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Information on EC 2.7.4.8 - guanylate kinase and Organism(s) Homo sapiens and UniProt Accession Q16774
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2.7.4.8 guanylate kinaseIUBMB Comments
dGMP can also act as acceptor, and dATP can act as donor.
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Word Map
- 2.7.4.8
- junction
- synapses
- drosophila
- nmda
-
cell-cell
- src
-
excitatory
-
synapse-associated
- hippocampal
-
domain-containing
-
magi-1
- adaptor
-
spine
-
palmitoylated
- n-methyl-d-aspartate
-
presynaptic
-
glutamatergic
-
kinase-like
-
adherens
-
pdz-binding
-
zonula
- carma1
-
crumbs
- bcl10
-
neurexins
-
discs-large
- dgmp
-
septate
-
occludens
-
kinase-associated
-
junction-associated
-
tcr-induced
-
ampars
-
shank
-
mucosa-associated
-
card-containing
-
neuroligins
- drug development
- medicine
The taxonomic range for the selected organisms is: Homo sapiens
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Synonyms
maguk, guanylate kinase, membrane-associated guanylate kinase, maguks, membrane-associated guanylate kinases, guanylate kinase (gk), gmp kinase, membrane associated guanylate kinase, gmpk, cavbeta2a, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
5'-GMP kinase
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-
-
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ATP:GMP phosphotransferase
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-
-
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CASK polypeptide
cf. EC 2.7.11.1, the protein contains a guanylate kinase domain
deoxyguanylate kinase
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-
-
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GMP kinase
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-
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guanosine monophosphate kinase
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-
-
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kinase, guanylate (phosphorylating)
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-
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-
additional information
-
the enzyme belongs to the post-synaptic density-95 membrane associated guanylate kinase, MAGUK, family of scaffolding proteins,
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
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-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:(d)GMP phosphotransferase
dGMP can also act as acceptor, and dATP can act as donor.
CAS REGISTRY NUMBER
COMMENTARY
9026-59-9
-
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
ATP + (R)-3-((2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy)-4-hydroxybutylphosphonic acid
(R)-ganciclovir phosphonate monophosphate
-
i.e. R-ganciclovir phosphonate, (S) enantiomer 100fold less efficient, used for racemic resolution
-
?
ATP + 6-thioguanosine 5'-monophosphate
ADP + 8-thioguanosine 5'-diphosphate
-
-
-
-
?
ATP + 8-azaguanosine 5'-monophosphate
ADP + 8-azaguanosine 5'-diphosphate
-
-
-
-
?
ATP + GMP
ADP + GDP
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nucleoside monophosphate binding site is highly specific for guanine moiety
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-
?
ATP + GMP
ADP + GDP
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deoxyguanosine, guanosine are no acceptor substrates
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-
?
additional information
?
-
-
MAGUKs contain three PSD-95/Discs large/Zona occludens 1, i.e. PDZ, domains, an src-homology 3, i.e. SH3, domain and a C-terminal guanylate kinase domain and play a key role in the regulation of the intracellular trafficking and synaptic localization of ionotropic glutamate receptors. In particular, the postsynaptic density-95-like subfamily of MAGUKs, PSD-MAGUKs, organizes ionotropic glutamate receptors and their associated signaling proteins in the postsynaptic density of the excitatory synapse regulating the strength of synaptic activity. Alterations of PSD-MAGUK protein interaction with N-methyl-D-aspartate, NMDA, receptors regulatory subunits are common events in several CNS disorders, overview. NMDA receptors' synaptic localization and binding to PSD-MAGUK protein family play a key role in the control of downstream signals resulting from receptor activation, physiological function, overview. The enzyme plays a role in excitotoxicity and neurodegenerative disorders, e.g. in Parkinson disease and Alzheimer disease. Physiological functions, detailed overview
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-
?
additional information
?
-
-
the post-synaptic density-95 membrane associated guanylate kinase family of scaffolding proteins, MAGUK, associate with N-methyl-D-aspartate receptor NR2 subunits via their C-terminal glutamate serine, or aspartate/glutamate, valine motifs. N-methyl-D-aspartate receptors are a subclass of ionotropic glutamate receptors that are trafficked and/or clustered at synapses by MAGUK. Receptor binding of PSD variants differin the impact on the stabilisation, turnover and compartmentalisation of N-methyl-D-aspartate receptor subtypes in neurones during development and in the mature brain
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-
?
additional information
?
-
-
binding of N-methyl-D-aspartate receptors NR2B and NR2A, wild-type and mutant proteins, by PSD variants, overview
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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
additional information
?
