Information on EC 2.7.4.21 - inositol-hexakisphosphate kinase

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The expected taxonomic range for this enzyme is: Euteleostomi

EC NUMBER
COMMENTARY hide
2.7.4.21
-
RECOMMENDED NAME
GeneOntology No.
inositol-hexakisphosphate kinase
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + 1D-myo-inositol 1-diphosphate 2,3,4,5,6-pentakisphosphate = ADP + 1D-myo-inositol 1,5-bis(diphosphate) 2,3,4,6-tetrakisphosphate
show the reaction diagram
(2)
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-
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ATP + 1D-myo-inositol hexakisphosphate = ADP + 1D-myo-inositol 5-diphosphate 1,2,3,4,6-pentakisphosphate
show the reaction diagram
(1)
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-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phospho group transfer
phospho-group transfer
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-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
inositol pyrophosphates biosynthesis
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-
SYSTEMATIC NAME
IUBMB Comments
ATP:1D-myo-inositol-hexakisphosphate 5-phosphotransferase
Three mammalian isoforms are known to exist.
CAS REGISTRY NUMBER
COMMENTARY hide
176898-37-6
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ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
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-
-
Manually annotated by BRENDA team
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-
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Manually annotated by BRENDA team
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-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
malfunction
metabolism
-
isoform inositol hexakisphosphate kinase-2 acts as an effector of the vertebrate Hedgehog pathway. IP6K2 activity is required at the level or downstream of Smoothened but upstream of the transcription activator Gli1
physiological function
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + 1D-myo-inositol hexakisphosphate
ADP + 1-diphospho-1D-myo-inositol 2,3,4,5,6-pentakisphosphate
show the reaction diagram
-
-
-
r
ATP + 1D-myo-inositol hexakisphosphate
ADP + 5-diphospho-1D-myo-inositol (1,2,3,4,6)-pentakisphosphate
show the reaction diagram
ATP + 1D-myo-inositol hexakisphosphate
ADP + 5-diphospho-1D-myo-inositol 1,2,3,4,6-pentakisphosphate
show the reaction diagram
ATP + 1D-myo-inositol hexakisphosphate
ADP + diphosphoinositol pentakisphosphate + bisdiphosphoinositol tetrakisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1D-myo-inositol-1,3,4,5,6-pentakisphosphate
ADP + diphospho-1D-myo-inositol tetrakisphosphate
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 + 1D-myo-inositol hexakisphosphate
ADP + 5-diphospho-1D-myo-inositol 1,2,3,4,6-pentakisphosphate
show the reaction diagram
additional information
?
-
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mg2+
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-
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1,3,4,5,6-inositol pentakisphosphate
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IC50 for inositol hexakisphosphate kinase activity is 0.022 mM, IC50 for ATP synthase activity is 0.0128 mM
diphosphoinositol pentakisphosphate
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IC50 for inositol hexakisphosphate kinase activity is 0.0066 mM, IC50 for ATP synthase activity is 0.0018 mM
EDTA
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H2O2
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H2O2 as low as 0.1 mM dramatically reduces enzymatic activity
heat shock protein Hsp90
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binding of HSP90 inhibits IP6K2 catalytic activity, IP6K2 binds to HSP90's C terminus. Depletion of HSP90 by RNAi in HEK-293 cells increases IP6K catalytic activity about 2.5fold, specificity of IP6K2-HSP90 interaction, overview. Drugs and selective mutations that abolish HSP90IP6K2 binding elicit activation of IP6K2, leading to cell death. Overexpression of HSP90 markedly and specifically reduces IP6K catalytic activity in HEK-293 cells, overexpression of HSP90 does not influence catalytic activity of IP6K1
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inositol 1,2,4,5,6-pentakisphosphate
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IC50 for inositol hexakisphosphate kinase activity is 0.022 mM
Inositol 1,3,4,5-tetrakisphosphate
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IC50 for inositol hexakisphosphate kinase activity is 0.061 mM, IC50 for ATP synthase activity is 0.0325 mM
Inositol 1,4,5-trisphosphate
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IC50 for ATP synthase activity is 0.253 mM
Inositol hexakisphosphate
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IC50 for inositol hexakisphosphate kinase activity is 0.0008 mM, IC50 for ATP synthase activity is 0.0018 mM
N(2)-(m-(trifluoromethyl)benzyl) N(6)-(p-nitrobenzyl)purine
N2-(3-(trifluoromethyl)benzyl)-N6-(4-nitrobenzyl)purine
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-
additional information
isoform PPIP5K2 is insensitive to physiological changes in either [AMP] or [ATP]/[ADP] ratios
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
interferon beta
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treatment with interferon beta enhances binding of IHPK2 to TNF receptor-associated factor 2
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interferon-beta
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induces IHPK2 activity after 4 h exposure
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additional information
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drugs and selective mutations that abolish HSP90IP6K2 binding elicit activation of IP6K2, leading to cell death
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00039
1D-myo-inositol hexakisphosphate
isoform PPIP5K2, in 20 mM HEPES-NaOH pH 7.2, 50 m MKCl, at 37C
0.00197
5-diphospho-1D-myo-inositol (1,2,3,4,6)pentakisphosphate
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pH 6.8, 37C
1.57
ADP
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pH 6.8, 37C
0.037 - 1.4
ATP
0.0055
D-myo-inositol-1,3,4,5,6-pentakisphosphate
pH 7.0, 37C
0.0007 - 0.0061
Inositol hexakisphosphate
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.03
1D-myo-inositol hexakisphosphate
Homo sapiens
O43314
isoform PPIP5K2, in 20 mM HEPES-NaOH pH 7.2, 50 mM KCl, at 37C
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
76
1D-myo-inositol hexakisphosphate
Homo sapiens
O43314
isoform PPIP5K2, in 20 mM HEPES-NaOH pH 7.2, 50 mM KCl, at 37C
5734
0.79
ATP
Homo sapiens
O43314
