Any feedback?
Literature summary for 2.7.1.1 extracted from
- Redox regulation of hexokinases (2019), Antioxid. Redox Signal., 30, 415-442 .
Inhibitors
| Inhibitors | Comment | Organism | Structure |
|---|---|---|---|
| 1-[(2,4-dichlorophenyl)methyl]-1H-indazole-3-carboxylic acid | - |
Homo sapiens |  |
| 1-[(2,4-dichlorophenyl)methyl]-1H-indazole-3-carboxylic acid | - |
Oryctolagus cuniculus | |
| 2-(4-chlorophenyl)-1,2-benzothiazol-3(2H)-one | - |
Plasmodium falciparum | |
| 2-(4-chlorophenyl)-1,2-benzothiazol-3(2H)-one | - |
Trypanosoma brucei | |
| 2-(4-chlorophenyl)-5-fluoro-1,2-benzothiazol-3(2H)-one | - |
Plasmodium falciparum | |
| 2-(4-chlorophenyl)-5-fluoro-1,2-benzothiazol-3(2H)-one | - |
Trypanosoma brucei | |
| 2-bromoacetamido-4-nitrophenol | increasing concentrations of glucose protect the SH groups of hexokinase from reaction with 2-bromoacetamido-4-nitrophenol | Homo sapiens | |
| 2-deoxy-D-glucose | 2-deoxy-D-glucose is readily phosphorylated by hexokinase II but the product is not further processed by glucose-6-phosphate isomerase and thus accumulates in the cell to inhibit hexokinase II by a negative feedback loop | Homo sapiens | |
| 2-deoxy-D-glucose | 2-deoxy-D-glucose is readily phosphorylated by hexokinase II but the product is not further processed by glucose-6-phosphate isomerase and thus accumulates in the cell to inhibit hexokinase II by a negative feedback loop | Oryctolagus cuniculus | |
| 2-phenyl-1,2-benzothiazol-3(2H)-one | - |
Plasmodium falciparum | |
| 2-phenyl-1,2-benzothiazol-3(2H)-one | - |
Trypanosoma brucei | |
| 3-Bromopyruvate | - |
Homo sapiens | |
| 3-Bromopyruvate | - |
Oryctolagus cuniculus | |
| 5,5'-dithiobis-(2-nitrobenzoic acid) | - |
Homo sapiens | |
| 5-fluoro-N-phenyl-2-sulfanylbenzamide | - |
Plasmodium falciparum | |
| dehydroascorbic acid | dehydroascorbic acid-mediated inhibition completely and irreversibly inactivates the enzyme in a pseudo-first order manner, resulting in the covalent binding of dehydroascorbic acid to the thiol groups of multiple Cys residues within hexokinase, a reaction that depends on the deprotonation of the affected residue with an alkaline pKa. Dehydroascorbic acid does not cause any cleavage of hexokinase, and it does not lead to the formation of any intermolecular crosslinks within this enzyme. The action of dehydroascorbic acid can be prevented, but not reversed, by dithiothreitol, and can be suppressed by the presence of glucose | Homo sapiens | |
| ebselen | - |
Plasmodium falciparum | |
| ebselen | - |
Trypanosoma brucei | |
| pyrrolidinium pyrrolidine-1-carbodithioate | the minimum effective spermicidal concentration of pyrrolidinium pyrrolidine-1-carbodithioate, 0.145 mM, inhibits the sperm-specific activity of hexokinase by 58% | Homo sapiens | |
KM Value [mM]
| KM Value [mM] | KM Value Maximum [mM] | Substrate | Comment | Organism | Structure |
|---|---|---|---|---|---|
| 0.04 | 0.06 | D-glucose | pH and temperature not specified in the publication | Trypanosoma brucei | |
| 0.098 | - |
D-glucose | pH and temperature not specified in the publication | Plasmodium falciparum | |
| 0.3 | 0.4 | ATP | pH and temperature not specified in the publication | Trypanosoma brucei | |
Localization
| Localization | Comment | Organism | GeneOntology No. | Textmining |
|---|---|---|---|---|
| glycosome | - |
Trypanosoma brucei | 20015 | - |
| mitochondrion | - |
Homo sapiens | 5739 | - |
| mitochondrion | association of hexokinase II with mitochondria can be inhibited by methyl jasmonate or with clotrimazole | Oryctolagus cuniculus | 5739 | - |
