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Information on EC 2.7.1.1 - hexokinase and Organism(s) Homo sapiens and UniProt Accession P52789

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EC Tree
IUBMB Comments
D-Glucose, D-mannose, D-fructose, sorbitol and D-glucosamine can act as acceptors; ITP and dATP can act as donors. The liver isoenzyme has sometimes been called glucokinase.
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This record set is specific for:
Homo sapiens
UNIPROT: P52789
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Word Map
The taxonomic range for the selected organisms is: Homo sapiens
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
hexokinase, hexokinase ii, hexokinase 2, hexokinase i, hk ii, hxk, liver glucokinase, hexokinase 1, hexokinase-2, hkdc1, more
SYNONYM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
hexokinase II
-
type II hexokinase
-
ATP-D-hexose 6-phosphotransferase
-
-
-
-
ATP-dependent hexokinase
-
-
-
-
ATP: D-glucose 6-phosphotransferase
-
-
ATP: D-hexose 6-phosphotransferase
-
brain form hexokinase
-
-
-
-
GKbeta
-
-
glucokinase
glucokinase 1
glucokinase B
-
glucose ATP phosphotransferase
-
-
-
-
hexokinase (phosphorylating)
-
-
-
-
hexokinase 1
-
hexokinase 2
-
-
hexokinase 3
-
hexokinase D
hexokinase Dor
-
-
hexokinase I
-
hexokinase II
hexokinase III
-
hexokinase IV
hexokinase PI
-
-
-
-
hexokinase PII
-
-
-
-
hexokinase type IV
-
-
-
-
hexokinase type IV glucokinase
-
-
-
-
hexokinase, tumor isozyme
-
-
-
-
hexokinase-1
-
hGK isoform 1
-
HK
-
-
-
-
HK-1
-
-
HK4
-
-
-
-
HKII
-
isozyme
HXK
-
-
-
-
kinase, hexo- (phosphorylating)
-
-
-
-
liver glucokinase isoform 2
-
MODY2 glucokinase
-
muscle form hexokinase
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY hide
ORGANISM
UNIPROT
LITERATURE
ATP + D-glucose = ADP + D-glucose 6-phosphate
show the reaction diagram
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
phospho group transfer
-
-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:D-hexose 6-phosphotransferase
D-Glucose, D-mannose, D-fructose, sorbitol and D-glucosamine can act as acceptors; ITP and dATP can act as donors. The liver isoenzyme has sometimes been called glucokinase.
CAS REGISTRY NUMBER
COMMENTARY hide
9001-51-8
-
SUBSTRATE
PRODUCT                       
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + 2-deoxy-D-glucose
ADP + 2-deoxy-D-glucose 6-phosphate
show the reaction diagram
ATP + beta-D-glucose
ADP + beta-D-glucose 6-phosphate
show the reaction diagram
-
-
-
-
?
ATP + D-fructose
ADP + D-fructose 6-phosphate
show the reaction diagram
-
-
-
-
?
ATP + D-glucose
ADP + D-glucose 6-phosphate
show the reaction diagram
ATP + D-mannose
ADP + D-mannose 6-phosphate
show the reaction diagram
ATP + mannoheptulose
?
show the reaction diagram
-
sugar binding to recombinant wild-type and mutant glucokinase monitored by kinetic measurement and tryptophan fluorescence
-
-
?
ATP + N-acetyl-alpha-D-glucosamine
ADP + N-acetyl-alpha-D-glucosamine 6-phosphate
show the reaction diagram
-
sugar binding to recombinant wild-type and mutant glucokinase monitored by kinetic measurement and tryptophan fluorescence
-
-
?
CTP + D-glucose
CDP + D-glucose 6-phosphate
show the reaction diagram
D-fructose + ATP
ADP + D-fructose 6-phosphate
show the reaction diagram
D-glucosamine + ATP
ADP + D-glucosamine 6-phosphate
show the reaction diagram
D-glucose + ATP
ADP + D-glucose 6-phosphate
show the reaction diagram
D-glucose + ATP
D-glucose 6-phosphate + ADP
show the reaction diagram
D-mannose + ATP
ADP + D-mannose 6-phosphate
show the reaction diagram
ITP + D-glucose
IDP + D-glucose 6-phosphate
show the reaction diagram
UTP + D-glucose
UDP + D-glucose 6-phosphate
show the reaction diagram
additional information
?
-
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate) hide
LITERATURE
(Substrate)
COMMENTARY
(Product) hide
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + D-glucose
ADP + D-glucose 6-phosphate
show the reaction diagram
D-glucose + ATP
D-glucose 6-phosphate + ADP
show the reaction diagram
additional information
?
-
-
loss of enzyme activity is involved in type 2 diabetes mellitus
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
(22E,24R)-6beta-methoxyergosta-7,9(11),22-triene-3beta,5alpha-diol
steroid from Ganoderma sinense. Potential drug candidate targeting at hexokinase 2 for cancer therapy
1-[(2,4-dichlorophenyl)methyl]-1H-indazole-3-carboxylic acid
-
2,5-dihydroxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
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
2-hydroxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
2-[([1,1'-biphenyl]-3-carbonyl)amino]-2,6-dideoxy-6-[(2,3-dichlorobenzene-1-sulfonyl)amino]-D-glucopyranose
inhibits in situ glycolysis in a UM-UC-3 bladder tumor cell line
22E-6beta-methoxyergosta-7,22-diene-3beta,5alpha-diol
-
3-(methanesulfonyl)-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
3-Bromopyruvate
3-chloro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
3-methoxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
-
3-nitro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
4-(2-hydroxyethoxy)-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
4-(methanesulfonyl)-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
4-butyl-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
4-chloro-3-nitro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
4-chloro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
4-fluoro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
4-methoxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
4-nitro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
5-hydroxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]-2,3-dihydro-1H-indole-2-carbohydrazide
-
5-[[(2R,3S,4R,5R,6S)-5-[(3-bromophenyl)carbonylamino]-3,4,6-tris(oxidanyl)oxan-2-yl]methylsulfamoyl]-2-methyl-furan-3-carboxylic acid
-
6-hydroxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]naphthalene-2-carbohydrazide
-
Benserazide
-
lonidamine
-
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]-2,3-dihydro-1,4-benzodioxine-2-carbohydrazide
-
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
-
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]pyridine-3-carbohydrazide
-
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]pyridine-4-carbohydrazide
-
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]quinoline-2-carbohydrazide
-
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]thiophene-2-carbohydrazide
-
N-(4-[(2E)-2-[(2,3,4-trihydroxyphenyl)methylidene]hydrazinecarbonyl]phenyl)cyclopropanecarboxamide
-
ZINC03232404
-
ZINC03233449
