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Literature summary for 2.7.1.137 extracted from
- Targeting the gatekeeper residue in phosphoinositide 3-kinases (2005), Bioorg. Med. Chem., 13, 2825-2836.
Application
| Application | Comment | Organism |
|---|---|---|
| drug development | the enzyme is a potential target for drug development, e.g. in cancer therapy, analysis of inhibitory potential of LY294002 inhibotr analogues | Homo sapiens |
Cloned(Commentary)
| Cloned (Comment) | Organism |
|---|---|
| expression of the catalytic subunit p110alpha of the wild-type and mutant enzymes in COS-1 cells | Homo sapiens |
| expression of wild-type VPS34 and PI3-K-related protein MEC1 in a enzyme-knockout mutant strain, functional complementation analysis, overview | Saccharomyces cerevisiae |
Protein Variants
| Protein Variants | Comment | Organism |
|---|---|---|
| C838C/I848A | site-directed mutagenesis, 10% activity compared to the wild-type enzyme | Homo sapiens |
| C838I/I848A | site-directed mutagenesis, below 10% activity compared to the wild-type enzyme | Homo sapiens |
| C838L/I848A | site-directed mutagenesis, highly reduced activity, 0.1% compared to the wild-type enzyme | Homo sapiens |
| D2243E | site-directed mutagenesis, no functional complementation of a yeast enzyme-knockout mutant strain | Saccharomyces cerevisiae |
| D749E | site-directed mutagenesis, no functional complementation of a yeast enzyme-knockout mutant strain | Saccharomyces cerevisiae |
| I670A | site-directed mutagenesis, functional complementation of a yeast enzyme-knockout mutant strain | Saccharomyces cerevisiae |
| I670G | site-directed mutagenesis, no functional complementation of a yeast enzyme-knockout mutant strain | Saccharomyces cerevisiae |
| I848A | site-directed mutagenesis, mutation of a catalytic subunit p110 residue, highly reduced activity, 1% compared to the wild-type enzyme | Homo sapiens |
| I848G | site-directed mutagenesis, mutation of a catalytic subunit p110 residue, highly reduced activity, 0.1% compared to the wild-type enzyme | Homo sapiens |
| L2129A | site-directed mutagenesis, functional complementation of a yeast enzyme-knockout mutant strain | Saccharomyces cerevisiae |
| L2129G | site-directed mutagenesis, functional complementation of a yeast enzyme-knockout mutant strain | Saccharomyces cerevisiae |
| additional information | activating mutations of the enzyme are often identified at high frequency in several types of cancer | Homo sapiens |
| Y836A | site-directed mutagenesis, completely inactive p110alpha mutant | Homo sapiens |
| Y836D | site-directed mutagenesis, completely inactive p110alpha mutant | Homo sapiens |
| Y836G | site-directed mutagenesis, completely inactive p110alpha mutant | Homo sapiens |
| Y836H | site-directed mutagenesis, completely inactive p110alpha mutant | Homo sapiens |
| Y836L | site-directed mutagenesis, completely inactive p110alpha mutant | Homo sapiens |
| Y836M | site-directed mutagenesis, completely inactive p110alpha mutant | Homo sapiens |
| Y836T | site-directed mutagenesis, completely inactive p110alpha mutant | Homo sapiens |
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| 2-morpholin-4-yl-3-phenylchromen-4-one | weak inhibition, IC50 is above 0.2 mM for the recombinant wild-type enzyme and for the recombinant mutant C838V/I848A | Homo sapiens |  |
| 2-morpholin-4-yl-3-propylchromen-4-one | IC50 is 0.0031 mM for the recombinant wild-type enzyme and 0.068 mM for the recombinant mutant C838V/I848A | Homo sapiens | |
