Information on EC 2.7.1.153 - phosphatidylinositol-4,5-bisphosphate 3-kinase and Organism(s) Homo sapiens

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The taxonomic range for the selected organisms is: Homo sapiens

The enzyme appears in selected viruses and cellular organisms

EC NUMBER
COMMENTARY hide
2.7.1.153
-
RECOMMENDED NAME
GeneOntology No.
phosphatidylinositol-4,5-bisphosphate 3-kinase
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phospho-group transfer
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
3-phosphoinositide biosynthesis
-
-
Inositol phosphate metabolism
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:1-phosphatidyl-1D-myo-inositol-4,5-bisphosphate 3-phosphotransferase
This enzyme also catalyses the phosphorylation of PtdIns4P to PtdIns(3,4)P2, and of PtdIns to PtdIns3P. Four mammalian isoforms are known to exist.
CAS REGISTRY NUMBER
COMMENTARY hide
103843-30-7
-
115926-52-8
cf. EC 2.7.1.137
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
evolution
class 1 phosphoinositide 3-kinases are heterodimers consisting of an 85 kDa regulatory/adapter subunit (p85) coupled to a 110 kDa catalytic subunit (p110) with both subunits possessing several isoforms. The class I enzymes are further subdivided into two subclasses: class Ia and class Ib. The class 1a phosphoinositol 3-kinases (p110alpha, p110beta and p110delta) signal downstream of tyrosine kinases, while the single class Ib phosphoinositol 3-kinase (p110gamma) operates downstream of heterotrimeric GPCRs (G-protein-coupled receptors); class 1 phosphoinositide 3-kinases are heterodimers consisting of an 85 kDa regulatory/adapter subunit (p85) coupled to a 110 kDa catalytic subunit (p110) with both subunits possessing several isoforms. The class I enzymes are further subdivided into two subclasses: class Ia and class Ib. The class 1a phosphoinositol 3-kinases (p110alpha, p110beta and p110delta) signal downstream of tyrosine kinases, while the single class Ib phosphoinositol 3-kinase (p110gamma) operates downstream of heterotrimeric GPCRs (G-protein-coupled receptors)
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 3-phosphate
show the reaction diagram
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate
show the reaction diagram
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate
show the reaction diagram
ATP + phosphatidylinositol
ADP + phosphatidylinositol 3-phosphate
show the reaction diagram
ATP + phosphatidylinositol 4-phosphate
ADP + phosphatidylinositol 4,5-diphosphate
show the reaction diagram
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
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 + 1-phosphatidyl-1D-myo-inositol
ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
show the reaction diagram
-
catalyzed by class I and III, and probably by class II enzymes, overview. PI3K is part of the plasma membrane E-cadherin signaling complex
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate
show the reaction diagram
-
catalyzed by class I enzyme, overview. PI3K is part of the plasma membrane E-cadherin signaling complex
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate
show the reaction diagram
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catalyzed by class I enzyme, overview. PI3K is part of the plasma membrane E-cadherin signaling complex
-
-
?
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
show the reaction diagram
additional information
?