-
ZINC39948337
-
1,5-Anhydro-D-glucitol 6-phosphate
2,3-bisphosphoglycerate
-
feedback regulation. The phosphorylation of glucose is the reaction whose rate controls that of the formation of diphosphoglyceric acid. It is therefore clear that this phosphorylation by diphosphoglyceric acid serves as the automatic regulation of the former by the latter
2-bromoacetamido-4-nitrophenol
increasing concentrations of glucose protect the SH groups of hexokinase from reaction with 2-bromoacetamido-4-nitrophenol
2-[([1,1'-biphenyl]-3-carbonyl)amino]-2,6-dideoxy-6-[(2,3-dichlorobenzene-1-sulfonyl)amino]-D-glucopyranose
inhibits in situ glycolysis in a UM-UC-3 bladder tumor cell line. Not selective for isoforms hexokinase 1 or hexokinase 2
3-phosphoglycerate
-
feedback regulation
5,5'-dithiobis-(2-nitrobenzoic acid)
-
5-[[(2R,3S,4R,5R,6S)-5-[(3-bromophenyl)carbonylamino]-3,4,6-tris(oxidanyl)oxan-2-yl]methylsulfamoyl]-2-methyl-furan-3-carboxylic acid
not selective for isoforms hexokinase 1 or hexokinase 2
atorvastatin
-
chlorpromazine
-
Cl-
-
reversible, 0.25 M NaCl or KCl: 50% inhibition, at a comparable concentration of LiCl: 30% inhibition
clozapine
-
D-glucose
D-glucose 1,6-diphosphate
D-glucose 6-phosphate
D-mannoheptulose
-
competitive inhibition
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
diltiazem
-
enalaprilat
-
gabapentin
-
gatifloxacin
-
GK regulatory protein
-
-
-
glucokinase regulatory protein
-
glucokinase-regulatory protein
GK regulatory protein, relative inhibition of glucokinase activity through GKRP alone wild-type: 32.5% and GKRP plus 10 microM sorbitol 6-phosphate: 55
-
human glucokinase regulatory protein
-
inhibition is reversed by activator RO-28-1675
-
I-
-
at about 0.25 M KI, 70% inhibition, reversible
indomethacin
-
KSCN
-
at about 0.25 M, 90% inhibition, reversible
N,N'-[furan-2,5-diylbis(2-chloro-4,1-phenylene)]diguanidine
-
N-acetyl-D-glucosamine
-
potent inhibitor of hexokinase I
N-acetylglucosamine
-
-
N-methylglucosamine
-
potent inhibitor of hexokinase I
NO3-
-
at about 0.25 M NaNO3, 40% inhibition, reversible
palmitoyl-CoA
-
-
phosphate
-
at high concentrations, 10-50 mM, inhibition of recombinant full-length HK I, a truncated form lacking the first 11 amino acids named HK-11aa, and of the 50 kDa C-terminal half containing the catalytic domain, competitive versus MgATP2-
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%
Triethyltin bromide
Valproic acid
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
1-[6'-(2-hydroxy-2-methylpropoxy)-4-[(5-methylpyridin-3-yl)oxy]-3,3'-bipyridin-6-yl]-3-methylurea
i.e. AM-2394. Compound activates glucokinase with an EC50 of 60 nM, increases the affinity of glucokinase for glucose by approximately 10fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes
(2E)-3-cyclopentyl-2-[4-(cyclopropylsulfonyl)phenyl]-N-[4-(1,2-dihydroxyethyl)-1,3-thiazol-2-yl]prop-2-enamide
-
-
(2R)-2-[4-(cyclopropylsulfonyl)phenyl]-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
96% maximum activation above control at 6.5 mM glucose
(2R)-3-cyclopentyl-2-[4-(methylsulfonyl)phenyl]-N-(1,3-thiazol-2-yl)propanamide
-
activator associates with glucokinase in a glucose-independent fashion. Kinetic assays reveal a lag in enzyme progress curves that is systematically reduced when the enzyme is preincubated with the activator. Activator binding is enthalpically driven. The kcat value of glucokinase is almost fully limited by product release, both in the presence and absence of activator
(2R)-3-cyclopentyl-2-[4-(methylsulfonyl)phenyl]-N-(1,3-thiazol-2-yl)propanamide}
-
RO0281675, 1.5fold change in Vmax or kcat at 0.003 mM
(6-ethoxyquinazolin-4-yl)(1-methyl-1H-pyrazol-3-yl)amine
-
increases glucokinase activity at glucose concentrations up to approximately 20 mM
(6-ethoxyquinazolin-4-yl)pyridin-2-ylamine
-
increases glucokinase activity at glucose concentrations below approximately 7 mM
(6-isopropoxyquinazolin-4-yl)(1-methyl-1H-pyrazol-3-yl)amine
-
increases glucokinase activity at glucose concentrations up to approximately 20 mM
(R)-2-(4-(methylsulfonyl)phenyl)-3-((R)-3-oxocyclopentyl)-N-(pyrazin-2-yl)propanamide
-
piragliatin
(S)-2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-fluorothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
PSN-GK1, 1.1fold change in Vmax or kcat at 0.0001 mM
(S)-2-[3-chloro-4-(ethylsulfonyl)-2-oxopyridin-1(2H)-yl]-N-(5-methylpyridin-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
26% maximum activation above control at 6.5 mM glucose
(S)-2-[3-chloro-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-3-(4,4-difluorocyclohexyl)-N-(5-methylpyridin-2-yl)propanamide
-
15% maximum activation above control at 6.5 mM glucose
(S)-2-[3-chloro-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-3-cyclobutyl-N-(5-methylpyridin-2-yl)propanamide
-
72% maximum activation above control at 6.5 mM glucose
(S)-2-[3-chloro-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-3-cyclohexyl-N-(5-methylpyridin-2-yl)propanamide
-
46% maximum activation above control at 6.5 mM glucose
(S)-2-[3-chloro-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-3-cyclopentyl-N-(5-methylpyridin-2-yl)propanamide
-
57% maximum activation above control at 6.5 mM glucose
(S)-2-[3-chloro-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-4-methyl-N-(5-methylpyridin-2-yl)pentanamide
-
37% maximum activation above control at 6.5 mM glucose
(S)-2-[3-chloro-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-N-(5-methylpyridin-2-yl)-3-phenylpropanamide
-
30% maximum activation above control at 6.5 mM glucose
(S)-2-[4-(cyclobutylsulfonyl)-2-oxopyridin-1(2H)-yl]-3-cyclopentyl-N-(5-methylpyridin-2-yl)propanamide
-
67% maximum activation above control at 6.5 mM glucose
(S)-2-[4-(cyclobutylsulfonyl)-2-oxopyridin-1(2H)-yl]-3-cyclopentyl-N-pyrazin-2-ylpropanamide
-
66% maximum activation above control at 6.5 mM glucose
(S)-2-[5-chloro-4-(cyclobutylsulfonyl)-2-oxopyridin-1(2H)-yl]-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)propanamide
-
67% maximum activation above control at 6.5 mM glucose
(S)-2-[5-chloro-4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl]-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)propanamide
-
84% maximum activation above control at 6.5 mM glucose
(S)-2-[5-chloro-4-(methylsulfonyl)-2-oxopyridin-1(2H)-yl]-3-cyclopentyl-N-(5-methylpyridin-2-yl)propanamide
-
122% maximum activation above control at 6.5 mM glucose
(S)-2-[5-chloro-4-(methylsulfonyl)-2-oxopyridin-1(2H)-yl]-N-(5-chloropyridin-2-yl)-3-cyclopentylpropanamide
-
82% maximum activation above control at 6.5 mM glucose