| 3-benzyl-2-morpholin-4-yl-chromen-4-one | weak inhibition, IC50 is above 0.2 mM for the recombinant wild-type enzyme and for the recombinant mutant C838V/I848A | Homo sapiens | |
| 3-butyl-2-morpholin-4-yl-chromen-4-one | IC50 is 0.025 mM for the recombinant wild-type enzyme and 0.048 mM for the recombinant mutant C838V/I848A | Homo sapiens | |
| 3-ethyl-2-morpholin-4-yl-chromen-4-one | IC50 is 0.028 mM for the recombinant wild-type enzyme and 0.0044 mM for the recombinant mutant C838V/I848A | Homo sapiens | |
| 3-isopropyl-2-morpholin-4-yl-chromen-4-one | IC50 is 0.051 mM for the recombinant wild-type enzyme and more than 0.2 mM for the recombinant mutant C838V/I848A | Homo sapiens | |
| 3-methyl-2-morpholin-4-yl-chromen-4-one | IC50 is 0.033 mM for the recombinant wild-type enzyme and 0.040 mM for the recombinant mutant C838V/I848A | Homo sapiens | |
| LY292223 | i.e. 2-morpholin-4-yl-chromen-4-one, IC50 is 0.0026 mM for the recombinant wild-type enzyme and 0.025 mM for the recombinant mutant C838V/I848A | Homo sapiens | |
| LY294002 | IC50 is 0.0011 mM for the recombinant wild-type enzyme and for the recombinant mutant C838V/I848A | Homo sapiens | |
Metals/Ions
| Metals/Ions | Comment | Organism | Structure |
|---|---|---|---|
| Mg2+ | - |
Homo sapiens | |
| Mg2+ | - |
Saccharomyces cerevisiae | |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + phosphatidylinositol-4,5-bisphosphate | Saccharomyces cerevisiae | - |
ADP + phosphatidylinositol-3,4,5-trisphosphate | - |
? | |
| ATP + phosphatidylinositol-4,5-bisphosphate | Homo sapiens | synthesis of a second messenger, enzyme is involved in several cellular signaling processes important for cell growth and survival, cell differentiation and motility | ADP + phosphatidylinositol-3,4,5-trisphosphate | - |
? | |
| ATP + phosphatidylinositol-4-phosphate | Saccharomyces cerevisiae | - |
ADP + phosphatidylinositol-3,4-bisphosphate | - |
? | |
| ATP + phosphatidylinositol-4-phosphate | Homo sapiens | synthesis of a second messenger, enzyme is involved in several cellular signaling processes important for cell growth and survival, cell differentiation and motility | ADP + phosphatidylinositol-3,4-bisphosphate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | - |
isozyme alpha | - |
| Saccharomyces cerevisiae | - |
enzyme VPS34 and a PI3-K-related protein MEC1 | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + phosphatidylinositol-4,5-bisphosphate | - |
Homo sapiens | ADP + phosphatidylinositol-3,4,5-trisphosphate | - |
? | |
| ATP + phosphatidylinositol-4,5-bisphosphate | - |
Saccharomyces cerevisiae | ADP + phosphatidylinositol-3,4,5-trisphosphate | - |
? | |
| ATP + phosphatidylinositol-4,5-bisphosphate | synthesis of a second messenger, enzyme is involved in several cellular signaling processes important for cell growth and survival, cell differentiation and motility | Homo sapiens | ADP + phosphatidylinositol-3,4,5-trisphosphate | - |
? | |
| ATP + phosphatidylinositol-4-phosphate | - |
Homo sapiens | ADP + phosphatidylinositol-3,4-bisphosphate | - |
? | |
| ATP + phosphatidylinositol-4-phosphate | - |
Saccharomyces cerevisiae | ADP + phosphatidylinositol-3,4-bisphosphate | - |
? | |
| ATP + phosphatidylinositol-4-phosphate | synthesis of a second messenger, enzyme is involved in several cellular signaling processes important for cell growth and survival, cell differentiation and motility | Homo sapiens | ADP + phosphatidylinositol-3,4-bisphosphate | - |
? | |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| More | the enzyme belongs to the PI3-K family | Homo sapiens |
| More | the enzyme belongs to the PI3-K family | Saccharomyces cerevisiae |
