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Literature summary for 2.7.1.127 extracted from
- 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
| Activating Compound | Comment | Organism | Structure |
|---|---|---|---|
| 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)
| Cloned (Comment) | Organism |
|---|---|
| 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 |
| 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 |
| 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 |
| 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
| Protein Variants | Comment | Organism |
|---|---|---|
| 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
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| 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 | |
| 3',4',7,8-tetrahydroxyflavone | - |
Homo sapiens | |
| 3',4',7,8-tetrahydroxyflavone | - |
Rattus norvegicus | |
| aurintricarboxylic acid | - |
Gallus gallus | |
| aurintricarboxylic acid | - |
Homo sapiens | |
| aurintricarboxylic acid | - |
Rattus norvegicus | |
| chlorogenic acid | - |
Gallus gallus | |
| chlorogenic acid | - |
Homo sapiens | |
| chlorogenic acid | - |
Rattus norvegicus | |
| ellagic acid | - |
Gallus gallus | |
| ellagic acid | - |
Homo sapiens | |
| ellagic acid | - |
Rattus norvegicus | |
| epicatechin-3-gallate | - |
Gallus gallus | |
| epicatechin-3-gallate | - |
Homo sapiens | |
| epicatechin-3-gallate | - |
Rattus norvegicus | |
| epigallocatechin-3-gallate | - |
Gallus gallus | |
| epigallocatechin-3-gallate | - |
Homo sapiens | |
| epigallocatechin-3-gallate | - |
Rattus norvegicus | |
| gossypol | - |
Gallus gallus | |
| gossypol | - |
Homo sapiens | |
| gossypol | - |
Rattus norvegicus | |
| hypericin | - |
Gallus gallus | |
| hypericin | - |
Homo sapiens | |
| hypericin | - |
Rattus norvegicus | |
| 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 | |
| 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 | |
| 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 | |
| myricetin | - |
Gallus gallus | |
| myricetin | - |
Homo sapiens | |
| myricetin | - |
Rattus norvegicus | |
| quercetin | - |
Gallus gallus | |
| quercetin | - |
Homo sapiens | |
| quercetin | - |
Rattus norvegicus | |
| Rose bengal | - |
Gallus gallus | |
| Rose bengal | - |
Homo sapiens | |
| Rose bengal | - |
Rattus norvegicus | |
KM Value [mM]
| KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|
| additional information | - |
additional information | All potent inhibitors increases the KM-value for ATP | Gallus gallus | |
| additional information | - |
additional information | All potent inhibitors increases the KM-value for ATP | Rattus norvegicus | |
| 0.0002 | - |
InsP3 | recombinant enzyme IP3K-C fragment comprising calmodulin binding domain and catalytic domain | Rattus norvegicus | |
| 0.0004 | - |
1D-myo-inositol 1,4,5-trisphosphate | recombinant enzyme fragment comprising calmodulin binding domain | Gallus gallus | |
| 0.00054 | - |
1D-myo-inositol 1,4,5-trisphosphate | IP3K-A K336Q mutant | Gallus gallus | |
| 0.0017 | - |
InsP3 | recombinant enzyme IP3K-C fragment comprising catalytic domain | Rattus norvegicus | |
| 0.033 | - |
ATP | recombinant enzyme IP3K-C fragment comprising calmodulin binding domain and catalytic domain | Rattus norvegicus | |
| 0.042 | - |
ATP | recombinant enzyme IP3K-C fragment comprising catalytic domain | Rattus norvegicus | |
| 0.074 | - |