(S)-2-[5-chloro-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-3-cyclopentyl-N-(1-methyl-1H-pyrazol-3-yl)propanamide
-
57% maximum activation above control at 6.5 mM glucose
(S)-2-[5-chloro-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-3-cyclopentyl-N-(5-methylpyrazin-2-yl)propanamide
-
104% maximum activation above control at 6.5 mM glucose
(S)-2-[5-chloro-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-3-cyclopentyl-N-(5-methylpyridin-2-yl)propanamide
-
69% maximum activation above control at 6.5 mM glucose
(S)-2-[5-chloro-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-3-cyclopentyl-N-1,3-thiazol-2-ylpropanamide
-
42% maximum activation above control at 6.5 mM glucose
(S)-2-[5-chloro-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-3-cyclopentyl-N-1H-pyrazol-3-ylpropanamide
-
50% maximum activation above control at 6.5 mM glucose
(S)-3-(4-((3-fluoropyrrolidin-1-yl)sulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide
-
activation: 1.9fold
(S)-3-(4-((3-fluoropyrrolidin-1-yl)sulfonyl)phenoxy)-N-(5-fluorothiazol-2-yl)-5-((3-methylbut-2-en-1-yl)oxy)benzamide
-
activation: 2.2fold
(S)-3-cyclopentyl-2-[4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl]-N-(5-methylpyridin-2-yl)propanamide
-
76% maximum activation above control at 6.5 mM glucose
(S)-3-cyclopentyl-2-[4-(cyclopropylsulfonyl)-2-oxopyridin-1(2H)-yl]-N-pyrazin-2-ylpropanamide
-
94% maximum activation above control at 6.5 mM glucose
(S)-3-cyclopentyl-2-[4-(ethylsulfonyl)-2-oxopyridin-1(2H)-yl]-N-(5-methylpyridin-2-yl)propanamide
-
73% maximum activation above control at 6.5 mM glucose
(S)-3-cyclopentyl-2-[4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-N-(5-methylpyridin-2-yl)propanamide
-
65% maximum activation above control at 6.5 mM glucose
(S)-3-cyclopentyl-2-[4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-N-pyridin-2-ylpropanamide
-
43% maximum activation above control at 6.5 mM glucose
(S)-3-cyclopentyl-2-[4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]propanamide
-
35% maximum activation above control at 6.5 mM glucose
(S)-3-cyclopentyl-2-[5-methyl-4-(methylsulfonyl)-2-oxopyridin-1(2H)-yl]-N-(5-methylpyridin-2-yl)propanamide
-
103% maximum activation above control at 6.5 mM glucose
(S)-3-cyclopentyl-2-[5-methyl-4-[(1-methylethyl)sulfonyl]-2-oxopyridin-1(2H)-yl]-N-(5-methylpyridin-2-yl)propanamide
-
48% maximum activation above control at 6.5 mM glucose
(S)-3-cyclopentyl-N-(5-methylpyrazin-2-yl)-2-[4-(methylsulfonyl)-2-oxopyridin-1(2H)-yl]propanamide
-
101% maximum activation above control at 6.5 mM glucose
(S)-3-cyclopentyl-N-(5-methylpyridin-2-yl)-2-[4-(methylsulfonyl)-2-oxopyridin-1(2H)-yl]propanamide
-
58% maximum activation above control at 6.5 mM glucose
(S)-6-(3-cyclopentyl-2-[4-(trifluoromethyl)-1H-imidazol-1-yl]propanamido)nicotinic acid
-
in the presence of liver-specific GKA, progress curves at 1 mM glucose are similar to those at 5 mM, reflecting activation of GK. With steady-state kinetic methods it is shown that there are at least two kinetically distinct forms of glucokinase that interconvert through a slow conformational change and that this interconversion is affected by glucose concentration and a liver-specific GKA
(Z)-2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-(2-methylpropylidene)-4-oxo-4,5-dihydro thiazol-2-yl)-3-(tetrahydro-2Hpyran-4-yl)propanamide
-
activation: 1.17fold
(Z)-N-(5-benzylidene-4-oxo-4,5-dihydrothiazol-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 1.24fold
1-(1-(4-chlorophenyl)cyclohexyl)-3-(thiazol-2-yl)urea
-
-
2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-N,N-dimethyl-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxamide
-
maximal activation: 2.35fold
2-(4-(cyclopropylsulfonyl)phenyl)-3-(tetrahydro-2Hpyran-4-yl)-N-(4,5,6,7-tetrahydrobenzo[d]thiazol-2-yl)propanamide
-
activation: 2.27fold
2-(4-(cyclopropylsulfonyl)phenyl)-N-(4-(prop-1-en-2-yl)thiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 2.4fold
2-(4-(cyclopropylsulfonyl)phenyl)-N-(4-isopropylthiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 2.97fold
2-(4-(cyclopropylsulfonyl)phenyl)-N-(4-oxo-4,5-dihydrothiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 1.65fold
2-(4-(cyclopropylsulfonyl)phenyl)-N-(5,6-dihydro-4Hcyclopenta[d]thiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 3.4fold
2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-iodo-4-isopropylthiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 1.34fold
2-(4-(cyclopropylsulfonyl)phenyl)-N-(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c] pyridin-2-yl)-3-(tetrahydro-2Hpyran-4-yl)propanamide
-
activation: 2.26fold
2-(4-(methylsulfonyl)phenyl)-N-(4-phenylthiazol-2-yl)-3-(tetrahydro-2H-pyran-4-yl)-propanamide
-
activation: 1.3fold
2-amino-4-fluoro-5-((1-methyl-1H-imidazol-2-yl)thio)-N-(thiazol-2-yl)benzamide
2-amino-4-fluoro-5-(1,3,4-thiadiazol-2-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)-benzamide
-
1.14fold activation at 0.01 mM
2-amino-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)-benzamide
-
1.47fold activation at 0.01 mM
2-amino-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide
2-amino-4-fluoro-5-(4-methyl-thiazol-2-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)-benzamide
-
0.89fold activation at 0.01 mM
2-amino-4-fluoro-5-(thiazol-2-ylsulfanyl)-N-(3-trifluoromethyl-phenyl)-benzamide
-
1.15fold activation at 0.01 mM
2-amino-4-fluoro-5-[(1-methyl-1H-imidazol-2-yl)sulfanyl]-N-(4-methylthiazol-2-yl)benzamide
-
108% maximum activation above control at 6.5 mM glucose
2-amino-4-fluoro-N-(3-fluoro-phenyl)-5-(1,3,4-thiadiazol-2-ylsulfanyl)-benzamide
-
1.36fold activation at 0.01 mM
2-amino-4-fluoro-N-(3-fluoro-phenyl)-5-(1-methyl-1Himidazol-2-ylsulfanyl)-benzamide
-
2.04fold activation at 0.01 mM
2-amino-4-fluoro-N-(3-fluoro-phenyl)-5-(pyridin-2-ylsulfanyl)-benzamide
-
1.1fold activation at 0.01 mM
2-amino-4-fluoro-N-(3-fluoro-phenyl)-5-(thiazol-2-ylsulfanyl)-benzamide
-
1.25fold activation at 0.01 mM
2-amino-4-fluoro-N-(3-methoxy-phenyl)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzamide
-
1.15fold activation at 0.01 mM
2-amino-4-fluoro-N-(4-methoxy-phenyl)-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzamide
-
2.01fold activation at 0.01 mM
2-amino-5-((4-methyl-4H-1,2,4-triazol-3-yl)thio)-N-(5-methylthiazol-2-yl)benzamide
-
1.3fold change in Vmax or kcat at 0.01 mM
2-amino-5-(benzoxazol-2-ylsulfanyl)-4-fluoro-N-(3-fluoro-phenyl)-benzamide
-
0.83fold activation at 0.01 mM
2-amino-N-(3,4-dimethoxy-phenyl)-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzamide
-
1.32fold activation at 0.01 mM
2-amino-N-(3-amino-phenyl)-4-fluoro-5-(1,3,4-thiadiazol-2-ylsulfanyl)-benzamide
