Information on EC 2.4.2.17 - ATP phosphoribosyltransferase

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The expected taxonomic range for this enzyme is: Eukaryota, Bacteria

EC NUMBER
COMMENTARY hide
2.4.2.17
-
RECOMMENDED NAME
GeneOntology No.
ATP phosphoribosyltransferase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
1-(5-phospho-beta-D-ribosyl)-ATP + diphosphate = ATP + 5-phospho-alpha-D-ribose 1-diphosphate
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pentosyl group transfer
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
Biosynthesis of secondary metabolites
-
-
histidine metabolism
-
-
Histidine metabolism
-
-
L-histidine biosynthesis
-
-
Metabolic pathways
-
-
SYSTEMATIC NAME
IUBMB Comments
1-(5-phospho-D-ribosyl)-ATP:diphosphate phospho-alpha-D-ribosyl-transferase
Involved in histidine biosynthesis.
CAS REGISTRY NUMBER
COMMENTARY hide
9031-46-3
-
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
metabolism
essential for histidine biosynthesis
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + 5-phospho-alpha-D-ribose 1-diphosphate
1-(5-phospho-alpha-D-ribosyl)-ATP + diphosphate
show the reaction diagram
ATP + 5-phospho-alpha-D-ribose 1-diphosphate
1-(5-phospho-D-ribosyl)-ATP + diphosphate
show the reaction diagram
ATP + 5-phospho-alpha-D-ribose 1-diphosphate
diphosphate + N-1-(5'-phosphoribosyl)-ATP
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
ATP + 5-phospho-alpha-D-ribose 1-diphosphate
1-(5-phospho-D-ribosyl)-ATP + diphosphate
show the reaction diagram
ATP + 5-phospho-alpha-D-ribose 1-diphosphate
diphosphate + N-1-(5'-phosphoribosyl)-ATP
show the reaction diagram
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
maximal activity is achieved when the concentration of free magnesium reaches about 2 mM, concentrations higher than 5 mM lead to inhibition perhaps due to the formation of MgATP2- complex
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(4E)-4-[(4-chlorophenyl)(hydroxy)methylidene]-1-(pyridin-3-ylmethyl)-5-(3,4,5-trimethoxyphenyl)pyrrolidine-2,3-dione
binds to the cavity between the domains I and II. The terminal chlorobenzoyl group of 1 makes hydrophobic interactions with the amphiphilic pocket near the phosphoribosyl pyrophosphate binding site
1,2,4-Triazole-3-alanine
;
1-(5-phospho-alpha-D-ribosyl)-ATP
-
product inhibition, competitive to both substrates
1-[(5,6-diphenyl-1,2,4-triazin-3-yl)sulfanyl]-3-(1,3-thiazol-2-yl)propan-2-one
most potent inhibitor, spans the PR-ATP binding site, exhibits greater than 50% inhibition at 0.01 mM, 40% inhibition at 0.001 mM
2-([7-[(3-hydroxyphenyl)amino]-4-nitro-2,1,3-benzoxadiazol-5-yl]amino)-5-nitrophenol
2-[(2-bromo-3,5-dinitrophenyl)carbonyl]-N-phenylhydrazinecarboxamide
4-methoxybenzyl 2-methyl-5-oxo-4,7-dithiophen-2-yl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
interacts with the phosphoribosyl diphosphate binding site but less strongly compared to compound 6 , exhibits greater than 50% inhibition at 0.01 mM
5-phospho-alpha-D-ribose 1-diphosphate
-
noncompetitive inhibitor with respect to both substrates in the reaction producing ATP and 5-phospho-alpha-D-ribose 1-diphosphate
adenine
-
competitive to ATP and 5-phospho-alpha-D-ribose 1-diphosphate
ATP
-
inhibits the reaction at high concentrations
beta,gamma-methylene-ATP
-
competitive with respect to N-1-(5-phosphoribosyl)-ATP, noncompetitive with respect to diphosphate; inhibitor of the reaction producing ATP and 5-phospho-alpha-D-ribose 1-diphosphate
Ca2+
moderate inhibitory effect
dicoumarol
-
competitive with respect to ATP, inhibitor in both directions, diminishes yield of phosphoribosyladenosine triphosphate by acting as parasite substrate
Dinitrophenol
-
diminishes yield of phosphoribosyladenosine triphosphate by acting as parasite substrate
