Information on EC 2.7.1.67 - 1-phosphatidylinositol 4-kinase and Organism(s) Homo sapiens

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


The taxonomic range for the selected organisms is: Homo sapiens

EC NUMBER
COMMENTARY hide
2.7.1.67
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RECOMMENDED NAME
GeneOntology No.
1-phosphatidylinositol 4-kinase
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phospho group transfer
-
-
-
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PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
3-phosphoinositide biosynthesis
-
-
D-myo-inositol (1,4,5)-trisphosphate biosynthesis
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Inositol phosphate metabolism
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Metabolic pathways
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SYSTEMATIC NAME
IUBMB Comments
ATP:1-phosphatidyl-1D-myo-inositol 4-phosphotransferase
This reaction is catalysed by at least two different isoforms.
CAS REGISTRY NUMBER
COMMENTARY hide
37205-54-2
-
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
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in vertebrates, PtdIns4P is synthesized by four distinct PI4K enzymes that belong to either the type-II or type-III family, each having alpha- and beta-forms. The type-III PI4Ks are relatives of the PI 3-kinase family, while the smaller type-II enzymes form a separate family
malfunction
metabolism
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
ATP + 1-phosphatidyl-1D-myo-inositol
ADP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
show the reaction diagram
additional information
?
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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 + 1-phosphatidyl-1D-myo-inositol
ADP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
show the reaction diagram
additional information
?
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Mn2+
-
optimal activation at 0.5 mM
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
2'-dATP
-
-
2,3-Dihydroxybenzaldehyde
-
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2-amino-1-(isopropylsulfonyl)-6-benzimidazole phenylketone oxime
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i.e. enviroxime, inhibitor of the in vitro replication of rhinoviruses and enteroviruses, inhibits hepatitis C virus subgenomic replicon replication
3'-dATP
-
-
5'-AMP
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0.5 mM, 10% inhibition
8-bromo-ATP
-
-
adenosine
amyloid beta
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amino acids 1-42, inhibits type II phosphatidylinositol 4-kinase and enhances glutamate toxicity
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amyloid beta protein
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pathophysiological concentrations of amyloid beta proteins directly inhibit. Abeta25-35 inhibits in a non-competitive manner. Inhibition by 10 nM Abeta25-35 is reversible
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arachidonic acid
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0.5 mg/ml, 91.3% inhibition of mPIK-III
Caffeine
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6.5 mM, 18% inhibition
cholesterol
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cholesterol sensitivity of PI4KIIalpha
Co2+
-
-
Cpd 6
-
-
-
Fe2+
-
-
Formycin A
-
-
GDP
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0.5 mM, 4% inhibition
N-(5-[4-chloro-3-[(2-hydroxyethyl)sulfamoyl]phenyl]-4-methyl-1,3-thiazol-2-yl)acetamide
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i.e. PIK93, a phenylthiazole
N6-dimethylamine-adenosine 5'-triphosphate
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-
Ni2+
-
-
orobol
-
-
PCMB
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0.01 mM, 74% inhibition
Phenylarsine oxide
phosphatidylinositol 4,5-bisphosphate
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50% inhibition when added in equimolar amounts to phosphatidylinositol
phosphatidylserine
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0.5 mg/ml, 64.3% inhibition of mPIK-III
PIK93
quercetin
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IC50: 0.004 mM
resveratrol
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inhibition of PtdIns 4-kinase activity by resveratrol/phenylarsine oxide reduces Jurkat cell adhesion to matrigel/fibronectin coated surfaces
sodium cholate
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inhibits activity of both mPIK-I and mPIK-III
tert-butyl N-[[8-(2-chlorophenyl)-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl]carbamoyl]-beta-alaninate
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i.e. Inhibitor A
theophylline
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2 mM, 21% inhibition
Toyocamycin
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IC50 is 0.0033 mg/ml
Triton X-100
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inhibits activity of mPIK-I but rather weakly enhances mPIK-III activity
Wortmannin
[5-(4-[[4-(morpholin-4-yl)phenyl]amino]quinazolin-6-yl)furan-2-yl]methanol
additional information
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some anti-viral molecules are isoform selective phosphatidylinositol 4-kinase inhibitors. Isozymes PI4KIIalpha and PI4KIIbeta are wortmannin-insensitive
