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Literature summary extracted from

  • Mayr, G.W.; Windhorst, S.; Hillemeier, K.
    Antiproliferative plant and synthetic polyphenolics are specific inhibitors of vertebrate inositol-1,4,5-trisphosphate 3-kinases and inositol polyphosphate multikinase. [Erratum to document cited in CA143:003106] (2007), J. Biol. Chem., 282, 35424.
No PubMed abstract available

Activating Compound

EC Number Activating Compound Comment Organism Structure
2.7.1.127 Triton X-100 Antagonizing the effect of all inhibitors identified with GgIP3K-A. When 0.2% Triton X-100 is added to assays containing the respective inhibitors at IC50, the previous inhibition of GgIP3K-A is immediately reversed by an extent between 49 and 100% Gallus gallus

Cloned(Commentary)

EC Number Cloned (Comment) Organism
2.7.1.127 Cloning and expression of isoform A and of a fragment comprising the catalytic calmodulin binding domain (amino acids 165-462) in Escherichia coli BL21(DE3). Homo sapiens
2.7.1.127 Cloning and expression of isoform A and of an enzyme fragment comprising the catalytic calmodulin binding domain in Escherichia coli BL21(DE3). Creating of a point mutant by using PCR-based site-directed QuikChange mutagenesis and expression in Escherichia coli. Gallus gallus
2.7.1.127 Cloning and expression of isoform B and of a fragment comprising the catalytic calmodulin binding domain (amino acids 165-462) in Escherichia coli BL21(DE3). Homo sapiens
2.7.1.127 Cloning, Expression, and Purification of RnIP3K-C isoform and of two different recombinant fragments IP3K-C, one comprising the catalytic domain and the calmodulin binding domain, the other comprising only the catalytic domain, are expressed in Escherichi coli BL21(DE3) cells. Rattus norvegicus

Protein Variants

EC Number Protein Variants Comment Organism
2.7.1.127 K336Q By substituting lysine 336, involving in ATP binding and located in the C-lobe, an inhibitor-resistant IP3K-A with full enzymatic activity and normal substrate affinity is created. Gallus gallus