diphosphate
-
non competitive to both substrates
ethyl [(6-nitro-1,3-benzothiazol-2-yl)amino](oxo)acetate
exhibits 39% inhibition
Guanosine 5'-diphosphate-3'-diphosphate
-
in presence of partially inhibiting concentrations of histidine guanosine 5'-diphosphate-3'-diphosphate becomes a potent inhibitor of the residual activity of ATP phosphoribosyltransferase, no inhibition in absence of histidine, inhibition is slowly reversible
histidine
L-histidine
Mg2+
-
at high concentrations, Ki = 23 mM
Mn2+
moderate inhibitory effect
N-[3-[(6-nitro-1,3-benzothiazol-2-yl)amino]-3-oxo-1-phenylpropyl]benzamide
occupies only the phosphoribosyl diphosphate binding site, exhibits greater than 50% inhibition at 0.01 mM, 35% inhibition at 0.001 mM
Pentachlorophenol
-
competitive to ATP, inhibitor in both directions, diminishes yield of phosphoribosyladenosine triphosphate by acting as parasite substrate
additional information
-
carbonylcyanide m-chlorophenylhydrazone, which is a potent inhibitor of several enzymes with adenine-containing substrates or coenzymes has no effect
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
ATP
-
binding activates the enzyme complex to the R-state
potassium chloride
-
stimulates ATP-PRT activity in crude extracts, adding KCl to a final concentration of 0.13 M in reaction mixture increases the reaction rate by about 40%
additional information
-
other salts like ammonium sulfate or ammonium chloride show the same effect as KCl
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0184 - 37
5-phospho-alpha-D-ribose 1-diphosphate
0.2 - 89
ATP
additional information
additional information
-
steady-state kinetics
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TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.84 - 6.16
5-phospho-alpha-D-ribose 1-diphosphate
additional information
5-phospho-alpha-D-ribose 1-diphosphate
Lactococcus lactis
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25C, pH 8, mutant enzyme K50A
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.002
1-[(5,6-diphenyl-1,2,4-triazin-3-yl)sulfanyl]-3-(1,3-thiazol-2-yl)propan-2-one
-
0.88
ADP
wild type protein, pH 8.5, temperature not specified in the publication
1.29 - 1.44
AMP
0.0811
histidine
-
25C, pH 8
0.004 - 4.15
L-histidine
0.002
N-[3-[(6-nitro-1,3-benzothiazol-2-yl)amino]-3-oxo-1-phenylpropyl]benzamide
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0119
(4E)-4-[(4-chlorophenyl)(hydroxy)methylidene]-1-(pyridin-3-ylmethyl)-5-(3,4,5-trimethoxyphenyl)pyrrolidine-2,3-dione
Mycobacterium tuberculosis
P9WMN1
-
0.004
1-[(5,6-diphenyl-1,2,4-triazin-3-yl)sulfanyl]-3-(1,3-thiazol-2-yl)propan-2-one
Mycobacterium tuberculosis
P9WMN1
-
0.0139
2-[(2-bromo-3,5-dinitrophenyl)carbonyl]-N-phenylhydrazinecarboxamide
Mycobacterium tuberculosis
P9WMN1
-
0.0055
4-methoxybenzyl 2-methyl-5-oxo-4,7-dithiophen-2-yl-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate
Mycobacterium tuberculosis
P9WMN1
-
0.033
L-histidine
Mycobacterium tuberculosis
-
pH 8.5, 25C
0.006
N-[3-[(6-nitro-1,3-benzothiazol-2-yl)amino]-3-oxo-1-phenylpropyl]benzamide
Mycobacterium tuberculosis
P9WMN1
-
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.39
N215K/L231F/T235A/A270P mutant protein, pH 8.5, temperature not specified in the publication
1.96
A270P mutant protein, pH 8.5, temperature not specified in the publication
2.01
N215K mutant protein, pH 8.5, temperature not specified in the publication
2.04
L231F/T235A mutant protein, pH 8.5, temperature not specified in the publication
2.1
N215K/L231F/T235A mutant protein, pH 8.5, temperature not specified in the publication
2.19
wild type protein, pH 8.5, temperature not specified in the publication
additional information
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.5 - 13
>40% relative activity, rapid loss of activity below pH 7.5