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ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
amyloid beta31-34
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fragment of amyloid beta, blocks amyloid beta1-42-induced inhibition of type II phosphatidylinositol 4-kinase activity
amyloid beta32-34
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fragment of amyloid beta, blocks amyloid beta1-42-induced inhibition of type II phosphatidylinositol 4-kinase activity. 50% protection at around 1 nM
amyloid beta32-35
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fragment of amyloid beta, blocks amyloid beta1-42-induced inhibition of type II phosphatidylinositol 4-kinase activity
dichlorodiphenyltrichloroethane
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i.e. DDT, 0.01 mM enhances activity but no changes are observed by lower concentration, membrane associated enzyme
Dimethylsulfoxide
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1.0%, activation to 160% of the original activity
eukaryotic protein translation elongation factor 1 alpha 2
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up to a 2fold molar excess of recombinant eEF1A2 is required to maximally increase PI4KIIIbeta activity
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heparin
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0.01 mM, activation to 116% of the orginal activity
heptachlor
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0.0001 mM enhances activity by 88%, 0.01 mM enhances activity by 52%, membrane associated enzyme
histone
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stimulates
M7 analogue of mastoparan
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0.02 mM
Mastoparan
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0.01 mM, 3-4fold increase of activity
neuronal calcium sensor 1
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Golgi-localized isozyme PI4KIIIbeta can be activated by protein kinase D phosphorylation, and also through interactions with neuronal calcium sensor 1
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NS5A
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stimulates phosphatidylinositol 4-phosphate production in vivo and enhances PI4KA kinase activity in vitro, but not other viral proteins from hepatitis C virus, overview
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phosvitin
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stimulates
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poly(L-lysine)
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stimulates
Polyarginine
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stimulates
spermidine
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half-maximal stimulation at 1.5 mM
spermine
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2.0 mM, activation to 121% of the original activity
Triton X-100
additional information
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.016
1-phosphatidyl-1D-myo-inositol
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pH 7.2, 30°C
0.02 - 1
ATP
0.04 - 1
phosphatidylinositol
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.014
2'-dATP
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pH 7.4, 25°C, in presence of 3 mM spermidine
0.012
3'-dATP
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pH 7.4, 25°C, in absence of spermidine
0.11
8-bromo-ATP
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pH 7.4, 25°C, in presence of 3 mM spermidine
0.07 - 0.365
adenosine
0.01
ADP
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pH 7.4, 25°C, in absence of spermidine
0.53
AMP
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pH 7.4, 25°C, in absence of spermidine
0.0019 - 0.1
Ca2+
0.5
cAMP
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pH 7.4, 25°C, in absence of spermidine
0.013
GTP
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pH 7.4, 25°C, in absence of spermidine
0.04 - 1.9
N6-dimethylamine-adenosine 5'-triphosphate
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00012 - 0.0014
2-amino-1-(isopropylsulfonyl)-6-benzimidazole phenylketone oxime
0.09
adenosine
Homo sapiens;
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IC50: 0.09 mM
0.000024
Cpd 6
Homo sapiens;
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isozyme PI4KIIIbeta, pH and temperature not specified in the publication
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0.000019 - 0.0011
N-(5-[4-chloro-3-[(2-hydroxyethyl)sulfamoyl]phenyl]-4-methyl-1,3-thiazol-2-yl)acetamide
0.004
quercetin
Homo sapiens;
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IC50: 0.004 mM
0.00045
tert-butyl N-[[8-(2-chlorophenyl)-4,5-dihydro[1,3]thiazolo[4,5-h]quinazolin-2-yl]carbamoyl]-beta-alaninate
Homo sapiens;
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isozyme PI4KIIIalpha, pH and temperature not specified in the publication
0.0003
Wortmannin
Homo sapiens;
Q9UBF8
IC50: about 300 nM
0.00057 - 0.0031
[5-(4-[[4-(morpholin-4-yl)phenyl]amino]quinazolin-6-yl)furan-2-yl]methanol
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.044