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.7.1.127 3',4',7,8-tetrahydroxyflavone the point mutant K336Q reveals a drastically reduced inhibition by THF. Substitution of Lys336 leads to a 260fold increase in the IC50. On the other hand, kinetic parameters of the enzyme with respect to both substrates are nearly unchanged. This region shows high homology between IP3K isoforms. Gallus gallus
2.7.1.127 3',4',7,8-tetrahydroxyflavone
-
 Homo sapiens
2.7.1.127 3',4',7,8-tetrahydroxyflavone
-
 Rattus norvegicus
2.7.1.127 aurintricarboxylic acid
-
 Gallus gallus
2.7.1.127 aurintricarboxylic acid
-
 Homo sapiens
2.7.1.127 aurintricarboxylic acid
-
 Rattus norvegicus
2.7.1.127 chlorogenic acid
-
 Gallus gallus
2.7.1.127 chlorogenic acid
-
 Homo sapiens
2.7.1.127 chlorogenic acid
-
 Rattus norvegicus
2.7.1.127 ellagic acid
-
 Gallus gallus
2.7.1.127 ellagic acid
-
 Homo sapiens
2.7.1.127 ellagic acid
-
 Rattus norvegicus
2.7.1.127 epicatechin-3-gallate
-
 Gallus gallus
2.7.1.127 epicatechin-3-gallate
-
 Homo sapiens
2.7.1.127 epicatechin-3-gallate
-
 Rattus norvegicus
2.7.1.127 epigallocatechin-3-gallate
-
 Gallus gallus
2.7.1.127 epigallocatechin-3-gallate
-
 Homo sapiens
2.7.1.127 epigallocatechin-3-gallate
-
 Rattus norvegicus
2.7.1.127 gossypol
-
 Gallus gallus
2.7.1.127 gossypol
-
 Homo sapiens
2.7.1.127 gossypol
-
 Rattus norvegicus
2.7.1.127 hypericin
-
 Gallus gallus
2.7.1.127 hypericin
-
 Homo sapiens
2.7.1.127 hypericin
-
 Rattus norvegicus
2.7.1.127 additional information All inhibitors display a mixed-type inhibition with respect to ATP and a noncompetitive inhibition with respect to 1D-myo-inositol 1,4,5-triphosphate. Mutagenesis studies reveal that both the calmodulin binding and the ATP binding domains in IP3K are involved in inhibitor binding. Most discovered potent IP3K inhibitors exert antiproliferative effects on cultured cells in vitro or in animal experiments and tumor treatment studies in vivo.; Reversal of enzyme inhibition by addition of Triton X-100 and Ca2+-calmodulin. Gallus gallus
2.7.1.127 additional information All inhibitors display a mixed-type inhibition with respect to ATP and a noncompetitive inhibition with respect to inositol-1,4,5-trisphosphate. Mutagenesis studies reveal that both the calmodulin binding and the ATP binding domains in IP3K are involved in inhibitor binding. Most discovered potent IP3K inhibitors exert antiproliferative effects on cultured cells in vitro or in animal experiments and tumor treatment studies in vivo.; All inhibitors display a mixed-type inhibition with respect to ATP and a noncompetitive inhibition with respect to Ins(1,4,5)P3. Mutagenesis studies reveal that both the calmodulin binding and the ATP binding domains in IP3K are involved in inhibitor binding. Most discovered potent IP3K inhibitors exert antiproliferative effects on cultured cells in vitro or in animal experiments and tumor treatment studies in vivo. Homo sapiens
2.7.1.127 additional information All inhibitors display a mixed-type inhibition with respect to ATP and a noncompetitive inhibition with respect to 1D-myo-inositol 1,4,5-triphosphate. Mutagenesis studies reveal that both the calmodulin binding and the ATP binding domains in IP3K are involved in inhibitor binding. Most discovered potent IP3K inhibitors exert antiproliferative effects on cultured cells in vitro or in animal experiments and tumor treatment studies in vivo.; The flavonoids myricetin, 3',4',7,8-tetrahydroxyflavone, and epigallocatechin-3-gallate have a markedly stronger effect on isoforms A and C than on isoform B Rattus norvegicus
2.7.1.127 myricetin
-
 Gallus gallus
2.7.1.127 myricetin
-
 Homo sapiens
2.7.1.127 myricetin
-
 Rattus norvegicus
2.7.1.127 quercetin
-
 Gallus gallus
2.7.1.127 quercetin
-
 Homo sapiens
2.7.1.127 quercetin
-
 Rattus norvegicus
2.7.1.127 Rose bengal
-
 Gallus gallus
2.7.1.127 Rose bengal
-
 Homo sapiens
2.7.1.127 Rose bengal
-
 Rattus norvegicus

KM Value [mM]

EC Number KM Value [mM] KM Value Maximum [mM] Substrate Comment Organism Structure
2.7.1.127 additional information
-
 additional information All potent inhibitors increases the KM-value for ATP Gallus gallus
2.7.1.127 additional information
-
 additional information All potent inhibitors increases the KM-value for ATP Rattus norvegicus
2.7.1.127 0.0002
-
 InsP3 recombinant enzyme IP3K-C fragment comprising calmodulin binding domain and catalytic domain Rattus norvegicus
2.7.1.127 0.0004
-
 1D-myo-inositol 1,4,5-trisphosphate recombinant enzyme fragment comprising calmodulin binding domain Gallus gallus
2.7.1.127 0.00054
-
 1D-myo-inositol 1,4,5-trisphosphate IP3K-A K336Q mutant Gallus gallus
2.7.1.127 0.0017
-
 InsP3 recombinant enzyme IP3K-C fragment comprising catalytic domain Rattus norvegicus
2.7.1.127 0.033
-
 ATP recombinant enzyme IP3K-C fragment comprising calmodulin binding domain and catalytic domain Rattus norvegicus
2.7.1.127 0.042
-
 ATP recombinant enzyme IP3K-C fragment comprising catalytic domain Rattus norvegicus
2.7.1.127 0.074
-
 ATP recombinant enzyme fragment comprising calmodulin binding domain Gallus gallus
2.7.1.127 0.105
-
 ATP IP3K-A K336Q mutant Gallus gallus

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
2.7.1.127 actin filament IP3K-B is expressed in nearly all human tissues and is localized at actin filaments and the endoplasmic reticulum Homo sapiens 5884
-
2.7.1.127 endoplasmic reticulum
-
 Homo sapiens 5783
-

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
2.7.1.127 Ca2+
-
 Gallus gallus
2.7.1.127 Ca2+
-
 Homo sapiens
2.7.1.127 Ca2+
-
 Rattus norvegicus
2.7.1.127 Mg2+
-
 Gallus gallus
2.7.1.127 Mg2+
-
 Homo sapiens
2.7.1.127 Mg2+
-
 Rattus norvegicus