-
-
MAGUKs contain three PSD-95/Discs large/Zona occludens 1, i.e. PDZ, domains, an src-homology 3, i.e. SH3, domain and a C-terminal guanylate kinase domain and play a key role in the regulation of the intracellular trafficking and synaptic localization of ionotropic glutamate receptors. In particular, the postsynaptic density-95-like subfamily of MAGUKs, PSD-MAGUKs, organizes ionotropic glutamate receptors and their associated signaling proteins in the postsynaptic density of the excitatory synapse regulating the strength of synaptic activity. Alterations of PSD-MAGUK protein interaction with N-methyl-D-aspartate, NMDA, receptors regulatory subunits are common events in several CNS disorders, overview. NMDA receptors' synaptic localization and binding to PSD-MAGUK protein family play a key role in the control of downstream signals resulting from receptor activation, physiological function, overview. The enzyme plays a role in excitotoxicity and neurodegenerative disorders, e.g. in Parkinson disease and Alzheimer disease. Physiological functions, detailed overview
-
-
?
additional information
?
-
-
the post-synaptic density-95 membrane associated guanylate kinase family of scaffolding proteins, MAGUK, associate with N-methyl-D-aspartate receptor NR2 subunits via their C-terminal glutamate serine, or aspartate/glutamate, valine motifs. N-methyl-D-aspartate receptors are a subclass of ionotropic glutamate receptors that are trafficked and/or clustered at synapses by MAGUK. Receptor binding of PSD variants differin the impact on the stabilisation, turnover and compartmentalisation of N-methyl-D-aspartate receptor subtypes in neurones during development and in the mature brain
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
P1 -(5'-adenosyl)-P5 -(5'-guanosyl)pentaphosphate
a non-hydrolysable bi-substrate analogue
additional information
-
no inhibition by 2-mercaptoethanol, 1,4-dithiothreitol
-
additional information
-
no inhibition by guanosine, AMP, CMP, UMP, XMP, 6-thioinosine 5'-phosphate
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
kinetic parameters of several substrates for 4 isoenzymes
-
0.015
GMP
-
wild type enzyme, in 100 mM TrisHCl buffer pH 7.5, 4 mM ATP, 10 mM MgCl2, 1 mM dithiothreitol, 100 mM KCl, at 30°C
0.27
GMP
-
mutant S35N/V168F, in 100 mM TrisHCl buffer pH 7.5, 4 mM ATP, 10 mM MgCl2, 1 mM dithiothreitol, 100 mM KCl, at 30°C
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.043
9-(1,3-dihydroxy-2-propylmethyl)guanine 5'-monophosphate
-
pH 7.5, isoenzyme 4
0.052
9-(1,3-dihydroxy-2-propylmethyl)guanine 5'-monophosphate
-
pH 7.5, isoenzyme 4
0.06
9-(1,3-dihydroxy-2-propylmethyl)guanine 5'-monophosphate
-
pH 7.5, isoenzyme 1
0.067
9-(1,3-dihydroxy-2-propylmethyl)guanine 5'-monophosphate
-
pH 7.5, isoenzyme 2
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
4.9
-
4 isoelectric variants, agarose gel electrophoresis and isoelectric focusing
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
post-synaptic density-95 membrane associated, association with N-methyl-D-aspartate receptor NR2 subunits via their C-terminal glutamate serine, aspartate/glutamate, valine motifs
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
evolution
GMPK is a member of the family of ATP:NMP phosphoryltransferases, nucleoside monophosphate kinases, NMP kinases, or NMPKs
metabolism
physiological function
enzyme GMPK plays an important role in the recycling of the secondary messenger cGMP and thereby regulates the supply of guanine nucleotides to various signal transduction pathways. In addition to its physiological roles, GMPK is also required for the intracellular activation of numerous antiviral and anticancer purine nucleoside analog prodrugs
evolution
DLG1 is a member of the membrane associated guanylate kinase (MAGUK) family of proteins. The GK domains of the MAGUK family proteins are catalytically inactive, and instead are involved in protein-protein interactions
physiological function
additional information
metabolism
critical role in metabolic activation of antiviral and antineoplastic nucleoside-analog prodrugs
metabolism
the only known enzyme responsible for cellular GDP production, making it essential for cellular viability and proliferation
physiological function
-
guanylate kinase is the sole molecular target for the development of acquired resistance to the cytotoxic nucleotide 9-[2-(phosphonomethoxyethyl)]-guanine
physiological function
-
the guanylate kinase domain of DLG1/SAP97 binds to asymmetric cell division regulatory protein LGN in a phosphorylation-dependent manner
physiological function
tumor suppressor discs large homolog 1, i.e. DLG1/SAP97, is involved in the development and regulation of neuronal and immunological synapses. DLG1 is a member of the membrane associated guanylate kinase (MAGUK) family of proteins, which function as molecular scaffolds. The C-terminal guanylate kinase (GK) domain of DLG1 binds peptides with a phosphorylated serine residue. The GK domains of the MAGUK family proteins are catalytically inactive, and instead are involved in protein-protein interactions