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1-[2-methyl-3-(trifluoromethyl)benzyl]-2-methyl-7-(morpholin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
-
-
1-[2-methyl-3-(trifluoromethyl)benzyl]-7-(morpholin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
-
-
1-[2-methyl-3-(trifluoromethyl)benzyl]-7-[(2R)-2-methylmorpholin-2-yl]-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
-
-
1-[4-[(4-methylpiperazin-1-yl)carbonyl]phenyl]-3-[4-[4-morpholin-4-yl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d ]pyrimidin-2-yl]phenyl]urea
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dual catalytic subunit alpha isoform/mTOR kinase inhibitor, demonstrates inhibition of tumor cell growth in vitro and in vivo and causes suppression of the pathway specific biomarkers in the human MDA-361 cell line
17-hydroxywortmannin
-
-
2-(difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole
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lead compound for structure-activity study
2-(methylsulfanyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
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2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(2methylmorpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
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2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
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2-[(6-amino-9H-purin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone
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i.e. IC87114, selectively inhibits isoform p110delta
3-(2-morpholino-6-(2-(pyridin-4-yl)ethylamino)pyrimidin-4-yl)phenol
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3-(2-morpholino-6-(pyridin-2-ylmethoxy)pyrimidin-4-yl)phenol
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3-(4-morpholino-6-(pyridin-2-yl)pyrimidin-2-yl)phenol
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3-Methyladenine
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treatment in full medium for a prolonged period of time leads to marked increases of the autophagic markers in cells. The increase of autophagic markers is the result of enhanced autophagic flux. The autophagy promotion activity is due to its differential temporal effects on class I and class III PI3K enzymes. 3-Methyladenine blocks class I PI3K persistently, whereas its suppressive effect on class III PI3K is transient. Treatment with 3-methyladenine in full medium significantly reduces the level of phosphatidylinositol 3-phosphate, the product of class III PI3K, at early time points, but almost completely blocks the product of phosphatidylinositol 3,4,5-trisphosphate up to 9 h
3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one
i.e. CAL-101, highly selective and small molecule inhibitor of isoform PI3Kdelta. Inhibitor blocks constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis
3-[4-(4-morpholinyl)thieno(3,2-d)pyrimidin-2-yl]-phenol
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a p110 PI3K isoform selective inhibitor
3-[4-(morpholin-4-yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol
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among the compounds tested, treatment with 3-[4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-2-yl]phenol or 3-[4-(morpholin-4-yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol leads to the most efficient inhibition
3-[4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-2-yl]phenol
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among the compounds tested, treatment with 3-[4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-2-yl]phenol or 3-[4-(morpholin-4-yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol leads to the most efficient inhibition
4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
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not inhibitory to serine/threonine kinase mTOR; not inhibitory to serine/threonine kinase mTOR
4-[2-[(6-methoxypyridin-3-yl)amino]-5-phenylpyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
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not inhibitory to serine/threonine kinase mTOR; not inhibitory to serine/threonine kinase mTOR
4-[4-(morpholin-4-yl)-5a,6-dihydro[1]benzofuro[3,2-d]pyrimidin-2-yl]phenol
4-[5-(3,6-dihydro-2H-pyran-4-yl)-2-[(6-methoxypyridin-3-yl)amino]pyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
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not inhibitory to serine/threonine kinase mTOR; not inhibitory to serine/threonine kinase mTOR
5-[2,2-difluoro-benzo(1,3)-dioxol-5-ylmethylene]-thiazolidine-2,4-dione
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a p110 PI3K isoform selective inhibitor
6-amino-2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole
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inhibitory against all three class Ia PI 3-kinase enzymes, i.e. p110alpha, p110beta, and p110delta, and also displays significant potency against two mutant forms of the p110alpha isoform, H1047R and E545K. In an in vivo U87MG human glioblastoma tumor xenograftmodel in Rag1-/- mice, and at a dose of 50mg/kg given by intraperitoneal injection it dramatically reduces cancer growth by 81% compared to untreated controls
7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one