isoform PPIP5K2, using 1D-myo-inositol hexakisphosphate as cosubstrate, in 20 mM HEPES-NaOH pH 7.2, 50 mM KCl, at 37C
4
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0128
1,3,4,5,6-inositol pentakisphosphate
Rattus norvegicus
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IC50 for inositol hexakisphosphate kinase activity is 0.022 mM, IC50 for ATP synthase activity is 0.0128 mM
0.0018
diphosphoinositol pentakisphosphate
Rattus norvegicus
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IC50 for inositol hexakisphosphate kinase activity is 0.0066 mM, IC50 for ATP synthase activity is 0.0018 mM
0.0325
His3Cd-GST-protein
Rattus norvegicus
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IC50 for inositol hexakisphosphate kinase activity is 0.061 mM, IC50 for ATP synthase activity is 0.0325 mM
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0.253
human skin elastin
Rattus norvegicus
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IC50 for ATP synthase activity is 0.253 mM
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0.022
inositol 1,2,4,5,6-pentakisphosphate
Rattus norvegicus
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IC50 for inositol hexakisphosphate kinase activity is 0.022 mM
0.0018
Inositol hexakisphosphate
Rattus norvegicus
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IC50 for inositol hexakisphosphate kinase activity is 0.0008 mM, IC50 for ATP synthase activity is 0.0018 mM
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.4
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assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
37
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assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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cell culture
Manually annotated by BRENDA team
faintly expressed
Manually annotated by BRENDA team
additional information
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NIH-OVCAR-3 ovarian carcinoma cell
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
low level of activity
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
UNIPROT
Escherichia coli (strain ATCC 33849 / DSM 4235 / NCIB 12045 / K12 / DH1)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
49200
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calculated from amino acid sequence
57000
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SDS-PAGE
60000
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gel filtration
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
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1 * 54000, SDS-PAGE
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-70C, 20% glycerol, optimal stability
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4C, 7 days, 50% loss of activity
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
glutathione Sepharose column chromatography, and gel filtration
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GSTrap HP column chromatography
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in Escherichia coli BL21 cells
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expressed in Escherichia coli BL21(DE3) cells
expressed in NIH-OVCAR-3 cells
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expression in Escherichia coli
expression in Escherichia coli and HEK-293T cells, additionally wild-type IHPK2 and the NLS mutant is cloned into the pCXN2 mammalian expression vector and electroporated into NIH-OVCAR-3 cells
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expression in Escherichia coli, NIH-OVCAR-3 and Hey ovarian carcinoma cells, IP6K2 mRNA is not induced in NIH-OVCAR-3 cells following treatment with interferon-beta or gamma-irradiation, both gamma-irradiation and interferon-beta induce IP6K2 protein via a post-translational mechanism
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expression in HeLa cells, PC12 cells, Jurkat T cells, OVCAR-3 cells, HL-60 cells and HEK-293 cells
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expression of the wild-type enzyme in Saccharomyces cerevisiae mutant strains, overexpression of the GST-tagged or Myc-tagged enzyme in HEK-293, HeLa, and HCT116 cells, expression of wild-type and mutant enzymes in HEK-293 cells
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gene Ihpk1, located on chromosome 9, has 6 exons, of which exon 1 is exclusively noncoding, the start codon is located in exon 2, and the stop codon is located in exon 6, DNA and amino acid sequence determination and analysis. Expressionin MEF cell lines
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GST fusion protein is transfected into HEK293T cells
overexpression of wild-type and inactive mutant IHPK2 in ovarian carcinoma cell lines
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
K248A
the mutant shows a reduction in 1D-myo-inositol hexakisphosphate-stimulated ATPase activity of isofom PPIP5K2. The mutant shows a significant reduction in the rate of 1D-myo-inositol phosphate-independent ATPase activity of isofom PPIP5K2
R213A
the mutant shows a reduction in 1D-myo-inositol hexakisphosphate-stimulated ATPase activity of isofom PPIP5K2
S347A/S359A
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no IHPK2 activity
K226A/S334A
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catalytically inactive
R133A
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mutation of IP6K2 in its putative HSP90-binding motif, mutation of Arg133 abolishes IP6K2-HSP90 binding
R136A
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mutation of IP6K2 in its putative HSP90-binding motif, mutation of Arg136 abolishes IP6K2-HSP90 binding
S347A/S359A
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site-directed mutagenesis, the mutant displays 3.5fold greater TAK1 activation following TNF-alpha, the mutant demonstrates a 6-10fold increase in NF-kappaB DNA binding following TNF-alpha compared with wild type IHPK2-expressing cells in which NF-kappa B DNA binding is inhibited
W131A
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mutation of IP6K2 in its putative HSP90-binding motif, mutation of Trp131 modestly diminishes IP6K2-HSP90 binding, the catalytically impaired IP6K2-W131A does not induce cell death
additional information
Renatured/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
dialysis against renaturing buffer (25% sucrose, 0.1% Tween 40, 84 mM HEPES pH 7.5) after elution with denaturing buffer containing 150 mM imidazole
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
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selectively blocking HSP90-IP6K2 binding could provide effective and safer modes of chemotherapy to block apoptosis