyme catalyzes epimerization of the (5'S)-[5'-2H1]- and (5'R)-[5'-2H1]-isotopomers of adenosylcobalamin, no activity of mutant enzyme
C408S
-
only wild-type enzyme catalyzes epimerization of the (5'S)-[5'-2H1]- and (5'R)-[5'-2H1]-isotopomers of adenosylcobalamin, no activity of mutant enzyme
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
development of a rapid freeze-quench apparatus for the preparation of millisecond quench time rapid freeze-quench samples which can be packed into small sample tubes used for continuous-wave and pulsed high-frequency electron paramagnetic resonance spectroscopy
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