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i.e. TGX221, selectively inhibits isoform p110beta. Compound decreases secretion of vascular endothelial growth factor and interleukin-6 in nonasthmatic airway smooth muscle cells and lung fibroblasts
Baicalin
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10 microM, 35.5% inhibition of isoform PI3Kalpha
CAL-101
-
a specific inhibitor of the PI3Kdelta isoform
IC-87114
p110delta-specific small molecule inhibitor
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IC87114
idelalisib
5-fluoro-3-phenyl-2-[(1S)-1-(9H-purin-6-ylamino)propyl]quinazolin-4(3H)-one, a PI3Kdelta inhibitor used to treat hematological malignancies. The inhibitior idelalisib is selective, noncovalent, reversible, and ATP-competitive. The compound binds reversibly and noncovalently to the p110delta subunit of the kinase, analysis of binding interactions that confer the potency and selectivity of idelalisib, overview. Idelalisib is a propeller-shaped inhibitor
luteolin
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1 microM, 75.8% inhibition of isoform PI3Kalpha
Ly-294002
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LY294002
myricetin
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1 microM, almost complete inhibition of isoform PI3Kalpha
N-[(E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylidene]-N,2-dimethyl-5-nitrobenzenesulfonohydrazide
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i.e.PIK75, selectively inhibits isoform p110alpha. In cells stimulated with transforming growth factor-beta and/or 10% fetal bovine serum, compound attenuates transforming growth factor-induced fibronectin deposition in all cell types tested and decreases secretion of vascular endothelial growth factor and interleukin-6 in nonasthmatic airway smooth muscle cells and lung fibroblasts. Compound decreases cell survival in transforming growth factor-stimulated asthmatic, but not nonasthmatic, airway smooth muscle cells
N-[2-(dimethylamino)ethyl]-N-methyl-4-[([4-[4-morpholin-4-yl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d ]pyrimidin-2-yl]phenyl]carbamoyl)amino]benzamide
-
dual catalytic subunit alpha isoform/mTOR kinase inhibitor, demonstrates inhibition of tumor cell growth in vitro and in vivo and causes suppression of the pathway specific biomarkers in the human MDA-361 cell line. Good in vivo efficacy in the MDA361 human breast tumor xenograft model
PI-103
PI103
-
suppressing phosphatidylinositol 3-kinase activity by inhibitors LY294002 and PI103 selectively reduces both the mRNA and protein levels of peroxisome proliferator-activated receptor gamma coactivator PGC-1beta but not PGC-1alpha. Reducing PGC-1b expression also leads to reduced mRNA expression levels of uncoupling protein 1, 2 and superoxide dismutase 2. Correspondingly, mitochondrial membrane potential and reactive oxygen species levels are increased
PIK-75
PX-866
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irreversible PI3K inhibitor, shows selectivity for the alpha, delta, and gamma class I PI3K isoforms, inhibits the beta isoform at higher concentrations, and shows decreased selectivity for mTor
quercetagetin
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1 microM, almost complete inhibition of isoform PI3Kalpha
quercetin
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1 microM, 54.1% inhibition of isoform PI3Kalpha
TGX-221
TGX-221-R
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R-enantiomer of inhibitor TGX-221, 100fold more potent as a PI3K-beta inhibitor than the S-enantiomer
WAY-266175
-
-
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WAY-266176
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Wortmannin
XL147
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targets only the class I PI3Ks
YM024
a p110alpha-selective PI3K inhibitor
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ZSTK474
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a phosphatidylinositol 3-kinase inhibitor, inhibited phosphorylation of Ser65, Thr70 and Thr37/46 in 4E-BP1 by PI3K. Identification of the ZSTK474-sensitive phosphoproteins in A-549 cells, overview
[(4-[2-[(3-hydroxyphenyl)amino]-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl)amino]acetonitrile
-
lead compound for structure-based design of inhibitors, dual inhibitor of phosphatidylinositol 3-kinase and serine/threonine kinase mTOR; lead compound for structure-based design of inhibitors, dual inhibitor of phosphatidylinositol 3-kinase and serine/threonine kinase mTOR
[3-[4-morpholin-4-yl-7-(pyrrolidin-1-ylmethyl)-5H-pyrrolo-[3,2-d ]pyrimidin-2-yl]phenyl]methanol
-
selective for catalytic subunit alpha isoform
additional information
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
beta-catenin
-
tyrosine-phopshorylated
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c-Src
-
-
-
Dlg
-
tyrosine-phopshorylated
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G-protein alpha, beta and gamma subunit
strong
-
G-protein beta,gamma
in vivo, activation of enzyme by a mechanism assigning specific roles for both enzyme subunits, membrane recruitment via the noncatalytic p101 subunit, and direct stimulation of p110gamma
-
G-protein beta,gamma subunits
significant stimulation of enzyme beta and gamma isoforms in the presence as well as in the absence of non-catalytic subunits such as p85alpha or p101, stimulation of autophosphorylation of the catalytic subunit of enzyme