-
1.22fold activation at 0.01 mM
2-amino-N-(3-amino-phenyl)-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzamide
-
2.09fold activation at 0.01 mM
2-amino-N-(3-amino-phenyl)-4-fluoro-5-(4-methylthiazol-2-ylsulfanyl)-benzamide
-
1.1fold activation at 0.01 mM
2-amino-N-(3-amino-phenyl)-4-fluoro-5-(pyridin-2-ylsulfanyl)-benzamide
-
1.12fold activation at 0.01 mM
2-amino-N-(3-amino-phenyl)-4-fluoro-5-(thiazol-2-ylsulfanyl)-benzamide
-
1.21fold activation at 0.01 mM
2-amino-N-(3-amino-phenyl)-5-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)-4-fluoro-benzamide
-
1.09fold activation at 0.01 mM
2-amino-N-(3-aminomethyl-phenyl)-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-benzamide
-
1.01fold activation at 0.01 mM
2-amino-N-(3-cyano-phenyl)-4-fluoro-5-(1,3,4-thiadiazol-2-ylsulfanyl)-benzamide
-
1.2fold activation at 0.01 mM
2-amino-N-(3-cyano-phenyl)-4-fluoro-5-(1-methyl-1Himidazol-2-ylsulfanyl)-benzamide
-
1.95fold activation at 0.01 mM
2-amino-N-(3-cyano-phenyl)-4-fluoro-5-(4-methylthiazol-2-ylsulfanyl)-benzamide
-
0.99fold activation at 0.01 mM
2-amino-N-(3-cyano-phenyl)-4-fluoro-5-(thiazol-2-ylsulfanyl)-benzamide
-
1.2fold activation at 0.01 mM
2-amino-N-(3-cyano-phenyl)-5-(4,6-dimethyl-pyrimidin-2-ylsulfanyl)-4-fluoro-benzamide
-
1.01fold activation at 0.01 mM
2-amino-N-(4-methyl-1,3-thiazol-2-yl)-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]benzamide
2-cyclopentyl-1-(4-(methylsulfonyl)phenyl)-N-(thiazol-2-yl)ethanesulfonamide
-
-
2-[(3-cyclopentyl-2-[4-[(4-methylpiperazin-1-yl)sulfonyl]phenyl]propanoyl)amino]-5-methoxy-1H-[1,3]thiazolo[5,4-b]pyridin-3-ium
-
-
2-[4-(2,4-difluoro-phenyl)-piperazin-1-yl]-N-(3,4-dimethoxy-phenyl)-acetamide
-
1.01fold activation at 0.01 mM
2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-N-(3-trifluoromethyl-phenyl)-acetamide
-
1.06fold activation at 0.01 mM
2-[4-(methylsulfonyl)phenyl]-3-(tetrahydro-2H-pyran-4-yl)-N-(1,3-thiazol-2-yl)propanamide
-
activation: 2.45fold
28-homobrassinolide
28-homobrassinolide is able to protect or restore the native structure of hexokinase when exposed to diabetic levels of glucose. The denatured hexokinase is renatured upon binding with homobrassinolide. Homobrassinolide is able to bind to the drug-binding pocket of glucokinase. The glide energy is -7.1 kcal/mol
3-((3-methylbut-2-en-1-yl)oxy)-5-(4-(morpholinosulfonyl)phenoxy)-N-(thiazol-2-yl)benzamide
-
activation: 2.1fold
3-(4-(((2S,6R)-2,6-dimethylmorpholino)sulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide
-
activation: 1.5fold
3-(4-(((2S,6R)-2,6-dimethylmorpholino)sulfonyl)phenoxy)-N-(5-fluorothiazol-2-yl)-5-((3-methylbut-2-en-1-yl)oxy)benzamide
-
activation: 1.7fold
3-(4-((4-methoxypiperidin-1-yl)sulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide
-
activation: 1.7fold
3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylsulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide
-
activation: 1.7fold
3-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-ylsulfonyl)phenoxy)-N-(5-fluorothiazol-2-yl)-5-((3-methylbut-2-en-1-yl)oxy)benzamide
-
activation: 1.9fold
3-(4-(cyclopropylsulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(4-oxo-4,5-dihydrothiazol-2-yl)benzamide
-
activation: 1.5fold
3-(4-(cyclopropylsulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(5-methylpyrazin-2-yl)benzamide
-
activation: 1.6fold
3-(4-(cyclopropylsulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)-N-(thiazol-2-yl)benzamide
-
activation: 2.4fold
3-(4-(cyclopropylsulfonyl)phenoxy)-N-(1,5-dimethyl-1H-pyr-azol-3-yl)-5-((3-methylbut-2-en-1-yl)oxy)benzamide
-
activation: 1.5fold
3-(4-(cyclopropylsulfonyl)phenoxy)-N-(4-(4-fluorophenyl)thiazol-2-yl)-5-((3-methylbut-2-en-1-yl)oxy)benzamide
-
activation: 0.9fold
3-(4-(cyclopropylsulfonyl)phenoxy)-N-(5-fluorothiazol-2-yl)-5-((3-methylbut-2-en-1-yl)oxy)benzamide
-
activation: 1.8fold
3-(5-chloro-1,3-thiazol-2-yl)-1-[4-(methylsulfonyl)phenyl]-1-(thiophen-2-ylmethyl)urea
-
-
3-(5-chlorothiazol-2-yl)-1-(4-(methylsulfonyl)phenyl)-1-(thiophen-3-ylmethyl)urea
-
-
3-amino-N-[2-amino-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-phenyl]-benzamide
-
1.16fold activation at 0.01 mM
3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]-N-(4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzamide
-
maximal activation: 2.2fold
3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]-N-[5-(2-oxo-1,2-dihydropyridin-4-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide
-
maximal activation: 2.13fold
3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]-N-[5-(pyridin-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide
-
maximal activation: 1.92fold
3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]-N-[5-(pyrimidin-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide
-
maximal activation: 2.35fold
3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]-N-[5-(pyrimidin-4-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide
-
maximal activation: 2.53fold
3-[4-(azetidine-1-carbonyl)phenoxy]-N-[5-(2-hydroxyethyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamide
-
maximal activation: 1.97fold
3-[4-(azetidine-1-carbonyl)phenoxy]-N-[5-(2-methoxyethyl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamide
-
maximal activation: 1.76fold
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-(4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzamide
-
maximal activation: 3.42fold
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-(5-methyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzamide
-
maximal activation: 3.41fold
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-(5-phenyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)benzamide
-
maximal activation: 2.05fold
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-(7-oxo-4,5,6,7-tetrahydro-1,3-benzothiazol-2-yl)benzamide
-
maximal activation: 2.61fold
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-[5-(propan-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide
-
maximal activation: 2fold
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-[5-(pyridin-2-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide
-
maximal activation: 2.39fold
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-[5-(pyridin-3-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide
-
maximal activation: 2.7fold
3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]-N-[5-(pyridin-4-yl)-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl]benzamide
-
maximal activation: 2.97fold
4-[4-(dimethylcarbamoyl)-3-fluorophenoxy]-2-ethyl-2-methyl-N-(5-methylpyridin-2-yl)-2,3-dihydro-1-benzofuran-6-carboxamide
-
-