| mitochondrion | association of hexokinase II with mitochondria can be inhibited by methyl jasmonate or with clotrimazole | Homo sapiens | 5739 | - |
| additional information | hexokinase III does not bind to mitochondria | Homo sapiens | - |
- |
Natural Substrates/ Products (Substrates)
| Natural Substrates | Organism | Comment (Nat. Sub.) | Natural Products | Comment (Nat. Pro.) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + D-glucose | Trypanosoma brucei | - |
ADP + D-glucose 6-phosphate | - |
? | |
| ATP + D-glucose | Plasmodium falciparum | - |
ADP + D-glucose 6-phosphate | - |
? | |
Organism
| Organism | UniProt | Comment | Textmining |
|---|---|---|---|
| Homo sapiens | P19367 | - |
- |
| Homo sapiens | P52789 | - |
- |
| Homo sapiens | P52790 | - |
- |
| Mus musculus | P17710 | - |
- |
| Oryctolagus cuniculus | - |
- |
- |
| Plasmodium falciparum | Q02155 | - |
- |
| Trypanosoma brucei | - |
- |
- |
Source Tissue
| Source Tissue | Comment | Organism | Textmining |
|---|---|---|---|
| erythrocyte | - |
Oryctolagus cuniculus | - |
| HEK-293 cell | - |
Homo sapiens | - |
| merozoite | Plasmodium falciparum hexokinase is associated with the membrane via its C-terminal hydrophobic sequence, and this membrane association improves the efficiency of glucose phosphorylation immediately upon entering the host cell. Plasmodium hexokinase ensures a dramatic increase in reduced glutathione production in infected erythrocytes | Plasmodium falciparum | - |
| MIN-6 cell | - |
Mus musculus | - |
| semen | - |
Homo sapiens | - |
Substrates and Products (Substrate)
| Substrates | Comment Substrates | Organism | Products | Comment (Products) | Rev. | Reac. |
|---|---|---|---|---|---|---|
| ATP + D-glucose | - |
Trypanosoma brucei | ADP + D-glucose 6-phosphate | - |
? | |
| ATP + D-glucose | - |
Plasmodium falciparum | ADP + D-glucose 6-phosphate | - |
? | |
| ATP + D-glucose | the enzyme shows a narrow substrate specificity, as it does not display activity towards fructose, mannose or galactose | Trypanosoma brucei | ADP + D-glucose 6-phosphate | - |
? | |
Subunits
| Subunits | Comment | Organism |
|---|---|---|
| dimer | the enzyme exists in a tetramer-dimer equilibrium | Trypanosoma brucei |
| dimer | the enzyme is present mainly as a dimer in quiescent sperm and converts fully to a monomer in the forward progressing sperm | Homo sapiens |
| monomer | the enzyme is present mainly as a dimer in quiescent sperm and converts fully to a monomer in the forward progressing sperm | Homo sapiens |
| tetramer | the enzyme exists in a tetramer-dimer equilibrium | Trypanosoma brucei |
Synonyms
| Synonyms | Comment | Organism |
|---|---|---|
| hexokinase | - |
Trypanosoma brucei |
| hexokinase | - |
Plasmodium falciparum |
| hexokinase 1 | - |
Mus musculus |
| hexokinase 2 | - |
Oryctolagus cuniculus |
| hexokinase 2 | - |
Homo sapiens |
| hexokinase 3 | - |
Homo sapiens |
| hexokinase I | - |
Homo sapiens |
| hexokinase II | - |
Homo sapiens |
| hexokinase III | - |
Homo sapiens |
| HKI | - |
Homo sapiens |
| HKI | - |
Mus musculus |
| HKII | - |
Oryctolagus cuniculus |
| HKII | - |
Homo sapiens |
| HKIII | - |
Homo sapiens |
IC50 Value
| IC50 Value | IC50 Value Maximum | Comment | Organism | Inhibitor | Structure |
|---|---|---|---|---|---|
| 0.00001 | - |
pH and temperature not specified in the publication | Plasmodium falciparum | ebselen | |
| 0.00005 | - |
pH and temperature not specified in the publication | Trypanosoma brucei | ebselen | |