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1.05
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1.18
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
8.5 - 9
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mPIK-I and mPIK-III
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.5 - 9
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pH 5.5: 60% of maximal activity for mPIK-I and 45% of maximal activity of mPIK-III, pH 8.5-9.0: pH-optimum for enzyme form mPIK-I and mPIK-III
6 - 9
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activity of cPIK-I and cPIK-III is almost undetectable at pH 6.0, pH 9.0: about 80% of maximal activity
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
-
assay at room temperature
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
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non-specific infiltrating duct and infiltrating lobular carcinomas
Manually annotated by BRENDA team
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isozyme PI4KIIalpha expression is upregulated in many human cancers but is especially highly expressed in malignant melanoma, fibrosarcoma, breast cancer (non-specific infiltrating duct and infiltrating lobular carcinomas) bladder transitional cell carcinoma and thyroid papillary carcinoma
Manually annotated by BRENDA team
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isozyme PI4KIIbeta is strongly expressed in the liver
Manually annotated by BRENDA team
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cell lines with inducible expression of the HCV polyprotein or individual viral proteins
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
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intracellular, isozyme PI4KIIbeta
Manually annotated by BRENDA team
additional information
PDB
SCOP
CATH
UNIPROT
ORGANISM
Homo sapiens;
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
45000
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x * 45000, SDS-PAGE
50000
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x * 50000, SDS-PAGE
56000
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x * 56000, SDS-PAGE
59000
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x * 59000, SDS-PAGE
76000
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mPIK-I, gel filtration
80000
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mPIK-III, gel filtration
91000
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isozyme PI4KIIIbeta
92000
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SDS-PAGE
100000
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SDS-PAGE
230000
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isozyme PI4KIIIalpha
240000
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gel filtration
550000
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cPIK-I and cPIK-II, gel filtration
additional information
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the enzyme binds substantial amounts of Triton X-100 and is actually present in detergent-containing solutions as a complex with a molecular weight of 120000 Da. It seems likely that the active species of the enzyme is a single 55000 Da polypeptide chain bound to essentially one Triton X-100 micelle
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
monomer
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1 * 55000, SDS-PAGE
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
lipoprotein
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PI4KIIbeta and PI4KIIalpha are palmitoylated
phosphoprotein
additional information
-
PI4KIIalpha undergoes multi-ubiquitination via ubiquitin ligase Itch
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
in complex with inhibitors
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phosphatidylinositol 4-kinase type IIalpha in complex with ATP, vapor diffusion method
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sitting drop vapor diffusion method, using 100 mM MES-imidazole pH 6.5, 10% (w/v) PEG 4000, 20% (v/v) glycerol, 20 mM 1,6-hexanediol, 20 mM 1-butanol, 20 mM 1,2-propanediol, 20 mM 2-propanol, 20 mM 1,4-butanediol, 20 mM 1,3-propanediol; sitting drop vapor diffusion method, using 100 mM MES-imidazole pH 6.5, 10% (w/v) PEG 4000, 20% (v/v) glycerol, 20 mM 1,6-hexanediol, 20 mM 1-butanol, 20 mM 1,2-propanediol, 20 mM 2-propanol, 20 mM 1,4-butanediol, 20 mM 1,3-propanediol
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GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
molecular chaperone Hsp90 is a binding partner of isozyme PI4KIIbeta. Geldanamycin, a specific Hsp90 inhibitor, disrupts the Hsp90-PI4KIIbeta interaction and destabilizes PI4KIIbeta, reducing its half-life by 40% and increasing its susceptibility to ubiquitylation and proteasomal degradation. Cytosolic PI4KIIbeta is much more sensitive to geldanamycin treatment than is the integrally membrane-associated species. Stimuli such as PDGF receptor activation that also induce recruitment of the kinase to membranes disrupt the Hsp90-PI4KIIbeta interaction to a similar extent as inhibitor treatment
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STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, 50% glycerol, stable for 4 weeks