TEMPERATURE RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
PDB
SCOP
CATH
ORGANISM
UNIPROT
Bacillus subtilis (strain 168)
Campylobacter jejuni (strain RM1221)
Campylobacter jejuni (strain RM1221)
Campylobacter jejuni (strain RM1221)
Escherichia coli (strain K12)
Escherichia coli (strain K12)
Lactococcus lactis subsp. lactis (strain IL1403)
Lactococcus lactis subsp. lactis (strain IL1403)
Methanothermobacter thermautotrophicus (strain ATCC 29096 / DSM 1053 / JCM 10044 / NBRC 100330 / Delta H)
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
Mycobacterium tuberculosis (strain ATCC 25618 / H37Rv)
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)
Thermus thermophilus (strain HB27 / ATCC BAA-163 / DSM 7039)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
44600
calculated mass from amino acid sequence
44800
calculated mass from amino acid sequence
63000
homodimer, gel filtration
180000
-
gel filtration
186000
-
dynamic light scattering in the presence of AMP or histidine
192000
homohexamer, gel filtration
200000 - 220000
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gel filtration
210000 - 221000
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sedimentation, equilibrium centrifugation with meniscus depletion method
216000
-
ultracentrifugation analysis
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
-
active form
hexamer
homodimer
2 * 32191, MALDI-TOF MS, gel filtration, theoretical molecular mass 31000
homohexamer
octamer
additional information
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
purified recombinant selenomethionine-labeled enzyme in complex with inhibitor AMP or with product 1-(5-phospho-D-ribosyl)-ATP, X-ray diffraction enzyme-inhibitor complex structure determination and analysis at 2.7 A resolution, X-ray diffraction enzyme-product complex structure determination and analysis at 2.9 A resolution, modeling
vapour diffusion method, trigonal prisms are obtained using 1.3 M sodium tartrate, 50-200 mM magnesium chloride, 100 mM citrate buffer pH 5.6 and enzyme in the presence of 2 mM AMP, round shaped crystals are obtained with 1.36-1.44 M ammonium sulfate, 0-0.3 M sodium chloride, 100 mM HEPES buffer pH 7.5 and enzyme in the presence of 2 mM AMP
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purified recombinant wild-type and selenomethionine-labeled enzyme complex, the latter additionally by microseeding, hanging drop vapour diffusion method, 0.002 ml well solution containing 15-25% v/v PEG 400, 0.1 M Tris-HCl, pH 7.5, 0.2 M MgCl2, mixed with equal volume of protein solution containing 10-16 mg/ml protein, 10 mM ATP, or 10 mM N-1-methyl-ATP and 5 mM 5-phospho-alpha-D-ribose 1-diphosphate, crystal growth is dependent on ATP or N-1-methyl-ATP, derivatization with 2.5 mM sodium tungstate dihydrate, cryoprotection with 17-18% glycerol, X-ray diffraction structure determination and analysis at 2.9-3.2 A resolution
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hanging drop vapour diffusion method at 16C, the apocrystals are obtained using 0.1 M buffer MES pH 6.5 and magnesium sulfate as precipitant, crystals in the presence of AMP and histidine are obtained using 0.1 M sodium citrate pH 5.6, 0.5 M ammonium sulfate and 1 M lithium sulfate with 5 mM AMP and 0.1 mM histidine
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HisG co-crystallized with compound 6, to 2.9 A resolution
purified recombinant wild-type and selenomethionine-labeled subunits HisGs and HisZ separately, in a binary complex with histidine, sitting drop vapour diffusion method, 0.002 ml of 8 mg/ml protein mixed with 0.002 ml reservoir solution containing 22.5% w/v methyl-2,4-pentanediol, 0.2 M phosphate/citrate buffer, pH 4.2, 2 days, X-ray diffraction structure determination and analysis at 2.5 A resolution, modeling