5-(2-methylpropyl)-N-(1,3-thiazol-2-yl)-1H-indazol-3-amine
-
-
5-({3-(propan-2-yloxy)-5-[2-(thiophen-3-yl)ethoxy]benzoyl}amino)-1,3,4-thiadiazole-2-carboxylic acid
-
-
6-(3-(((S)-1-methoxypropan-2-yl)oxy)-5-(((S)-1-phenylpropan-2-yl)oxy)benzamido)nicotinic acid
6-({3-(propan-2-yloxy)-5-[2-(thiophen-3-yl)ethoxy]benzoyl}amino)pyridine-3-carboxylic acid
-
GKA22
6-ethoxy-N-(1-methyl-1H-pyrrol-3-yl)-quinazolin-4-amine
-
0.95fold change in Vmax or kcat at 0.05 mM
6-ethoxy-N-(pyridin-2-yl)-quinazolin-4-amine
-
0.62fold change in Vmax or kcat at 0.05 mM
6-isopropoxy-N-(1-methyl-1H-pyrrol-3-yl)quinazolin-4-amine
-
0.8fold change in Vmax or kcat at 0.05 mM
6-Phosphofructo-2-kinase/fructose-2,6-bisphosphatase
-
-
-
6-[[3-hydroxy-5-(propan-2-yloxy)benzoyl]amino]pyridine-3-carboxylic acid
-
activator associates with glucokinase in a glucose-independent fashion. Kinetic assays reveal a lag in enzyme progress curves that is systematically reduced when the enzyme is preincubated with the activator. Activator binding is enthalpically driven. The kcat value of glucokinase is almost fully limited by product release, both in the presence and absence of activator
6-{[3-(2-methylpropoxy)-5-(propan-2-yloxy)benzoyl]amino}pyridine-3-carboxylic acid
-
-
alpha-D-glucose
-
ethyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.22fold
fructose
-
-
GKA50
-
-
glucokinase-associated protein
-
stimulates glucokinase activity by 30-40% when present at a 3-5fold molar excess and 2.5fold at a 50fold molar excess
-
LY-2121260
methyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.38fold
N,N'-bis-(2-methoxy-phenyl)-isophthalamide
-
1.02fold activation at 0.01 mM
N,N'-bis-(3-methoxy-phenyl)-isophthalamide
-
0.81fold activation at 0.01 mM
N,N'-bis-(4-methoxy-phenyl)-isophthalamide
-
0.89fold activation at 0.01 mM
N,N-dicyclohexyl-N'-methyldicarbonimidic diamide
-
-
N-(3-amino-phenyl)-2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-acetamide
-
1.08fold activation at 0.01 mM
N-(3-cyano-phenyl)-2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-acetamide
-
0.96fold activation at 0.01 mM
N-(3-fluoro-phenyl)-2-[4-(2-fluoro-phenyl)-piperazin-1-yl]-acetamide
-
1.01fold activation at 0.01 mM
N-(4,5-dimethylthiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 1.72fold
N-(4-(4-fluorophenyl)thiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 1.25fold
N-(4-(4-methoxyphenyl)thiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 1.22fold
N-(4-(tert-butyl)thiazol-2-yl)-3-(4-(cyclopropylsulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)benzamide
-
activation: 0.7fold
N-(4-cyclopropylthiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 1.87fold
N-(4-ethylthiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)-propanamide
-
activation: 2.17fold
N-(4-isobutylthiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)-propanamide
-
activation: 2.05fold
N-(4-isopropylthiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)-propanamide
-
activation: 2.49fold
N-(4-methyl-1,3-thiazol-2-yl)-3-(pyridin-3-ylmethoxy)pyridin-2-amine
-
-
N-(4-tert-butylthiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)-propanamide
-
activation: 1.29fold
N-(5,6-dihydro-4H-cyclopenta[d][1,3]thiazol-2-yl)-3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamide
-
maximal activation: 4.8fold
N-(5-acetyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamide
-
maximal activation: 2.5fold
N-(5-benzyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamide
-
maximal activation: 2.1fold
N-(5-bromo-4-isopropylthiazol-2-yl)-2-(4-(cyclopropylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 1.67fold
N-(5-ethyl-4,5,6,7-tetrahydro[1,3]thiazolo[5,4-c]pyridin-2-yl)-3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamide
-
maximal activation: 2.08fold
N-(5-fluorothiazol-2-yl)-3-((3-methylbut-2-en-1-yl)oxy)-5-(4-(morpholinosulfonyl)phenoxy)benzamide
-
activation: 1.8fold
N-(5-fluorothiazol-2-yl)-3-(4-((4-methoxypiperidin-1-yl)sulfonyl)phenoxy)-5-((3-methylbut-2-en-1-yl)oxy)benzamide
-
activation: 1.7fold
N-(5-isopropyl-4-methylthiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 1.13fold
N-(6,7-dihydro-4H-pyrano[4,3-d][1,3]thiazol-2-yl)-3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamide
-
maximal activation: 2.17fold
N-(6-fluorobenzo[d]thiazol-2-yl)-2-(4-(methylsulfonyl)phenyl)-3-(tetrahydro-2H-pyran-4-yl)propanamide
-
activation: 1.3fold
N-[2-amino-4-fluoro-5-[(1-methyl-1H-imidazol-2-yl)sulfanyl]benzyl]-1,3-thiazol-2-amine
-
addition of 0.02 mM N-[2-amino-4-fluoro-5-[(1-methyl-1H-imidazol-2-yl)sulfanyl]benzyl]-1,3-thiazol-2-amine results in the loss of positive cooperativity with glucose and in activation of glucokinase catalysis increasing both kcat and the apparent glucose affinity
pentaubiquitin
-
the recombinant glucokinase is allosterically activated up to 1.4fold by purified free pentaubiquitin chains at about 100 nM, and possibly also by unidentified polyubiquitinated proteins
-
PF-04937319
-
maximal activation: 2.11fold
polyubiquitin
-
causes modest activation
-
RO-0275145
-
-
RO-0281675
RO-1440
-
148% maximum activation above control at 6.5 mM glucose
RO-28-0450
-
racemic, activates the enzyme
RO-28-1675
-
R-enantiomer, highly activates the enzyme by elevating Vmax 1.5fold and decreasing Km about 4fold, reverses enzyme inhibition by human glucokinase regulatory protein, the S-enantiomer is inactive
RO-281675
-
-
RO-4389620
-
also known as R1440, GK2, or piragliatin
RO0274375
-
wild-type enzyme V62A, V62T, and V62L respond to the activator. V62Q, V62E, V62F, and V62K are resistant to the activators
RO0281675
-
wild-type enzyme V62A, V62T, and V62L respond to the activator. V62Q, V62E, V62F, and V62K are resistant to the activators
RO0283946
-
wild-type enzyme V62A, V62T, and V62L respond to the activator. V62Q, V62E, V62F, and V62K are resistant to the activators
-
tert-butyl (S)-2-(3-(4-(azetidine-1-carbonyl)phenoxy)-5-((1-methoxypropan-2-yl)oxy)benzamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate
-
glucokinase activators are being developed for the treatment of type 2 diabetes mellitus. Glucokinase activators have risks of hypoglycemia caused by over-activation of glucokinase in islet cells and dyslipidemia caused by over-activation of intrahepatic glucokinase. In the effort to mitigate risks of hypoglycemia and dyslipidemia while maintaining the promising efficacy of glucokinase activator. tert-Butyl (S)-2-(3-(4-(azetidine-1-carbonyl)phenoxy)-5-((1-methoxypropan-2-yl)oxy)benzamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate shows a good balance between in vitro potency and enzyme kinetic parameters, and protects beta-cells from streptozotocin-induced apoptosis. Chronic treatment of this compound demonstrates its potent activity in regulation of glucose homeostasis and low risk of dyslipidemia with diabetic db/db mice in oral glucose tolerance test. Acute treatment of this compound does not induce hypoglycemia in C57BL/6J mice even at 200 mg/kg via oral administration