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-20°C, buffer containing 30% glycerol and 2 mM DTT, minimal loss of activity after 2 weeks
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
affinity, anion exchange column chromatography, and gel filtration
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COS-7 cells transfected with the HA-tagged PI 4-kinase construct
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enzyme type II
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mPIK-I and mPIK-III from membrane fraction and cPIK-I and cPIK-II from cytoslic fraction
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Ni-NTA resin column chromatography, and Superdex 200 gel filtration; Ni-NTA resin column chromatography, and Superdex 200 gel filtration
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recombinant His-tagged catalytic domain of isozyme PI4KIIIalpha from Sf9 cells by nickel affinity chromatography
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type III kinase, isoform PI4K92 is expressed as His6 tagged protein in Sf9 cells
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expressed in COS-7 cells
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expressed in Escherichia coli
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expressed in Escherichia coli BL21 Star cells
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expressed in Escherichia coli BL21 Star cells; expressed in Escherichia coli BL21 Star cells
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expression of HA-tagged isozyme PI4KIIalpha in HEK-293 cells, co-expression of FLAG-tagged ubiquitin, PI4KIIalpha undergoes multi-ubiquitination
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FLAG-tagged PI4KIIIbeta is stably expressed in HEK-293 cells
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isoform PI4K92 is expressed as His6 tagged protein in Sf9 cells reaching a level of approximately 5% of cellular proteins
isolated catalytic domain of isozyme PI4KIIIalpha as His-tagged protein in Spodoptera frugiperda Sf9 cells via transfection by recombinant baculovirus
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isozyme PI4KA, DNA and amino acid sequence determination and analysis, expression of GFP-tagged wild-type and mutant enzymes in HEK-293T cells and in U2OS cells
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PI4KIIIalpha is one of the genes found in Chr22q11, region affected by chromosomal instability, no substantiation of the existence of a functionally relevant short form of PI4KIIIalpha, expression of a cDNA encoding isoform 1 yields a protein of about 97 kDa that shows no catalytic activity and fails to rescue hepatitis C virus replication. expression in COS-7 cells and HEK-293 cells
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recombinant expression of N-terminal myc-tagged PI4KB and 3xFLAG-tagged PI4KA in Huh7.5.1 cells
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transient expression of GFP-PI4KIIalpha in CHO cells, the tagged enzyme is present in perinuclear vesicles in control and 25-hydroxycholesterol-treated cells, overview
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
inactivation of isozyme PI4KIIalpha by expression of siRNAs in HeLa cells
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D1899A
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mutant of isozyme PI4KA
D308A
-
enzymatically inactive isozyme PI4KIIalpha
K165-K172
-
when the entire membrane binding segment K165-K172 was mutated to alanines, the kinase is inactive
K1792L
-
site-direcetd mutagenesis, inactive isozyme PI4KA
N163A
-
the mutant shows about 10% of wild type activity
N249A
-
the mutant shows slightly reduced wild type activity
PI4K230 DELTA1-1189
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deletion mutant with 97000 Da compared to wild-type enzyme of 230000 Da, the enzyme is stable but activity is not detectable
PI4K230 DELTA1-1427
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deletion mutant with 68000 Da compared to wild-type enzyme of 230000 Da, the enzyme is stable but activity is not detectable
PI4K230 DELTA1-1531
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deletion mutant with 56000 Da compared to wild-type enzyme of 230000 Da, the enzyme is stable but activity is not detectable
PI4K230 DELTA1-872
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deletion mutant with 130000 Da compared to wild-type enzyme of 230000 Da, the enzyme is stable, 0.048 mM/mg*min compared to 0.058 mM/mg*min for the wild-type enzyme
R275A
-
the mutant shows about 15% of wild type activity
V339A
-
the mutant shows slightly reduced wild type activity
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug development
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type II phosphatidylinositol 4-kinases are promising targets for therapeutic intervention against viral infections, detailed overview
medicine
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PI4Ks are panviral host therapeutic targets
pharmacology
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type II phosphatidylinositol 4-kinases are promising targets for therapeutic intervention against viral infections, detailed overview