| 0.00016 | - |
pH and temperature not specified in the publication | Plasmodium falciparum | 2-(4-chlorophenyl)-5-fluoro-1,2-benzothiazol-3(2H)-one | |
| 0.00023 | - |
pH and temperature not specified in the publication | Plasmodium falciparum | 2-phenyl-1,2-benzothiazol-3(2H)-one | |
| 0.00027 | - |
pH and temperature not specified in the publication | Plasmodium falciparum | 2-(4-chlorophenyl)-1,2-benzothiazol-3(2H)-one | |
| 0.0011 | - |
pH and temperature not specified in the publication | Trypanosoma brucei | 2-(4-chlorophenyl)-1,2-benzothiazol-3(2H)-one | |
| 0.002 | - |
pH and temperature not specified in the publication | Trypanosoma brucei | 2-phenyl-1,2-benzothiazol-3(2H)-one | |
| 0.0031 | - |
pH and temperature not specified in the publication | Plasmodium falciparum | 5-fluoro-N-phenyl-2-sulfanylbenzamide | |
| 0.0038 | - |
pH and temperature not specified in the publication | Trypanosoma brucei | 2-(4-chlorophenyl)-5-fluoro-1,2-benzothiazol-3(2H)-one | |
Expression
| Organism | Comment | Expression |
|---|---|---|
| Homo sapiens | when oroxylin A, isolated from Scutellaria baicalensis and Oroxylum indicum, is applied to two breast carcinoma cell lines, it decreases hexokinase II expression and causes detachment of the enzyme from the mitochondria, thereby inhibiting glycolysis and decreasing ATP levels | down |
| Mus musculus | in the MIN6 beta-cell line, enzyme expression increases following the application of redox-sensitive transcription factor Nrf1 shRNA. 2-deoxy-D-glucose is able to suppress the basal release of insulin in MIN6 cells treated with Nrf1 shRNA, which suggests that increased hexokinase resulting from Nrf1 silencing is one of the critical downstream events affecting glucose metabolism and glucose-stimulated insulin secretion in pancreatic beta-cells | up |
General Information
| General Information | Comment | Organism |
|---|---|---|
| drug target | given the absence of energy stores in this parasite and the key role of the Plasmodium falciparum hexose transporter, the pathway involving Plasmodium falciparum hexokinase and the bifunctional glucose-6-phosphate dehydrogenase 6-phosphogluconolactonase is promising as a pharmacotherapeutic target, particularly because Plasmodium falciparum hexokinase shows a low sequence identity with human hexokinases | Plasmodium falciparum |
| metabolism | hexokinase 2 serves as a hinge that connects the Src/AKT pathway with glycolysis and anoikis | Oryctolagus cuniculus |
| metabolism | hexokinase II serves as a hinge that connects the Src/AKT pathway with glycolysis and anoikis | Homo sapiens |
| metabolism | hexokinase III overexpression in O/N starved cells increases cell survival following H2O2 application and increases ATP levels both before and after challenge with 0.5 mM H2O2. The overexpression of hexokinase III in H2O2-treated cells also decreases the mitochondrial superoxide levels | Homo sapiens |
| metabolism | Plasmodium falciparum hexokinase activity is important for the NADPH-dependent reduction of oxidized glutathione in the parasite by providing glucose-6-phosphate, which allows glucose-6-phosphate dehydrogenase to generate NADPH for downstream redox reactions | Plasmodium falciparum |
| physiological function | hexokinase III plays a role in hypoxia | Homo sapiens |
| physiological function | the antioxidant function of hexokinase II is independent of its enzymatic activity | Homo sapiens |
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