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pH STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
additional information
-
overview: stability at various pH-values
637669
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
45
-
very sensitive to heat inactivation, 0.4 mM histidine stabilizes the enzyme to inactivation by heat
47.5
-
1.9 mg enzyme/ml, 80 min, 75% loss of activity without addition of AMP, with 0.05 mM AMP about 60% loss of activity, with 0.5 mM AMP about 40% loss of activity, with 5 mM AMP about 25% loss of activity
48
-
3 mg enzyme/ml, 10 min, 15% remaining activity without addition of histidine, with 0.000086 mM histidine about 15% remaining activity after 15 min, with 0.00069 mM histidine about 70% remaining activity after 80 min, with 0.00345 mM histidine about 80% remaining activity after 80 min, with 0.0069 mM histidine about 55% remaining activity after 50 min
additional information
-
heat inactivation depends on protein concentration and inhibitors
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
histidine or AMP stabilizes the enzyme with respect to thermal inactivation
-
L-histidine, 0.4 mM, stabilizes against heat inactivation, 0.04 mM does not stabilize against heat inactivation, at 1.33 mM and higher heat inactivation is greater than the control
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NaCl and 2-mercaptoethanol stabilize the very labile enzyme
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overview, stability of the enzyme at various pH-values, salt concentrations and histidine concentrations
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slight stabilization by 10 mM MgCl2 or CaCl2 by 1 mM MnCl2 and by 1 mM histidine at pH-values above 7
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20C, 50 mM Tris-HCl, pH 7.5, 0.4 mM DTT and one protease inhibitor per litre, 50% v/v glycerol, long term storage
-
4C, 0.01 M Tris, 0.10 M NaCl, 0.4 mM histidine, 2.8 mM 2-mercaptoethanol, 0.5 mM EDTA, pH 7.5, 50% loss of activity after several days
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4C, HEPES buffer pH 7.5, final ammonium sulfate microcrystalline enzyme in 60% saturated ammonium sulfate, 0.1 M NaCl, 0.01 M Tris, 1.5 mM EDTA, 10 mM dithiothreitol, stable for 1 month, greater than 95% activity retained
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storage in liquid nitrogen of quick-frozen enzyme in HEPES buffer pH 7.5, 0.1 M NaCl, 0.01 M Tris, 0.5 mM EDTA, 1 mM dithiothreitol, 1 mM histidine, indefinitely stable, preserves 100% activity. The critical factor for stability seems to be the maintenance of a sulfhydryl-reducing environment, high dithiothreitol concentrations has no adverse effect at either 0C or 37C
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ammonium sulfate precipitation and DEAE-cellulose chromatography
-
centrifugation and DEAE-Sephacel anion-exchange column
-
first purification by heating the crude extract, ammonium sulfate precipitation and selective histidine-dependent ammonium sulfate precipitation
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immobilized metal ion affinity chromatography (Ni2+)
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immobilized metal ion affinity chromatography, gel filtration
Mn2+ precipitation, DEAE-cellulose and ammonium sulfate precipitation, later on Sephadex G-150
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nickel-nitrilotriacetic acid column, Sephadex G-200 later on
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recombinant selenomethionine-labeled enzyme from strain B834(DE3)
recombinant wild-type and selenomethionine-labeled enzyme complex comprising subunits HisGs and HisZ from Escherichia coli
-