Molecular Weight [Da]

EC Number Molecular Weight [Da] Molecular Weight Maximum [Da] Comment Organism
2.7.1.127 36250
-
 IP3K-A, determined with MALDI-TOF-MS. Calculated mass is 36228 Da Gallus gallus

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.7.1.127 ATP + 1D-myo-inositol 1,4,5-triphosphate Rattus norvegicus
-
 ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
 r
2.7.1.127 ATP + 1D-myo-inositol 1,4,5-trisphosphate Gallus gallus
-
 ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
 r
2.7.1.127 ATP + 1D-myo-inositol 1,4,5-trisphosphate Homo sapiens
-
 ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
 r

Organism

EC Number Organism UniProt Comment Textmining
2.7.1.127 Gallus gallus
-
-
-
2.7.1.127 Homo sapiens P23677
-
-
2.7.1.127 Homo sapiens P27987
-
-
2.7.1.127 Rattus norvegicus Q80ZG2
-
-

Purification (Commentary)

EC Number Purification (Comment) Organism
2.7.1.127 By phosphocellulose. Rattus norvegicus
2.7.1.127 Purification of IP3K isoform A and point mutant are performed by phosphocellulose and calmodulin affinity chromatography. Gallus gallus
2.7.1.127 Purification of IP3K isoform A is performed by phosphocellulose and calmodulin affinity chromatography. Homo sapiens
2.7.1.127 Purification of IP3K isoform B is performed by phosphocellulose and calmodulin affinity chromatography. Homo sapiens

Source Tissue

EC Number Source Tissue Comment Organism Textmining
2.7.1.127 brain IP3K-A Homo sapiens
-
2.7.1.127 cell culture cloning and expression in Escherichia coli Homo sapiens
-
2.7.1.127 cell culture Enzymes and their fragments expressed in Escherichia coli. Rattus norvegicus
-
2.7.1.127 cell culture Enzymes expressed in Escherichia coli Gallus gallus
-
2.7.1.127 testis IP3K-A is identified mainly in brain and testis and shows an exclusive F-actin localization Homo sapiens
-

Specific Activity [micromol/min/mg]

EC Number Specific Activity Minimum [µmol/min/mg] Specific Activity Maximum [µmol/min/mg] Comment Organism
2.7.1.127 3
-
 IP3K-C, recombinant enzyme fragment comprising calmodulin binding and catalytic domain Rattus norvegicus
2.7.1.127 15
-
 recombinant enzyme fragment comprising calmodulin binding domain Gallus gallus
2.7.1.127 16
-
 IP3K-A, K336Q mutant Gallus gallus
2.7.1.127 16
-
 IP3K-C, recombinant enzyme fragment comprising catalytic domain Rattus norvegicus

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.7.1.127 ATP + 1D-myo-inositol 1,4,5-triphosphate
-
 Rattus norvegicus ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
 r
2.7.1.127 ATP + 1D-myo-inositol 1,4,5-trisphosphate
-
 Gallus gallus ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
 r
2.7.1.127 ATP + 1D-myo-inositol 1,4,5-trisphosphate
-
 Homo sapiens ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
 r

Synonyms

EC Number Synonyms Comment Organism
2.7.1.127 GsIP3K-A
-
 Gallus gallus
2.7.1.127 HsIP3K-A
-
 Homo sapiens
2.7.1.127 inositol polyphosphate multikinase
-
 Rattus norvegicus
2.7.1.127 inositol-1,4,5-trisphosphate 3-kinase
-
 Gallus gallus
2.7.1.127 inositol-1,4,5-trisphosphate 3-kinase
-
 Homo sapiens
2.7.1.127 inositol-1,4,5-trisphosphate 3-kinase
-
 Rattus norvegicus
2.7.1.127 IP3K
-
 Gallus gallus
2.7.1.127 IP3K
-
 Rattus norvegicus
2.7.1.127 IP3K The IP3K family consists of three isoenzymes referred to as IP3K-A, IP3K-B, and IP3K-C differing in their degree of activation by Ca2+-calmodulin, affinity for inositol-1,4,5-trisphosphate, tissue and intracellular distribution Homo sapiens
2.7.1.127 IP3K-A
-
 Homo sapiens
2.7.1.127 IP3K-B
-
 Homo sapiens
2.7.1.127 RnIP3K-C
-
 Rattus norvegicus

Temperature Optimum [°C]