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)-3-fluorophenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.83 fold
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2R)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.96fold
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-hydroxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.62fold
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.65fold
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[5,4-b]pyridine-4(5H)-carboxylate
-
maximal activation: 1.8fold
tert-butyl 2-(3-[4-(azetidine-1-carbonyl)phenoxy]-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido)-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.84fold
tert-butyl 2-(3-[[6-(azetidine-1-carbonyl)pyridin-3-yl]oxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.1fold
tert-butyl 2-(3-[[6-(methanesulfonyl)pyridin-3-yl]oxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido)-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 4.07fold
tert-butyl 2-[3-(3,5-difluorophenoxy)-5-[[(2S)-1-methoxypropan-2-yl]oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.72fold
tert-butyl 2-[3-(benzyloxy)-5-[4-(methanesulfonyl)phenoxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.3fold
tert-butyl 2-[3-(cyclohexyloxy)-5-[4-(methanesulfonyl)phenoxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 1.71fold
tert-butyl 2-[3-(cyclopentylmethoxy)-5-[4-(methanesulfonyl)phenoxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.11fold
tert-butyl 2-[3-(cyclopentyloxy)-5-[4-(methanesulfonyl)phenoxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 3.17fold
tert-butyl 2-[3-[2-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 1.89fold
tert-butyl 2-[3-[3-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.74fold
tert-butyl 2-[3-[4-(azetidine-1-carbonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.89fold
tert-butyl 2-[3-[4-(azetidine-1-sulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 3.26fold
tert-butyl 2-[3-[4-(cyclopropanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 3.12fold
tert-butyl 2-[3-[4-(dimethylcarbamoyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 1.91fold
tert-butyl 2-[3-[4-(ethanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.37fold
tert-butyl 2-[3-[4-(methanesulfonyl)phenoxy]-5-(2-methoxyethoxy)benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.3fold
tert-butyl 2-[3-[4-(methanesulfonyl)phenoxy]-5-[(1-methoxypropan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[5,4-c]pyridine-5(4H)-carboxylate
-
maximal activation: 2.94fold
tert-butyl 2-[3-[4-(methanesulfonyl)phenoxy]-5-[(propan-2-yl)oxy]benzamido]-6,7-dihydro[1,3]thiazolo[4,5-c]pyridine-5(4H)-carboxylate
-
maximal activation: 3.55fold
additional information
-
RO-28-1674 is inactive
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.5 - 1.9
2-deoxy-D-glucose
18
2-deoxyglucose
-
30°C, pH 7.5, wild-type
0.00000023 - 12.6
ATP
5
CTP
-
MgCTP2-, hexokinase I, at 37°C, pH 8.1
4.7 - 240
D-fructose
0.5 - 1.5
D-glucosamine
0.032 - 10.6
D-glucose
0.07 - 4.6
D-mannose
16.6
ITP
-
MgITP2-, hexokinase I, at 37°C, pH 8.1
5
UTP
-
MgUTP2-, hexokinase I, at 37°C, pH 8.1
additional information
additional information
-
TURNOVER NUMBER [1/s]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
29
2-deoxy-D-glucose
-
wild-type enzyme
0.61 - 68.4
ATP
5.9 - 166
beta-D-glucose
0.00091 - 122
D-glucose
additional information
additional information
-
kcat/KM VALUE [1/mMs-1]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.01 - 11
D-glucose
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.0107 - 23
1,5-Anhydro-D-glucitol 6-phosphate
0.015
atorvastatin
pH 8.5, 37°C
0.05 - 22
D-glucose 1,6-diphosphate
0.029 - 0.24
D-glucose 6-phosphate
0.0000128 - 0.000113
GK regulatory protein
-
13 - 15
glucose 6-phosphate
-
hexokinase Ia, Ib and Ic, at 37°C, pH 7.2
0.015
indomethacin
pH 8.5, 37°C
33
phosphate
-
recombinant HK I, a truncate HK I form lacking the first 11 amino acids named HK-11aa, and the 50 kDa C-terminal half of HK I, at 37°C, pH 7.2
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
IMAGE
0.00206
(22E,24R)-6beta-methoxyergosta-7,9(11),22-triene-3beta,5alpha-diol
Homo sapiens
pH and temperature not specified in the publication
0.00102
2,5-dihydroxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00207
2-hydroxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.000025
2-[([1,1'-biphenyl]-3-carbonyl)amino]-2,6-dideoxy-6-[(2,3-dichlorobenzene-1-sulfonyl)amino]-D-glucopyranose
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
0.01452
22E-6beta-methoxyergosta-7,22-diene-3beta,5alpha-diol
Homo sapiens
pH and temperature not specified in the publication
0.00419
3-(methanesulfonyl)-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.026
3-Bromopyruvate
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00108
3-chloro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00589
3-methoxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
-
0.0007
3-nitro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00151
4-(2-hydroxyethoxy)-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00332
4-(methanesulfonyl)-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00115
4-butyl-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00117
4-chloro-3-nitro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00098
4-chloro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00516
4-fluoro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00521
4-methoxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00053
4-nitro-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.0023
5-hydroxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]-2,3-dihydro-1H-indole-2-carbohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00001
5-[[(2R,3S,4R,5R,6S)-5-[(3-bromophenyl)carbonylamino]-3,4,6-tris(oxidanyl)oxan-2-yl]methylsulfamoyl]-2-methyl-furan-3-carboxylic acid
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
0.00126
6-hydroxy-N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]naphthalene-2-carbohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00552
Benserazide
Homo sapiens
pH and temperature not specified in the publication
0.00074
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]-2,3-dihydro-1,4-benzodioxine-2-carbohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00108