recombinant wild-type and selenomethionine-labeled subunits HisGs and HisZ from Escherichia coli in a multistep procedure
-
the recombinant enzymes are produced as fused proteins with a maltose-binding protein, and the purification is made by a two step amylose resin column followed by a digestion with Factor Xa
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
codon adapted to Escherichia coli, synthetically prepared, His-tagged protein expressed in Escherichia coli BL21(DE3)pLysS
-
expressed in Escherichia coli
-
expression in Escherichia coli; expression in Escherichia coli
expression of selenomethionine-labeled enzyme in strain B834(DE3)
His-tagged protein expressed in Escherichia coli BL21(DE3)
overexpression of an Alyssum lesbiacum ATP-PRT cDNA in transgenic Arabidopsis thaliana increases the pool of free His up to 15fold in shoot tissue, without affecting the concentration of any other amino acid. His-overproducing lines also display elevated tolerance to Ni but do not exhibit increased Ni concentrations in either xylem sap or shoot tissue, suggesting that additional factors are necessary to recapitulate the complete hyperaccumulator phenotype
overexpression of an Alyssum lesbiacum ATP-PRT cDNA in transgenic Arabidopsis thaliana increases the pool of free His up to 15fold in shoot tissue, without affecting the concentration of any other amino acid. His-overproducing lines also display elevated tolerance to Ni but do not exhibit increased Ni concentrations in either xylem sap or shoot tissue, suggesting that additional factors are necessary to recapitulate the complete hyperaccumulator phenotype; overexpression of an Alyssum lesbiacum ATP-PRT cDNA in transgenic Arabidopsis thaliana increases the pool of free His up to 15fold in shoot tissue, without affecting the concentration of any other amino acid. His-overproducing lines also display elevated tolerance to Ni but do not exhibit increased Ni concentrations in either xylem sap or shoot tissue, suggesting that additional factors are necessary to recapitulate the complete hyperaccumulator phenotype
overexpression of subunits HisGs and HisZ comprising complex in Escherichia coli strain BL21(DE3) as wild-type, or in strain B834 as selenomethionine-labeled complex
-
separate expression of subunits HisGs and HisZ in Escherichia coli strain BL21(DE3) as wild-type, or in strain B834 as selenomethionine-labeled proteins
-
ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A270P
conserved residue
L231F/T235A
conserved residues
N215K
conserved residue
N215K/L231F/T235A
conserved residues, 37fold increase in Ki-value of histidine
N215K/L231F/T235A/A270P
conserved residues
D155A
-
slight increase in kcat, 3.9fold increase in KM-value for 5-phospho-alpha-D-ribose 1-diphosphate, 1.7fold increase in Km-value for ATP
E130A
-
site-directed mutagenesis, about 60% reduced activity compared to the wild-type enzyme, no inhibition by histidine
K50A
-
2.3fold increase in kcat, 51fold increase in KM-value for 5-phospho-alpha-D-ribose 1-diphosphate, 1.8fold increase in Km-value for ATP
K8A
-
2.5fold decrease in kcat, 4.9fold increase in KM-value for 5-phospho-alpha-D-ribose 1-diphosphate, 3.1fold increase in Km-value for ATP
S140A
-
mutant is unstable, kinetic parameters can not be determined
T159A
-
2.2fold decrease in kcat, 280fold increase in KM-value for 5-phospho-alpha-D-ribose 1-diphosphate, 2.5fold decrease in Km-value for ATP
T162A
-
3.2fold decrease in kcat, 49fold increase in KM-value for 5-phospho-alpha-D-ribose 1-diphosphate, 2.6fold decrease in Km-value for ATP
Y268F/Y269F
-
site-directed mutagenesis, about 30% reduced activity compared to the wild-type enzyme, no inhibition by histidine
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
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