EC Number Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
2.7.1.127 30
-
 assay at Gallus gallus
2.7.1.127 30
-
 assay at Homo sapiens
2.7.1.127 30
-
 assay at Rattus norvegicus

pH Optimum

EC Number pH Optimum Minimum pH Optimum Maximum Comment Organism
2.7.1.127 7.5
-
 assay at Gallus gallus
2.7.1.127 7.5
-
 assay at Homo sapiens
2.7.1.127 7.5
-
 assay at Rattus norvegicus

Cofactor

EC Number Cofactor Comment Organism Structure
2.7.1.127 ATP
-
 Homo sapiens
2.7.1.127 ATP Involved in inhibitor binding. Gallus gallus
2.7.1.127 ATP Involved in inhibitor binding. Rattus norvegicus
2.7.1.127 Calmodulin The binding domain is present in all IP3K isoforms Homo sapiens
2.7.1.127 Calmodulin The binding domain is present in all IP3K isoforms, involved in inhibitor binding. Gallus gallus
2.7.1.127 Calmodulin The binding domain is present in all IP3K isoforms, involved in inhibitor binding. Rattus norvegicus

Ki Value [mM]

EC Number Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
2.7.1.127 0.00002
-
 epicatechin-3-gallate IP3K-A, mixed-type with respect to ATP Gallus gallus
2.7.1.127 0.000043
-
 ellagic acid IP3K-A, mixed-type with respect to ATP Gallus gallus
2.7.1.127 0.000043
-
 epicatechin-3-gallate IP3K-A, non-competitive with respect to Ins(1,4,5)P3 Gallus gallus
2.7.1.127 0.000059
-
 epigallocatechin-3-gallate IP3K-A, mixed-type with respect to ATP Gallus gallus
2.7.1.127 0.000059
-
 epigallocatechin-3-gallate IP3K-A, non-competitive with respect to Ins(1,4,5)P3 Gallus gallus
2.7.1.127 0.00006
-
 ellagic acid IP3K-A, non-competitive with respect to Ins(1,4,5)P3 Gallus gallus
2.7.1.127 0.000061
-
 gossypol IP3K-A, mixed-type with respect to ATP Gallus gallus
2.7.1.127 0.000074
-
 hypericin IP3K-A, mixed-type with respect to ATP Gallus gallus
2.7.1.127 0.000077
-
 gossypol IP3K-A, non-competitive with respect to Ins(1,4,5)P3 Gallus gallus
2.7.1.127 0.000096
-
 aurintricarboxylic acid IP3K-A, mixed-type with respect to ATP Gallus gallus
2.7.1.127 0.0001
-
 aurintricarboxylic acid IP3K-A, non-competitive with respect to Ins(1,4,5)P3 Gallus gallus
2.7.1.127 0.000156
-
 hypericin IP3K-A, non-competitive with respect to Ins(1,4,5)P3 Gallus gallus
2.7.1.127 0.000197
-
 quercetin IP3K-A, non-competitive with respect to Ins(1,4,5)P3 Gallus gallus
2.7.1.127 0.000312
-
 quercetin IP3K-A, mixed-type with respect to ATP Gallus gallus