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]benzohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00172
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]pyridine-3-carbohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00643
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]pyridine-4-carbohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00069
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]quinoline-2-carbohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.0048
N'-[(E)-(2,3,4-trihydroxyphenyl)methylidene]thiophene-2-carbohydrazide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00202
N-(4-[(2E)-2-[(2,3,4-trihydroxyphenyl)methylidene]hydrazinecarbonyl]phenyl)cyclopropanecarboxamide
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00817
ZINC03232404
Homo sapiens
pH 8.0, temperature not specified in the publication
0.00939
ZINC03233449
Homo sapiens
pH 8.0, temperature not specified in the publication
0.0101
ZINC39948337
Homo sapiens
pH 8.0, temperature not specified in the publication
0.000032
2-[([1,1'-biphenyl]-3-carbonyl)amino]-2,6-dideoxy-6-[(2,3-dichlorobenzene-1-sulfonyl)amino]-D-glucopyranose
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
0.00002
5-[[(2R,3S,4R,5R,6S)-5-[(3-bromophenyl)carbonylamino]-3,4,6-tris(oxidanyl)oxan-2-yl]methylsulfamoyl]-2-methyl-furan-3-carboxylic acid
Homo sapiens
pH not specified in the publication, temperature not specified in the publication
0.044
atorvastatin
Homo sapiens
pH 8.5, 37°C
0.077
chlorpromazine
Homo sapiens
pH 8.5, 37°C
0.006
clozapine
Homo sapiens
pH 8.5, 37°C
0.033
diltiazem
Homo sapiens
pH 8.5, 37°C
0.01
enalaprilat
Homo sapiens
pH 8.5, 37°C
0.03
gabapentin
Homo sapiens
pH 8.5, 37°C
0.008
gatifloxacin
Homo sapiens
pH 8.5, 37°C
0.005
indomethacin
Homo sapiens
pH 8.5, 37°C
0.00026
N,N'-[furan-2,5-diylbis(2-chloro-4,1-phenylene)]diguanidine
Homo sapiens
pH and temperature not specified in the publication
0.034
Valproic acid
Homo sapiens
pH 8.5, 37°C
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
0.34
-
S151G, D-mannose as substrate
0.55 - 1.95
-
hexokinases Ia, Ib and Ic from adult erythrocytes, at 37°C, pH 7.2
0.6
-
S151G, D-glucose as substrate
1.4
-
N166R-S151A, D-mannose as substrate
1.43 - 2.22
-
hexokinases Ia, Ib and Ic from umbilical cord blood, at 37°C, pH 7.2
122
-
wild-type, D-fructose as substrate
14.5
-
N166R-S151A, D-fructose as substrate
144
-
purified recombinant HK I, at 22°C
150
-
hexokinase from heart, at 25°C, pH 8
180
-
purified recombinant HK-11aa, a truncated HK I form lacking the first 11 amino acids, at 22°C
192.5
-
at 37°C
2.16
-
S151C, D-mannose as substrate
22.2
-
at 25°C, pH 7.2, hexokinase from erythrocytes
23.8
-
S151A, D-fructose as substrate
3.18
-
S151G, D-fructose as substrate
3.32
-
S151A, D-mannose as substrate
3.8
-
unpurified recombinant HK-11aa, a truncated HK I form lacking the first 11 amino acids, at 22°C
310
-
N166R, D-fructose as substrate
35.7
-
D-mannose as substrate
36
-
catalytically active recombinant carboxyl-domain of hexokinase type III, at 37°C, pH 8.1
37
-
hexokinase from blood, at 25°C
38.1
-
D-glucose as substrate
4.1
-
S151A, 2-deoxy-D-glucose as substrate
58
-
hexokinase from heart, at 25°C, pH 7.2
58.2
-
recombinant hexokinase I expressed in E. coli
6
-
S151C, D-glucose as substrate
6.6
-
S151A, D-glucose as substrate
60 - 61
wild-type and nonaggregating interface mutant hexokinase I, pH 7.8
60.8
-
N166R, D-mannose as substrate
68
-
wild-type, D-mannose and 2-deoxy-D-glucose as substrate
80
-
wild-type and N166R, D-glucose as substrate
9.12
-
S151C, D-fructose as substrate
98.7
-
D-fructose as substrate
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7.1
-
assay at
7.4
-
assay at
7.6
-
assay at
7.8
assay at
8 - 8.5
-
hexokinase I
8 - 9
-
-
8.1
-
assay at
8.5 - 8.7
-
pH RANGE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
7 - 9
-
activity increases more than 40% over the range of pH 7-8, after which the activity remains constant until pH 9
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
33
D209A mutant enzyme
37
wild-type enzyme
pI VALUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
5.35
-
hexokinase Ic, isoelectric focusing
5.5
-
hexokinase Ib, isoelectric focusing
5.7
-
hexokinase Ia, isoelectric focusing
5.9
-
isoelectric focusing
ORGANISM
COMMENTARY hide
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
SOURCE
the enzyme is expressed at high level in cancer cells compared with normal cells
Manually annotated by BRENDA team
fibroblasts from patients with idiopathic pulmonary fibrosis exhibit an increased abundance of hexokinase 2
Manually annotated by BRENDA team
-
very low expression
Manually annotated by BRENDA team
-
contains only hexokinase I
Manually annotated by BRENDA team
low expression
Manually annotated by BRENDA team
high expression in surface epithelium. Very low expression in crypt base epithelium
Manually annotated by BRENDA team
very low expression
Manually annotated by BRENDA team
intermediate expression in suprabasal squamous epithelium. Low expression in basal layer
Manually annotated by BRENDA team
-
human glioblastoma multiforme shows increased HK2 expression, correlating with poor overall survival
Manually annotated by BRENDA team
-
70-80% hexokinase III, 20-30% hexokinase I
Manually annotated by BRENDA team
low expression
Manually annotated by BRENDA team
-
overproduction of hexokinase
Manually annotated by BRENDA team
high expression in villous brush border. No expression in deep crypt epithelium
Manually annotated by BRENDA team
low expression
Manually annotated by BRENDA team
high expression in alveolar macrophages. Intermediate expression in bronchial epithelium. very low expression in alveolar lining cells
Manually annotated by BRENDA team
low expression
Manually annotated by BRENDA team
intermediate expression in basal cells. Low to intermediate expression in stromal cells. Low expression in gland epithelium
Manually annotated by BRENDA team
low expression
Manually annotated by BRENDA team
low expression
Manually annotated by BRENDA team
high expression in parietal cells and chief cells. Intermediate expression in superficial foveolar epithelium
Manually annotated by BRENDA team
low expression in sweat gland, intermediate expression in sweat gland duct
Manually annotated by BRENDA team
low expression
Manually annotated by BRENDA team
intermediate to high expression
Manually annotated by BRENDA team
additional information
-
not expressed in skeletal muscle and kidney
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY hide
GeneOntology No.