ATP | recombinant enzyme fragment comprising calmodulin binding domain | Gallus gallus | |
| 0.105 | - |
ATP | IP3K-A K336Q mutant | Gallus gallus | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| actin filament | IP3K-B is expressed in nearly all human tissues and is localized at actin filaments and the endoplasmic reticulum | Homo sapiens | 5884 | - |
| endoplasmic reticulum | - |
Homo sapiens | 5783 | - |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Ca2+ | - |
Gallus gallus | |
| Ca2+ | - |
Homo sapiens | |
| Ca2+ | - |
Rattus norvegicus | |
| Mg2+ | - |
Gallus gallus | |
| Mg2+ | - |
Homo sapiens | |
| Mg2+ | - |
Rattus norvegicus | |
Molecular Weight [Da]
| Molecular Weight [Da] | Molecular Weight Maximum [Da] | Comment | Organism |
|---|---|---|---|
| 36250 | - |
IP3K-A, determined with MALDI-TOF-MS. Calculated mass is 36228 Da | Gallus gallus |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + 1D-myo-inositol 1,4,5-triphosphate | Rattus norvegicus | - |
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate | - |
r | |
| ATP + 1D-myo-inositol 1,4,5-trisphosphate | Gallus gallus | - |
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate | - |
r | |
| ATP + 1D-myo-inositol 1,4,5-trisphosphate | Homo sapiens | - |
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate | - |
r | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Gallus gallus | - |
- |
- |
| Homo sapiens | P23677 | - |
- |
| Homo sapiens | P27987 | - |
- |
| Rattus norvegicus | Q80ZG2 | - |
- |
Purification (Commentary)
| Purification (Comment) | Organism |
|---|---|
| By phosphocellulose. | Rattus norvegicus |
| Purification of IP3K isoform A and point mutant are performed by phosphocellulose and calmodulin affinity chromatography. | Gallus gallus |
| Purification of IP3K isoform A is performed by phosphocellulose and calmodulin affinity chromatography. | Homo sapiens |
| Purification of IP3K isoform B is performed by phosphocellulose and calmodulin affinity chromatography. | Homo sapiens |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| brain | IP3K-A | Homo sapiens | - |
| cell culture | cloning and expression in Escherichia coli | Homo sapiens | - |
| cell culture | Enzymes and their fragments expressed in Escherichia coli. | Rattus norvegicus | - |
| cell culture | Enzymes expressed in Escherichia coli | Gallus gallus | - |
| testis | IP3K-A is identified mainly in brain and testis and shows an exclusive F-actin localization | Homo sapiens | - |
Specific Activity [micromol/min/mg]
| Specific Activity Minimum [µmol/min/mg] | Specific Activity Maximum [µmol/min/mg] | Comment | Organism |
|---|---|---|---|
| 3 | - |
IP3K-C, recombinant enzyme fragment comprising calmodulin binding and catalytic domain | Rattus norvegicus |
| 15 | - |
recombinant enzyme fragment comprising calmodulin binding domain | Gallus gallus |
| 16 | - |
IP3K-A, K336Q mutant | Gallus gallus |
| 16 | - |
IP3K-C, recombinant enzyme fragment comprising catalytic domain | Rattus norvegicus |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + 1D-myo-inositol 1,4,5-triphosphate | - |
Rattus norvegicus | ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate | - |
r | |
| ATP + 1D-myo-inositol 1,4,5-trisphosphate | - |
Gallus gallus | ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate | - |
r | |
| ATP + 1D-myo-inositol 1,4,5-trisphosphate | - |
Homo sapiens | ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate | - |
r | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| GsIP3K-A | - |
Gallus gallus |
| HsIP3K-A | - |
Homo sapiens |
| inositol polyphosphate multikinase | - |
Rattus norvegicus |
| inositol-1,4,5-trisphosphate 3-kinase | - |
Gallus gallus |
| inositol-1,4,5-trisphosphate 3-kinase | - |
Homo sapiens |
| inositol-1,4,5-trisphosphate 3-kinase | - |
Rattus norvegicus |
| IP3K | - |
Gallus gallus |
| IP3K | - |
Rattus norvegicus |
| 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 |
| IP3K-A | - |
Homo sapiens |
| IP3K-B | - |
Homo sapiens |
| RnIP3K-C | - |
Rattus norvegicus |
Temperature Optimum [°C]
| Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
|---|---|---|---|
| 30 | - |
assay at | Gallus gallus |
| 30 | - |
assay at | Homo sapiens |
| 30 | - |
assay at | Rattus norvegicus |
pH Optimum
| pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
|---|---|---|---|
| 7.5 | - |
assay at | Gallus gallus |
| 7.5 | - |
assay at | Homo sapiens |
| 7.5 | - |
assay at | Rattus norvegicus |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| ATP | - |
Homo sapiens | |
| ATP | Involved in inhibitor binding. | Gallus gallus | |
| ATP | Involved in inhibitor binding. | Rattus norvegicus | |
| Calmodulin | The binding domain is present in all IP3K isoforms | Homo sapiens | |
| Calmodulin | The binding domain is present in all IP3K isoforms, involved in inhibitor binding. | Gallus gallus | |
| Calmodulin | The binding domain is present in all IP3K isoforms, involved in inhibitor binding. | Rattus norvegicus | |
Ki Value [mM]
| Ki Value [mM] | Ki Value maximum [mM] | Inhibitor | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 0.00002 | - |
epicatechin-3-gallate | IP3K-A, mixed-type with respect to ATP | Gallus gallus | |
| 0.000043 | - |
ellagic acid | IP3K-A, mixed-type with respect to ATP | Gallus gallus | |
| 0.000043 | - |
epicatechin-3-gallate | IP3K-A, non-competitive with respect to Ins(1,4,5)P3 | Gallus gallus | |
| 0.000059 | - |
epigallocatechin-3-gallate | IP3K-A, mixed-type with respect to ATP | Gallus gallus | |
| 0.000059 | - |
epigallocatechin-3-gallate | IP3K-A, non-competitive with respect to Ins(1,4,5)P3 | Gallus gallus | |
| 0.00006 | - |
ellagic acid | IP3K-A, non-competitive with respect to Ins(1,4,5)P3 | Gallus gallus | |
| 0.000061 | - |
gossypol | IP3K-A, mixed-type with respect to ATP | Gallus gallus | |
| 0.000074 | - |
hypericin | IP3K-A, mixed-type with respect to ATP | Gallus gallus | |
| 0.000077 | - |
gossypol | IP3K-A, non-competitive with respect to Ins(1,4,5)P3 | Gallus gallus | |
| 0.000096 | - |
aurintricarboxylic acid | IP3K-A, mixed-type with respect to ATP | Gallus gallus | |
| 0.0001 | - |
aurintricarboxylic acid | IP3K-A, non-competitive with respect to Ins(1,4,5)P3 | Gallus gallus | |
| 0.000156 | - |
hypericin | IP3K-A, non-competitive with respect to Ins(1,4,5)P3 | Gallus gallus | |
| 0.000197 | - |
quercetin | IP3K-A, non-competitive with respect to Ins(1,4,5)P3 | Gallus gallus | |
| 0.000312 | - |
quercetin | IP3K-A, mixed-type with respect to ATP | Gallus gallus | |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| additional information | - |
IC > 0.1 | Homo sapiens | chlorogenic acid | |
| additional information | - |
IP3K-A, IC > 0.1 | Gallus gallus | chlorogenic acid | |
| additional information | - |
IP3K-C, IC > 0.1 | Rattus norvegicus | chlorogenic acid | |
| 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 | |