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monocyte chemotactic peptide-1
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i.e. MCP-1, stimulation can be inhibited by pertussis toxin, but not by wortmannin
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Pasteurella multocida toxin
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mediated by G protein betagamma-subunits and G protein alpha-subunit, EC 3.6.5.1
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Ras
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active RAs activates class 1 enzymes
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RAS-GTP
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regulatory domain p85 interacts with RAS-GTP. RAS binding is essential for oncogenic transformation by helical domain mutants of p110alpha
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additional information
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
additional information
additional information
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.000001
1-[2-methyl-3-(trifluoromethyl)benzyl]-2-methyl-7-(morpholin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
Homo sapiens;
-
pH not specified in the publication, temperature not specified in the publication
0.000003
1-[2-methyl-3-(trifluoromethyl)benzyl]-7-(morpholin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
Homo sapiens;
-
pH not specified in the publication, temperature not specified in the publication
0.000001
1-[2-methyl-3-(trifluoromethyl)benzyl]-7-[(2R)-2-methylmorpholin-2-yl]-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
Homo sapiens;
-
pH not specified in the publication, temperature not specified in the publication
0.0000024
1-[4-[(4-methylpiperazin-1-yl)carbonyl]phenyl]-3-[4-[4-morpholin-4-yl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d ]pyrimidin-2-yl]phenyl]urea
Homo sapiens;
-
pH not specified in the publication, temperature not specified in the publication
0.0000004 - 0.0013
2-(methylsulfanyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
0.0000003 - 0.00032
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(2methylmorpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
0.0000006 - 0.00079
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
0.00014 - 0.0016
3-(2-morpholino-6-(2-(pyridin-4-yl)ethylamino)pyrimidin-4-yl)phenol
0.00011 - 0.00073
3-(2-morpholino-6-(pyridin-2-ylmethoxy)pyrimidin-4-yl)phenol
0.000044 - 0.0001
3-(4-morpholino-6-(pyridin-2-yl)pyrimidin-2-yl)phenol
0.0000025 - 0.00082
3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one
0.00058
3-[4-(4-morpholinyl)thieno(3,2-d)pyrimidin-2-yl]-phenol
Homo sapiens;
-
versus p110alpha PI3K
0.000002 - 0.000009
4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
0.000001 - 0.000007
4-[2-[(6-methoxypyridin-3-yl)amino]-5-phenylpyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
0.000002 - 0.000005
4-[5-(3,6-dihydro-2H-pyran-4-yl)-2-[(6-methoxypyridin-3-yl)amino]pyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
0.00025
5-[2,2-difluoro-benzo(1,3)-dioxol-5-ylmethylene]-thiazolidine-2,4-dione
Homo sapiens;
-
about, versus p110gamma PI3K
0.00000022 - 0.0000014
6-amino-2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole
0.008
LY294002
Homo sapiens;
-
inhibition of bacterial entry into macrophages
0.0000009
N-[2-(dimethylamino)ethyl]-N-methyl-4-[([4-[4-morpholin-4-yl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d ]pyrimidin-2-yl]phenyl]carbamoyl)amino]benzamide
Homo sapiens;
-
pH not specified in the publication, temperature not specified in the publication
0.00004
TGX-221
Homo sapiens;
-
about, versus p110beta PI3K
0.000006
TGX-221-R
Homo sapiens;
-
pH not specified in the publication, temperature not specified in the publication
0.0000025
Wortmannin
Homo sapiens;
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inhibition of bacterial entry into macrophages
0.000052 - 0.00035
[(4-[2-[(3-hydroxyphenyl)amino]-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl)amino]acetonitrile
0.000021
[3-[4-morpholin-4-yl-7-(pyrrolidin-1-ylmethyl)-5H-pyrrolo-[3,2-d ]pyrimidin-2-yl]phenyl]methanol
Homo sapiens;
-
pH not specified in the publication, temperature not specified in the publication
additional information
additional information
Homo sapiens;
-
IC50 value of inhbitor 4-[4-(morpholin-4-yl)-5a,6-dihydro[1]benzofuro[3,2-d]pyrimidin-2-yl]phenol is 2 nmol/l against recombinant isoform p110alpha, 3 nmol/l against recombinant isoform p110beta, 3 nmol/l against recombinant isoform p110delta, 15 nmol/l against recombinant isoform p110agamma
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7
-
assay at
7.5
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
22
-
assay at room temperature
25
assay at
30
assay at
32
assay at; assay at
37
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
-
an airway epithelial cell line
Manually annotated by BRENDA team
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-
Manually annotated by BRENDA team
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CEM-R cell; CEM-S cell
Manually annotated by BRENDA team
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recombinant isoforms PI3Kalpha, beta, delta and gamma
Manually annotated by BRENDA team
renal proximal tubule epithelial cell
Manually annotated by BRENDA team