additional information
size and shape of open and closed enzyme GMPK are tracked by SAXS. The binding of substrates GMP and AMPPNP, or Ap5G, or GMP and ADP, results in the compaction of size and shape of human enzyme GMPK. Determination of structural changes between open and completely closed hGMPK conformation, overview. Homology modelling of hGMPK by using the crystal structure of mGMPK's closed conformation, residues 5-194 of 197, as template, PDB ID 1LVG
additional information
-
size and shape of open and closed enzyme GMPK are tracked by SAXS. The binding of substrates GMP and AMPPNP, or Ap5G, or GMP and ADP, results in the compaction of size and shape of human enzyme GMPK. Determination of structural changes between open and completely closed hGMPK conformation, overview. Homology modelling of hGMPK by using the crystal structure of mGMPK's closed conformation, residues 5-194 of 197, as template, PDB ID 1LVG
additional information
the DLG1 GK structure adopts an open conformation. Structural comparisons of the MAGUK guanylate kinase domains and the guanylate kinase enzyme, overview
additional information
-
the DLG1 GK structure adopts an open conformation. Structural comparisons of the MAGUK guanylate kinase domains and the guanylate kinase enzyme, overview
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). KGUA_HUMAN
197
0
21726
Swiss-Prot
Mitochondrion (Reliability: 4)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22010
deduced from the amino acid composition and detected by mass spectrometry, adducts with sulfate and not phosphate are detected in mass spectrometry
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
-
PSD-MAGUK's major phosphorylation sites, regulation by phosphorylation through Ser/Thr protein kinases and also Tyr-dependent kinases, overview
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
purified the GK domain fragment of human DLG1, hanging drop vapor diffusion method, mixing of 6.5 mg/ml protein in 20 mM Tris-HCl buffer, pH 8.0, 150 mM NaCl and 2 mM dithiothreitol, with reservoir solution containing 0.2 M sodium thiocyanate and 22% PEG 3350, 20°C, X-ray diffraction structure determination and analysis at 2.2 A resolution, molecular replacement and selenomethionine single-wavelength anomalous dispersion, using the PSD-95 GK domain, PDB ID 1JXO, as a search model
SAP97 SH3-guanylate kinase/p-LGN18 complex, hanging drop vapor diffusion method, using 0.2M ammonium nitrate, 20% (w/v) polyethylene glycol 3350
-
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
G3A
decrease in Tm-value by 1.4°C as compared to wild-type enzyme. Decrease in catalytic efficiency (kcat/Km) by 14%
R116Q
decrease in Tm-value by 1.8°C as compared to wild-type enzyme. Decrease in catalytic efficiency (kcat/Km) by 18%
R96H
decrease in Tm-value by 4°C as compared to wild-type enzyme. Increase in catalytic efficiency (kcat/Km) by 22%
S121F
decrease in Tm-value by 3.6°C as compared to wild-type enzyme. Decrease in catalytic efficiency (kcat/Km) by 25%
S186Y
decrease in Tm-value by 2.8°C as compared to wild-type enzyme. Decrease in catalytic efficiency (kcat/Km) by 7%
S2L
decrease in Tm-value by 1.9°C as compared to wild-type enzyme. Decrease in catalytic efficiency (kcat/Km) by 11%
V91M
decrease in Tm-value by 3°C as compared to wild-type enzyme. Decrease in catalytic efficiency (kcat/Km) by 14%
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant N-terminally His6-tagged and SUMO-tagged enzyme from Escherichia coli strain BL21-(DE3)-pLysS by nickel affinity chromatography and gel filtration
4 isoenzymes purified by a method that includes GMP agarose chromatography and isoelectric focusing
-
method that includes DEAE-cellulose, Sephadex-75 chromatography and isoelectric focusing
-
recombinant His-tagged GK domain fragment of human DLG1 from Escherichia coli by anion exchange chromatography and gel filtration. The tag is cleaved by TEV protease
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant expression of the N-terminally His6-tagged and SUMO-tagged enzyme in Escherichia coli strain BL21-(DE3)-pLysS
recombinant expression of His-tagged GK domain fragment of human DLG1 in Escherichia coli
transient expression in HEK293 cells, with N-methyl-D-aspartate receptor, wild-type and mutant, cell surface co-expression
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
there is an approximately 40% drop in guanylate kinase mRNA expression in cell lines resistant to 9-[2-(phosphonomethoxyethyl)guanine] and 9-[2-(phosphonomethoxyethyl)diaminopurine]
-
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Agarwal, K.C.; Miech, R.P.; Parks, R.E.