| phosphoinositide 3-kinase | - |
Homo sapiens |
| phosphoinositide 3-kinase | - |
Saccharomyces cerevisiae |
| PI3-K | - |
Homo sapiens |
| PI3-K | - |
Saccharomyces cerevisiae |
| PI3-K-related protein MEC1 | - |
Saccharomyces cerevisiae |
| VPS34 | - |
Saccharomyces cerevisiae |
Temperature Optimum [°C]
| Temperature Optimum [°C] | Temperature Optimum Maximum [°C] | Comment | Organism |
|---|---|---|---|
| 22 | - |
assay at room temperature | Homo sapiens |
| 22 | - |
assay at room temperature | Saccharomyces cerevisiae |
pH Optimum
| pH Optimum Minimum | pH Optimum Maximum | Comment | Organism |
|---|---|---|---|
| 7.4 | - |
assay at | Homo sapiens |
| 7.4 | - |
assay at | Saccharomyces cerevisiae |
Cofactor
| Cofactor | Comment | Organism | Structure |
|---|---|---|---|
| ATP | binding site structure, a single conserved residue 884, termed the gatekeeper, controls the sensitivity to a wide range of small molecule inhibitors, inhibitor resistance is conferred by a large resiude at this position, e.g. isoleucine, whereas a small amino acid at this position like alanine, glycine, or threonine renders the enzyme sensitive for inhibition by small molecule drugs, the effect can be reversed by mutation of residue C838 to valine or isoleucine | Homo sapiens | |
| ATP | binding site structure, a single conserved residue I670 of VPS34 and L2129 of PI3-K-related protein MEC1, termed the gatekeeper, controls the sensitivity to a wide range of small molecule inhibitors, inhibitor resistance id conferred by a large resiude at this position, e.g. isoleucine, whereas a small amino acid at this position like alanine, glycine, or threonine renders the enzyme sensitive for inhibition by small molecule drugs | Saccharomyces cerevisiae | |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 0.0011 | - |
IC50 is 0.0011 mM for the recombinant wild-type enzyme and for the recombinant mutant C838V/I848A | Homo sapiens | LY294002 | |
| 0.0026 | - |
i.e. 2-morpholin-4-yl-chromen-4-one, IC50 is 0.0026 mM for the recombinant wild-type enzyme and 0.025 mM for the recombinant mutant C838V/I848A | Homo sapiens | LY292223 | |
| 0.0031 | - |
IC50 is 0.0031 mM for the recombinant wild-type enzyme and 0.068 mM for the recombinant mutant C838V/I848A | Homo sapiens | 2-morpholin-4-yl-3-propylchromen-4-one | |
| 0.025 | - |
IC50 is 0.025 mM for the recombinant wild-type enzyme and 0.048 mM for the recombinant mutant C838V/I848A | Homo sapiens | 3-butyl-2-morpholin-4-yl-chromen-4-one | |
| 0.028 | - |
IC50 is 0.028 mM for the recombinant wild-type enzyme and 0.0044 mM for the recombinant mutant C838V/I848A | Homo sapiens | 3-ethyl-2-morpholin-4-yl-chromen-4-one | |
| 0.033 | - |
IC50 is 0.033 mM for the recombinant wild-type enzyme and 0.040 mM for the recombinant mutant C838V/I848A | Homo sapiens | 3-methyl-2-morpholin-4-yl-chromen-4-one | |
| 0.051 | - |
IC50 is 0.051 mM for the recombinant wild-type enzyme and more than 0.2 mM for the recombinant mutant C838V/I848A | Homo sapiens | 3-isopropyl-2-morpholin-4-yl-chromen-4-one | |
| 0.2 | - |
weak inhibition, IC50 is above 0.2 mM for the recombinant wild-type enzyme and for the recombinant mutant C838V/I848A | Homo sapiens | 2-morpholin-4-yl-3-phenylchromen-4-one | |
| 0.2 | - |
weak inhibition, IC50 is above 0.2 mM for the recombinant wild-type enzyme and for the recombinant mutant C838V/I848A | Homo sapiens | 3-benzyl-2-morpholin-4-yl-chromen-4-one | |
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Release 2023.1 (January 2023)
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