primary human acute myeloid leukemia (AML) cells
Manually annotated by BRENDA team
-
-
Manually annotated by BRENDA team
high expression
Manually annotated by BRENDA team
high expression
Manually annotated by BRENDA team
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68% of clinical cases and the MCL cell lines harbor a gain of PIK3 catalytic subunit alpha gene copy number. In addition, cases with increased PIK3CA gene copy number have elevated PIK3CA mRNA levels
Manually annotated by BRENDA team
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PI3Kdelta isoform is most prominently expressed in myeloid cells
Manually annotated by BRENDA team
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osteoclasts express multiple regulatory subunits of class IA PI3-K, although the expression of the full-length form of p85alpha is most abundant
Manually annotated by BRENDA team
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an epithelial ovarian cancer cell line SKOV3 with constitutively active PI3K
Manually annotated by BRENDA team
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all cell lines express the catalytic subunit isoforms p110alpha, p110beta, p110gamma, and p110delta
Manually annotated by BRENDA team
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monocytic cell line
Manually annotated by BRENDA team
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PI3Kgamma, small amounts
Manually annotated by BRENDA team
additional information
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
additional information
PDB
SCOP
CATH
UNIPROT
ORGANISM
Homo sapiens;
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
110000
119471
x * 119471, p110delta subunit, can bind the p85 adaptor subunit, calculation from nucleotide sequence
119505
x * 119505, calculated, x * 110000, SDS-PAGE
120000
x * 120000, calculated, x * 110000, SDS-PAGE
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
heterodimer
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phosphoprotein
stimulation of autophosphorylation of catalytic sunbunit by G-protein beta,gamma subunits
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cocrystal strucutre of inhibitor 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine bound to catalytic subunit gamma isoform. Compound binds with two hydrogen bonds from the aminotriazine ring to the hinge, with the triazine methyl substituent oriented toward the Tyr867 side chain, and with the 4-methoxypyridine substituent projected into the affinity pocket. The methoxypyridine nitrogen atom makes a hydrogen bond to an ordered water molecule sitting between Tyr867 and Asp841, and the piperazine sulfonamide extended into the ribose pocket
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docking of inhibitor TGX-221-R into a homology model of the PI3K-beta enzyme. The morpholine-oxygen accepts an H-bond from the hinge region Val854 while the pyrido-pyrimidinone template core interacts in the central pocket lined by Met926 and Ile residues 803, 851 and 936 from the N and C-terminal of the kinase domain
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purified enzyme mutant, mixing of 25 nl 11 mg/ml protein with 0.9 mM inhibitor delalisib in 20 mM Tris, pH 7.2, 50 mM (NH4)2SO4, 1% v/v ethylene glycol, 1% w/v betaine, 300 mM CHAPS, and 5 mM TCEP, with 25 nl of reservoir solution containing 25% w/v PEG 3350, 0.1 M Bis-Tris, pH 6.5, microseeding in 480 nl of 2.5% w/v n-dodecyl-beta-D-maltoside, 300 nl of 20 mM ligand, and 0.12 ml of 12 mg/ml DELTAABD-p110delta in storage buffer 20 mM Tris, pH 7.2, 50 mM (NH4)2SO4, 1% v/v ethylene glycol, 1% w/v betaine, 300 nM CHAPS, and 5mM TCEP, X-ray diffraction structure determination and analysis at 2.4-2.5 A resolution
structure activity relationship study of inhibitor 2-(difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole, i.e. ZSTK474, with catalytic subunit gamma isoform, PDB entry 2CHX
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant His6-tagged wild-type full-length PI3Kgamma isozyme from Spodoptera frugiperda Sf9 cells by nickel affinity chromatography
recombinant N-terminally His6-tagged p110 and nontagged p85 subunits from Spodoptera frugiperda Sf21 cells by nickel affinity chromatography
Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
coexpression of N-terminally His6-tagged p110 and nontagged p85 subunits in Spodoptera frugiperda Sf21 cells via baculovirus transfection method, recombinant expression of DELTAABC mutant p110delta with the iSH2 domain of p85alpha
expression in Saccharomyces cerevisiae
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expression of HA-tagged p85alpha in NIH 3T3 cells in a mouse cell model
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expression of P110delta in Sf9 insect cells
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expression of p85 constructus from a retroviral vector
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functional recombinant expression of wild-type and K802R mutant enzymes in Saccharomyces cerevisiae, the transcriptional profile of PI3K-expressing cells is consistent with sustained CWI activation, Pkc1 localizes to endosomes in PI3K-expressing cells, PI3K expression relocates Pkc1 to endosomal compartments. PI3K effects in yeast signaling and trafficking are reversible by a competitive inhibitor in a dose-dependent manner