Guanylate kinases from human erythrocytes, hog brain, and rat liver
Methods Enzymol.
51
483-490
1978
Homo sapiens, Rattus norvegicus, Sus scrofa
Boehme, R.E.
Phosphorylation of the antiviral precursor 9-(1,3-dihydroxy-2-propoxymethyl)guanine monophosphate by guanylate kinase isozymes
J. Biol. Chem.
259
12346-12349
1984
Homo sapiens
Brady, W.A.; Kokoris, M.S.; Fitzgibbon, M.; Black, M.E.
Cloning, characterization, and modeling of mouse and human guanylate kinases
J. Biol. Chem.
271
16734-16740
1996
Homo sapiens, Mus musculus (Q64520), Mus musculus
Prinz, H.; Lavie, A.; Scheidig, A.J.; Spangenberg, O.; Konrad, M.
Binding of nucleotides to guanylate kinase, p21(ras), and nucleoside-diphosphate kinase studied by nano-electrospray mass spectrometry
J. Biol. Chem.
274
35337-35342
1999
Homo sapiens (Q16774)
Miller, W.H.; Beauchamp, L.M.; Meade, E.; Reardon, J.E.; Biron, K.K.; Smith, A.A.; Goss, C.A.; Miller, R.L.
Phosphorylation of ganciclovir phosphonate by cellular GMP kinase determines the stereoselectivity of anti-human cytomegalovirus activity
Nucleosides Nucleotides Nucleic Acids
19
341-356
2000
Homo sapiens, Sus scrofa
Willmon, C.L.; Krabbenhoft, E.; Black, M.E.
A guanylate kinase/HSV-1 thymidine kinase fusion protein enhances prodrug-mediated cell killing
Gene Ther.
13
1309-1312
2006
Homo sapiens, Mus musculus
Gardoni, F.; Marcello, E.; Di Luca, M.
Postsynaptic density-membrane associated guanylate kinase proteins (PSD-MAGUKs) and their role in CNS disorders
Neuroscience
158
324-333
2008
Homo sapiens, Mus musculus, Rattus norvegicus
Mertlikova-Kaiserova, H.; Rumlova, M.; Tloustova, E.; Prochazkova, E.; Holy, A.; Votruba, I.
Point mutations in human guanylate kinase account for acquired resistance to anticancer nucleotide analogue PMEG
Biochem. Pharmacol.
82
131-138
2011
Homo sapiens
Zhu, J.; Shang, Y.; Xia, C.; Wang, W.; Wen, W.; Zhang, M.
Guanylate kinase domains of the MAGUK family scaffold proteins as specific phospho-protein-binding modules
EMBO J.
30
4986-4997
2011
Homo sapiens, Rattus norvegicus (Q62696)
Dembowski, J.A.; An, P.; Scoulos-Hanson, M.; Yeo, G.; Han, J.; Fu, X.D.; Grabowski, P.J.
Alternative splicing of a novel inducible exon diversifies the CASK guanylate kinase domain
J. Nucleic Acids
2012
816237
2012
Homo sapiens (O14936)
Mori, S.; Tezuka, Y.; Arakawa, A.; Handa, N.; Shirouzu, M.; Akiyama, T.; Yokoyama, S.
Crystal structure of the guanylate kinase domain from discs large homolog 1 (DLG1/SAP97)
Biochem. Biophys. Res. Commun.
435
334-338
2013
Homo sapiens (Q12959), Homo sapiens
Jain, R.; Khan, N.; Menzel, A.; Rajkovic, I.; Konrad, M.; Techert, S.
Insights into open/closed conformations of the catalytically active human guanylate kinase as investigated by small-angle X-ray scattering
Eur. Biophys. J.
45
81-89
2016
Homo sapiens (Q16774), Homo sapiens
Khan, N.; Shah, P.P.; Ban, D.; Trigo-Mourino, P.; Carneiro, M.G.; DeLeeuw, L.; Dean, W.L.; Trent, J.O.; Beverly, L.J.; Konrad, M.; Lee, D.; Sabo, T.M.
Solution structure and functional investigation of human guanylate kinase reveals allosteric networking and a crucial role for the enzyme in cancer
J. Biol. Chem.
294
11920-11933
2019
Homo sapiens (Q16774), Homo sapiens
EXTERNAL LINKS (specific for EC-Number 2.7.4.8)
Transporter Classification Database (TCDB): 8.A.24.1.8
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