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Literature summary for 2.7.1.32 extracted from

  • Zech, S.; Kohlmann, A.; Zhou, T.; Li, F.; Squillace, R.; Parillon, L.; Greenfield, M.; Miller, D.; Qi, J.; Thomas, R.; Wang, Y.; Xu, Y.; Miret, J.; Shakespeare, W.; Zhu, X.; Dalgarno, D.
    Novel small molecule inhibitors of choline kinase identified by fragment-based drug discovery (2016), J. Med. Chem., 59, 671-686 .
    View publication on PubMed
Search for more literature for 2.7.1.32

Cloned(Commentary)

Cloned (Comment) Organism
recombinant expression of tagged choline kinase alpha1 residues 75-457 Homo sapiens

Crystallization (Commentary)

Crystallization (Comment) Organism
purified recombinant tagged enzyme in apoform and in complex with inhibitor 1-[4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl]methanamine, mixing of 30 mg/ml protein solution with 0.1 M sodium formate, 8-12% PEG 3350 at 18°C, complex structures are obtained by soaking the inhibitors into the ChoKalpha1 crystals at a final concentration of 2-5 mM for 45-60 min before freezing in liquid nitrogen, X-ray diffraction structrue determination and analysis, modelling Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
(1-azabicyclo[2.2.2]octan-3-yl)bis(5-chlorothiophen-2-yl)methanol precursor of (1S)-1-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-3-[2-[(oxan-4-yl)oxy]phenyl]-1-phenylpropan-1-ol, inhibits competitively against ATP, but not against choline Homo sapiens
(1S)-1-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-3-[2-[(oxan-4-yl)oxy]phenyl]-1-phenylpropan-1-ol a structure-directed, selective ChoKalpha inhibitor. Treatment of HeLa cells and other cancer cells with the compound leads to a substantial reduction in the pCho level, and causes a reversible growth arrest but not cell death Homo sapiens
(4-methyl-1,4-diazepan-1-yl)(4'-((4-methyl-1,4-diazepan-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methanone
-
 Homo sapiens
(azepan-1-yl)(piperazin-1-yl)methanone
-
 Homo sapiens
1,1'-[butane-1,4-diylbis[(4,1-phenylene)methylene]]bis[4-(dimethylamino)pyridin-1-ium] a less toxic derivative of hemicholinium-3, it inhibits endogenous ChoKbeta activity and suppress breast cancer, colon cancer, and epidermoid carcinoma xenograft growth in vivo Homo sapiens
1,1'-[[1,1'-biphenyl]-4,4'-diylbis(methylene)]bis[4-[(4-chlorophenyl)(methyl)amino]quinolin-1-ium] RSM-932A or TDC-717, a potential cancer therapeutic agent targeting choline metabolism, strong inhibition Homo sapiens
1-((4'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-4-methyl-1,4-diazepane
-
 Homo sapiens
1-methyl-4-((4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)-methyl)-1,4-diazepane
-
 Homo sapiens
1-methyl-4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1,4-diazepane
-
 Homo sapiens
1-methyl-4-(naphthalen-2-ylmethyl)-1,4-diazepane
-
 Homo sapiens
1-[4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl]methanamine analysis of the enzyme bound structure, PDB ID 5EQE Homo sapiens
2'-fluoro-4,4'-bis((4-methyl-1,4-diazepan-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile
-
 Homo sapiens
4,4'-((2,3-difluoro-[1,1'-biphenyl]-4,4'-diyl)bis(methylene))bis-(1-methyl-1,4-diazepane)
-
 Homo sapiens
4,4'-((2-fluoro-[1,1'-biphenyl]-4,4'-diyl)bis(methylene))bis(1-methyl-1,4-diazepane)
-
 Homo sapiens
4,4'-((3,5-difluoro-[1,1'-biphenyl]-4,4'-diyl)bis(methylene))bis-(1-methyl-1,4-diazepane)
-
 Homo sapiens
4,4'-((3-chloro-[1,1'-biphenyl]-4,4'-diyl)bis(methylene))bis(1-methyl-1,4-diazepane)
-
 Homo sapiens
4,4'-bis((4-methyl-1,4-diazepan-1-yl)methyl)-1,1'-biphenyl
-
 Homo sapiens
4,4'-bis((4-methyl-1,4-diazepan-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile
-
 Homo sapiens
6-(trifluoromethyl)pyrimidin-4-amine
-
 Homo sapiens
6-[(1-methyl-1,4-diazepan-6-yl)methyl]quinoline
-
 Homo sapiens
7-((4-methyl-1,4-diazepan-1-yl)methyl)quinolone
-
 Homo sapiens
hemicholinium-3 HC-3, a substrate site inhibitor that bears structural homology to choline, which contributes to its toxicity Homo sapiens
methyl 4'-((4-methyl-1,4-diazepan-1-yl)methyl)-[1,1'-biphenyl]-4-carboxylate
-
 Homo sapiens
additional information small molecule inhibitors of choline kinase identified by fragment-based drug discovery (NMR fragment screening and competition experiments), quantification of protein-ligand affinities, overview Homo sapiens
N-(3,5-dimethylphenyl)-2-[[5-(4-ethylphenyl)-1H-1,2,4-triazol-3-yl]sulfanyl]acetamide CK37, identified through computational virtual screening, inhibits ChoKalpha activity both in enzymatic and in cellular assays, is able to suppress pCho production and tumor growth in vivo Homo sapiens
[4-(4-methyl-1,4-diazepan-1-yl)phenyl]methanol
-
 Homo sapiens

Localization

Localization Comment Organism GeneOntology No. Textmining
cytosol
-
 Homo sapiens 5829
-

Metals/Ions

Metals/Ions Comment Organism Structure
Mg2+ required Homo sapiens

Molecular Weight [Da]

Molecular Weight [Da] Molecular Weight Maximum [Da] Comment Organism
94000
-
-
 Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + choline Homo sapiens
-
 ADP + phosphocholine
-
 ?