| 0.000036 | - |
IP3K-A, maximal inhibition 75% | Gallus gallus | ellagic acid | |
| 0.000058 | - |
IP3K-A, maximal inhibition 100% | Gallus gallus | gossypol | |
| 0.000062 | - |
IP3K-C, maximal inhibition 100% | Rattus norvegicus | aurintricarboxylic acid | |
| 0.000094 | - |
IP3K-A, maximal inhibition 100% | Gallus gallus | epicatechin-3-gallate | |
| 0.00011 | - |
- |
Homo sapiens | aurintricarboxylic acid | |
| 0.000115 | - |
- |
Homo sapiens | gossypol | |
| 0.00012 | - |
IP3K-A, maximal inhibition 100% | Gallus gallus | epigallocatechin-3-gallate | |
| 0.000138 | - |
- |
Homo sapiens | aurintricarboxylic acid | |
| 0.00015 | - |
- |
Homo sapiens | myricetin | |
| 0.00015 | - |
- |
Homo sapiens | epigallocatechin-3-gallate | |
| 0.00015 | - |
IP3K-A, maximal inhibition 100% | Gallus gallus | aurintricarboxylic acid | |
| 0.00017 | - |
IP3K-A, maximal inhibition 100% | Gallus gallus | hypericin | |
| 0.00017 | - |
IP3K-C, maximal inhibition 100% | Rattus norvegicus | Rose bengal | |
| 0.00017 | - |
IP3K-C, maximal inhibition 100% | Rattus norvegicus | hypericin | |
| 0.000175 | - |
IP3K-C, maximal inhibition 100% | Rattus norvegicus | gossypol | |
| 0.00018 | - |
- |
Homo sapiens | hypericin | |
| 0.00018 | - |
- |
Homo sapiens | 3',4',7,8-tetrahydroxyflavone | |
| 0.00018 | - |
IP3K-A, maximal inhibition 80% | Gallus gallus | quercetin | |
| 0.00019 | - |
IP3K-C, maximal inhibition 75% | Rattus norvegicus | 3',4',7,8-tetrahydroxyflavone | |
| 0.00019 | - |
recombinant enzyme IP3K-C fragment comprising calmodulin binding and catalytic domain | Rattus norvegicus | 3',4',7,8-tetrahydroxyflavone | |
| 0.00021 | - |
- |
Homo sapiens | hypericin | |
| 0.00021 | - |
IP3K-C, maximal inhibition 100% | Rattus norvegicus | epigallocatechin-3-gallate | |
| 0.00022 | - |
- |
Homo sapiens | ellagic acid | |
| 0.00029 | - |
IP3K-A, maximal inhibition 97% | Gallus gallus | 3',4',7,8-tetrahydroxyflavone | |
| 0.00029 | - |
IP3K-C, maximal inhibition 62% | Rattus norvegicus | myricetin | |
| 0.00029 | - |
recombinant enzyme fragment comprising calmodulin binding domain | Gallus gallus | 3',4',7,8-tetrahydroxyflavone | |
| 0.0003 | - |
- |
Homo sapiens | quercetin | |
| 0.00034 | - |
- |
Homo sapiens | gossypol | |
| 0.000385 | - |
IP3K-C, maximal inhibition 100% | Rattus norvegicus | epicatechin-3-gallate | |
| 0.00039 | - |
IP3K-C, maximal inhibition 71% | Rattus norvegicus | quercetin | |
| 0.0004 | - |
- |
Homo sapiens | epicatechin-3-gallate | |
| 0.00052 | - |
- |
Homo sapiens | Rose bengal | |
| 0.00054 | - |
IP3K-A, maximal inhibition 85% | Gallus gallus | myricetin | |
| 0.00055 | - |
- |
Homo sapiens | ellagic acid | |
| 0.00056 | - |
- |
Homo sapiens | epicatechin-3-gallate | |
| 0.00061 | - |
recombinant enzyme IP3K-C fragment comprising catalytic domain | Rattus norvegicus | 3',4',7,8-tetrahydroxyflavone | |
| 0.00069 | - |
IP3K-C, maximal inhibition 85% | Rattus norvegicus | ellagic acid | |
| 0.00125 | - |
- |
Homo sapiens | quercetin | |
| 0.00219 | - |
- |
Homo sapiens | Rose bengal | |
| 0.00278 | - |
- |
Homo sapiens | epigallocatechin-3-gallate | |
| 0.00312 | - |
IP3K-A, maximal inhibition 100% | Gallus gallus | Rose bengal | |
| 0.0034 | - |
- |
Homo sapiens | 3',4',7,8-tetrahydroxyflavone | |
| 0.0042 | - |
- |
Homo sapiens | myricetin | |
| 0.0843 | - |
IP3K-A, K336Q mutant | Gallus gallus | 3',4',7,8-tetrahydroxyflavone | |
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