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
2.7.1.127 additional information
-
 IC > 0.1 Homo sapiens chlorogenic acid
2.7.1.127 additional information
-
 IP3K-A, IC > 0.1 Gallus gallus chlorogenic acid
2.7.1.127 additional information
-
 IP3K-C, IC > 0.1 Rattus norvegicus chlorogenic acid
2.7.1.127 additional information
-
 RnIP3K-C including the calmodulin binding and the catalytic domain shows a 3-fold lower IC50 value for 3',4',7,8-tetrahydroxyflavone than RnIP3K including only the calmodulin binding domain. The maximum degree of inhibition is unchanged. Together with the finding that Ca2+-calmodulin partly reverses IP3K inhibition indicates a facilitating but not essential involvement of the calmodulin binding domain in inhibitor binding. Rattus norvegicus additional information
2.7.1.127 0.000036
-
 IP3K-A, maximal inhibition 75% Gallus gallus ellagic acid
2.7.1.127 0.000058
-
 IP3K-A, maximal inhibition 100% Gallus gallus gossypol
2.7.1.127 0.000062
-
 IP3K-C, maximal inhibition 100% Rattus norvegicus aurintricarboxylic acid
2.7.1.127 0.000094
-
 IP3K-A, maximal inhibition 100% Gallus gallus epicatechin-3-gallate
2.7.1.127 0.00011
-
-
 Homo sapiens aurintricarboxylic acid
2.7.1.127 0.000115
-
-
 Homo sapiens gossypol
2.7.1.127 0.00012
-
 IP3K-A, maximal inhibition 100% Gallus gallus epigallocatechin-3-gallate
2.7.1.127 0.000138
-
-
 Homo sapiens aurintricarboxylic acid
2.7.1.127 0.00015
-
-
 Homo sapiens myricetin
2.7.1.127 0.00015
-
-
 Homo sapiens epigallocatechin-3-gallate
2.7.1.127 0.00015
-
 IP3K-A, maximal inhibition 100% Gallus gallus aurintricarboxylic acid
2.7.1.127 0.00017
-
 IP3K-A, maximal inhibition 100% Gallus gallus hypericin
2.7.1.127 0.00017
-
 IP3K-C, maximal inhibition 100% Rattus norvegicus Rose bengal
2.7.1.127 0.00017
-
 IP3K-C, maximal inhibition 100% Rattus norvegicus hypericin
2.7.1.127 0.000175
-
 IP3K-C, maximal inhibition 100% Rattus norvegicus gossypol
2.7.1.127 0.00018
-
-
 Homo sapiens hypericin
2.7.1.127 0.00018
-
-
 Homo sapiens 3',4',7,8-tetrahydroxyflavone
2.7.1.127 0.00018
-
 IP3K-A, maximal inhibition 80% Gallus gallus quercetin
2.7.1.127 0.00019
-
 IP3K-C, maximal inhibition 75% Rattus norvegicus 3',4',7,8-tetrahydroxyflavone
2.7.1.127 0.00019
-
 recombinant enzyme IP3K-C fragment comprising calmodulin binding and catalytic domain Rattus norvegicus 3',4',7,8-tetrahydroxyflavone
2.7.1.127 0.00021
-
-
 Homo sapiens hypericin
2.7.1.127 0.00021
-
 IP3K-C, maximal inhibition 100% Rattus norvegicus epigallocatechin-3-gallate
2.7.1.127 0.00022
-
-
 Homo sapiens ellagic acid
2.7.1.127 0.00029
-
 IP3K-A, maximal inhibition 97% Gallus gallus 3',4',7,8-tetrahydroxyflavone
2.7.1.127 0.00029
-
 IP3K-C, maximal inhibition 62% Rattus norvegicus myricetin
2.7.1.127 0.00029
-
 recombinant enzyme fragment comprising calmodulin binding domain Gallus gallus 3',4',7,8-tetrahydroxyflavone
2.7.1.127 0.0003
-
-
 Homo sapiens quercetin
2.7.1.127 0.00034
-
-
 Homo sapiens gossypol
2.7.1.127 0.000385
-
 IP3K-C, maximal inhibition 100% Rattus norvegicus epicatechin-3-gallate
2.7.1.127 0.00039
-
 IP3K-C, maximal inhibition 71% Rattus norvegicus quercetin
2.7.1.127 0.0004
-
-
 Homo sapiens epicatechin-3-gallate
2.7.1.127 0.00052
-
-
 Homo sapiens Rose bengal
2.7.1.127 0.00054
-
 IP3K-A, maximal inhibition 85% Gallus gallus myricetin
2.7.1.127 0.00055
-
-
 Homo sapiens ellagic acid
2.7.1.127 0.00056
-
-
 Homo sapiens epicatechin-3-gallate
2.7.1.127 0.00061
-
 recombinant enzyme IP3K-C fragment comprising catalytic domain Rattus norvegicus 3',4',7,8-tetrahydroxyflavone
2.7.1.127 0.00069
-
 IP3K-C, maximal inhibition 85% Rattus norvegicus ellagic acid
2.7.1.127 0.00125
-
-
 Homo sapiens quercetin
2.7.1.127 0.00219
-
-
 Homo sapiens Rose bengal
2.7.1.127 0.00278
-
-
 Homo sapiens epigallocatechin-3-gallate
2.7.1.127 0.00312
-
 IP3K-A, maximal inhibition 100% Gallus gallus Rose bengal
2.7.1.127 0.0034
-
-
 Homo sapiens 3',4',7,8-tetrahydroxyflavone
2.7.1.127 0.0042
-
-
 Homo sapiens myricetin
2.7.1.127 0.0843
-
 IP3K-A, K336Q mutant Gallus gallus 3',4',7,8-tetrahydroxyflavone