gene PIK3CA, encodes the catalytic subunit of PI3K, and resides in chromosomal area 3q26
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overexpression of the dominant negative PI3K mutant in J774A.1 cells
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PI 3-kinase genotyping
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recombinant coexpression of N-terminally His-tagged full-length wild-type and mutant class 1a isoform catalytic subunits with the p85 regulatory subunit, impacct of the His-tag on the catalytic activity, overview; recombinant coexpression of N-terminally His-tagged full-length wild-type and mutant class 1b isoform catalytic subunits with the p85alpha regulatory subunit, impact of the His-tag on the catalytic activity, overview
recombinant expression of His6-tagged wild-type full-length PI3Kgamma isozyme in Spodoptera frugiperda Sf9 cells using the baculovirus transfection method
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
gain of copy number of PIK3CA gene by gene amplification in mantle cell lymphoma is one mechanism of oncogenic activation of PI3K. Expression of PIK3CA in mantle cell lymphoma correlates with gene copy numbers determined by real-time PCR, overview
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upregulation of class I PI3K isozymes in cancer cells
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virulent Legionella pneumophila infection induces PI3K in human macrophages, while PI3K and protein kinase B, PKB/Akt, activities are lower in macrophages infected with an avirulent bacterial strain
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
A1066V
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a common naturally occuring mutation involved in cancer development
D1017H
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a common naturally occuring somatic mutation involved in cancer development
D915A
complete loss of enzymic activity
D933A/F934A
complete loss of enzymic activity
E542K
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a common naturally occuring mutation in the helical domain, the mutation is involved in cancer development, the mutant requires RAS binding but bot p85 binding
E542K/E545K
E545K/H1047R
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gain-of-function helical domain mutations result in upregulation of enzyme activity, Akt phosphorylation and cell transformation
E970A
90% of wild-type activity
H1047R
K227E
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the mutaion reduces enzyme activity
K802R
mutation in subunit p110alpha, inactive mutant
M1043I
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a common naturally occuring somatic mutation involved in cancer development
M326I
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a common naturally occuring polymorphism of the regulatory subunit p85alpha in women involved in the polycystic ovary syndrome, PCOS, genotyping in polycystic ovary syndrome patients from Korean female population
N345K
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the mutation significantly change the distance distribution for helical domain residues K379, I381 and K382
P124L
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a common naturally occuring somatic mutation involved in cancer development. P124L lies in a region of four helices in the protein between the adapter-binding and RAS-binding domains
P124T
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a naturally occuring missense mutation in codon 124 from a colorectal cancer cell
Q643R
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a common naturally occuring somatic mutation involved in cancer development
R274A
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the GTPase-activating protein activity toward Rab5 and Rab4 of PI3K p85alpha subunit is abolished in the mutant. Expression of p85alpha-R274A results in increased platelet-derived growth factor receptor, PDGFR, activation and downstream signaling, via Akt and MAPK pathways, and in decreased PDGFR degradation. Disrupted RabGAP function of the p85 subunit of phosphatidylinositol 3-kinase results in cell transformation, co-expression of a dominant negative Rab5-S34N mutant attenuates these transformed properties
R38C/R88C
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the mutation significantly change the distance distribution for helical domain residues K379, I381 and K382
R922A
80% of wild-type activity
additional information
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
analysis
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low-cost bioassay that readily measures phosphatidylinositol 3-kinase inhibition. The in vivo assay is based on the fact that the overproduction of phosphatidylinositol 3-kinase is toxic in yeast, and uses the ability of commercial phosphatidylinositol 3-kinase inhibitors to rescue cell growth. The use of 0.003% sodium dodecyl sulfate and the elimination of the Snq2 detoxification pump, optimize the bioassay by enhancing its sensitivity. From 9600 extracts tested, 0.6% lead to a recovery of yeast growth reproducibly, selectively, and in a dose-dependent manner
medicine
pharmacology
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the PI3Kgamma signaling pathway may represent a suitable target for the development of therapeutic strategies for human diseases characterized by vascular leakage