Organism

Organism UniProt Comment Textmining
Homo sapiens O54804
-
-

Purification (Commentary)

Purification (Comment) Organism
recombinant tagged choline kinase alpha1 residues 75-457 by affinity and ion exchange chromatography, and gel filtration Homo sapiens

Source Tissue

Source Tissue Comment Organism Textmining
breast cancer cell
-
 Homo sapiens
-
carcinoma cell
-
 Homo sapiens
-
colonic cancer cell
-
 Homo sapiens
-
HeLa cell
-
 Homo sapiens
-
MCF-12A cell
-
 Homo sapiens
-
MDA-MB-415 cell
-
 Homo sapiens
-
squamous cell carcinoma cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + choline
-
 Homo sapiens ADP + phosphocholine
-
 ?

Subunits

Subunits Comment Organism
homodimer
-
 Homo sapiens

Synonyms

Synonyms Comment Organism
ChoKalpha
-
 Homo sapiens
choline kinase alpha
-
 Homo sapiens

Temperature Optimum [°C]

Temperature Optimum [°C] Temperature Optimum Maximum [°C] Comment Organism
25
-
 assay at Homo sapiens

pH Optimum

pH Optimum Minimum pH Optimum Maximum Comment Organism
7
-
 assay at Homo sapiens

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
0.00002
-
 pH 7.0, 25°C, recombinant enzyme Homo sapiens (1S)-1-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-3-[2-[(oxan-4-yl)oxy]phenyl]-1-phenylpropan-1-ol
0.000066
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 4,4'-bis((4-methyl-1,4-diazepan-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile
0.000085
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 2'-fluoro-4,4'-bis((4-methyl-1,4-diazepan-1-yl)methyl)-[1,1'-biphenyl]-2-carbonitrile
0.000165
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 4,4'-((2-fluoro-[1,1'-biphenyl]-4,4'-diyl)bis(methylene))bis(1-methyl-1,4-diazepane)
0.000233
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 4,4'-((2,3-difluoro-[1,1'-biphenyl]-4,4'-diyl)bis(methylene))bis-(1-methyl-1,4-diazepane)
0.000251
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens (4-methyl-1,4-diazepan-1-yl)(4'-((4-methyl-1,4-diazepan-1-yl)-methyl)-[1,1'-biphenyl]-4-yl)methanone
0.000255
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 4,4'-((3,5-difluoro-[1,1'-biphenyl]-4,4'-diyl)bis(methylene))bis-(1-methyl-1,4-diazepane)
0.000268
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 4,4'-((3-chloro-[1,1'-biphenyl]-4,4'-diyl)bis(methylene))bis(1-methyl-1,4-diazepane)
0.000457
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 4,4'-bis((4-methyl-1,4-diazepan-1-yl)methyl)-1,1'-biphenyl
0.0013
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 1-methyl-4-((4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)-methyl)-1,4-diazepane
0.00143
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 1-((4'-methoxy-[1,1'-biphenyl]-4-yl)methyl)-4-methyl-1,4-diazepane
0.0015
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 1-methyl-4-((4'-(4-methylpiperazin-1-yl)-[1,1'-biphenyl]-4-yl)-methyl)-1,4-diazepane
0.0026
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 1-methyl-4-(naphthalen-2-ylmethyl)-1,4-diazepane
0.0026
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 1-methyl-4-((4'-(trifluoromethyl)-[1,1'-biphenyl]-4-yl)methyl)-1,4-diazepane
0.0039
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 7-((4-methyl-1,4-diazepan-1-yl)methyl)quinolone
0.00495
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens methyl 4'-((4-methyl-1,4-diazepan-1-yl)methyl)-[1,1'-biphenyl]-4-carboxylate
0.0172
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 6-[(1-methyl-1,4-diazepan-6-yl)methyl]quinoline
0.087
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens 1-[4-[(4-methyl-1,4-diazepan-1-yl)methyl]phenyl]methanamine
2
-
 pH 7.5, 25°C, recombinant enzyme Homo sapiens [4-(4-methyl-1,4-diazepan-1-yl)phenyl]methanol

General Information

General Information Comment Organism
evolution the mammalian choline kinase family is encoded by two distinct genes, ChoKalpha and ChoKbeta, resulting in three different isoforms, namely, ChoKalpha1, ChoKalpha2, and ChoKbeta. ChoKalpha1 (457 amino acids) and ChoKalpha2 (439 amino acids) are derived from a single gene (ChoKalpha) by alternative splicing Homo sapiens
additional information enzyme structure molecular modeling Homo sapiens
physiological function choline kinase (ChoK) is a cytosolic enzyme that catalyzes the MgATP-dependent phosphorylation of choline to phosphocholine (pCho) as the first step in the Kennedy pathway toward synthesis of the major membrane phospholipid, phosphatidylcholine (PtdCho) Homo sapiens