LITERATURE
SOURCE
structural and biochemical characterization of the mitochondrial conformation reveals higher conformational stability and slow protein unfolding rate compared with the cytosolic conformation
Manually annotated by BRENDA team
-
hexokinase I binds to the outer membrane of mitochondria, linear chains of enzyme dimers are stabilized by interactions with mitochondrial porin
Manually annotated by BRENDA team
-
in lymphocytes and platelets most of the hexokinase activity is particle-bound
-
Manually annotated by BRENDA team
compartmentalization of hexokinase-1 to plasma membrane of sperm cells is swappable to somatic HEK-293 cells
Manually annotated by BRENDA team
additional information
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
drug target
malfunction
knockdown of hexokinase 2 or pharmacological inhibition of hexokinase 2 activity with Lonidamine decreased TGF-beta-stimulated fibrogenic processes, including profibrotic gene expression, cell migration, colony formation, and activation of the transcription factors YAP and TAZ, with no apparent effect on cellular viability
metabolism
physiological function
drug target
-
glucokinase activators are being developed for the treatment of type 2 diabetes mellitus. Glucokinase activators have risks of hypoglycemia caused by over-activation of glucokinase in islet cells and dyslipidemia caused by over-activation of intrahepatic glucokinase. In the effort to mitigate risks of hypoglycemia and dyslipidemia while maintaining the promising efficacy of glucokinase activator. tert-Butyl (S)-2-(3-(4-(azetidine-1-carbonyl)phenoxy)-5-((1-methoxypropan-2-yl)oxy)benzamido)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate shows a good balance between in vitro potency and enzyme kinetic parameters, and protects beta-cells from streptozotocin-induced apoptosis. Chronic treatment of this compound demonstrates its potent activity in regulation of glucose homeostasis and low risk of dyslipidemia with diabetic db/db mice in oral glucose tolerance test. Acute treatment of this compound does not induce hypoglycemia in C57BL/6J mice even at 200 mg/kg via oral administration
malfunction
metabolism
physiological function
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION?
HXK2_HUMAN
917
0
102380
Swiss-Prot
other Location (Reliability: 4)
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
100000
103000
-
1 * 103000 or 1 * 112000, 2 subtypes of hexokinase type I, SDS-PAGE
108000
-
gel filtration
110000
-
1 * 110000, heart hexokinase, monomer with a tendency to form aggregates, SDS-PAGE
112000
-
1 * 103000 or 1 * 112000, 2 subtypes of hexokinase type I, SDS-PAGE
118000
-
both subtypes of hexokinase type I, gel filtration
50000
SDS-PAGE
52000
x * 52000, SDS-PAGE
54000
-
x * 54000, catalytically active recombinant carboxyl-domain of hexokinase type III, SDS-PAGE
additional information
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
dimer
homodimer
-
2 * 100000
monomer
additional information
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
lipoprotein
The N-terminal MGQICQ motif in the unique germ cell-specific domain of hexokinase acquires hydrophobicity by N-myristoylation and palmitoylation. The mutation of the myristoyl recipient Gly2 impedes plasma membrane association and relocates the enzyme to the cytosol but not the nucleus. Substitution of the putatively palmitoylated Cys5 is reflected in a similar loss of compartmentalization of the protein
additional information
-
poly/multiubiquitination of glucokinase in vitro serves as a signal for proteasomal degradation of the newly synthesized protein
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
in complex with inhibitor 5-[[(2R,3S,4R,5R,6S)-5-[(3-bromophenyl)carbonylamino]-3,4,6-tris(oxidanyl)oxan-2-yl]methylsulfamoyl]-2-methyl-furan-3-carboxylic acid. Cocrystal structures reveal the flexibility of the hexokinase 2 protein and that the catalytic site can adopt an induced-fit conformation with inhibitors
structure of HK2 in complex with glucose and glucose-6-phosphate. Crystals of DELTA16-hexokinase 2 are grown by sitting-drop vapor diffusion at 18°C
crystal structure of hexokinase I from brain complexed with glucose and glucose 6-phosphate
-
crystal structures of hexokinase I dimers
first structures of a glucokinase-glucose complex without activator, of glucokinase-glucose-AMP-PNP and of glucokinase-glucose-AMP-PNP with a bound activator are reported. All structures are extremely similar, thus demonstrating that binding of GK activators does not result in conformational changes of the active protein but in stabilization of the active form of glucokinase
hanging drop method
-
human enzyme expressed in Escherichia coli
-
molecular docking of 28-homobrassinolide. Homobrassinolide is able to bind to the drug-binding pocket of glucokinase. The glide energy is -7.1 kcal/mol
molecular docking of glucose and synthetic ligands (allosteric activators). Predicted position of glucose coincides with its position in the crystallographic complex. Glucose interacts with the residues of large (Ile225, Gly229, Cys230, Asn231, Glu256, Gln287, Glu290) and small (Ser151, Phe152, Pro153, Thr168, Lys169) domains and with the residues of connecting region Asn204, Asp205. Hydrogen bonds with Asp205, Glu256 and Glu290 stabilize this complex. The allosteric site formed by the small and large domains and two loops connecting them is located approximately 20 A away from the glucose binding site. There are two stable positions of glucokinase activators and approximately five sites of ligand binding with less favorable interaction energy. Predicted position of glucose coincides with its position in the crystallographic complex
multiple crystal forms of recombinant hexokinase I complexed with glucose/glucose 6-phosphate
-
purified recombinant hepatic wild-type and deletion mutant enzymes in complex with either D-glucose or the synthetic activator 2-amino-4-fluoro-5-(1-methyl-1H-imidazol-2-ylsulfanyl)-N-thiazol-2-yl-benzamide, hanging drop vapour diffusion method, 10 mg/ml protein in 20 mM Tris-HCl, pH 7.5, 50 mM NaCl, 5 mM Tris(2-carboxyethyl)phosphine hydrochloride, and 20 mM D-glucose, or 0.3 mM compound A, 0.0015-0.003 ml of the solution is mixed with an equal volume of precipitant solution containing 28-30% PEG 1500, 0.1 M HEPES-NaOH, pH 6.0, equilibration against 1 ml precipitant solution, 1 week, crystallization of the free hepatic enzyme by using precipitant solution containing 50 mM NaCl, 1.5-1.6 M ammonium sulfate, and 0.1 M bicine-NaOH, pH 8.7, 1 week, X-ray diffraction structure determination and analysis at 2.3 and 3.4 A resolution, respectively, molecular replacement
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
D209A
glucose binding enhances the stability of the wild-type enzyme and the single mutant D657A of the C-domain, but it does not increase the stability of the D209A mutant of the N-domain
D657A
glucose binding enhances the stability of the wild-type enzyme and the single mutant D657A of the C-domain, but it does not increase the stability of the D209A mutant of the N-domain
A188E
-
kinetic mutation effects are increased S0.5, decreased Hill number, decreased kcat, decreased Km for ATP
A188W
-
kinetic mutation effects are increased S0.5, decreased kcat, decreased Km for ATP
A208G
-
mutant displays a slightly higher glucose affinity and similar ATP affinity to the wild type enzyme. The activity of the enzyme at 5 mM glucose is moderately higher than the wild type activity
A208W
-
kinetic mutation effects are increased S0.5, decreased kcat, decreased Hill number, increased Km for ATP
A378V
-
kinetic mutation effects are increased S0.5, increased Km for ATP
A379S
-
mutation isolated in a type 2 diabetes patient
A379T
kcat(1/sec): 61.2, D-glucose S05 (mM): 12.3, Km (ATP): 0.87 mM, relative inhibition of glucokinase activity through GKRP alone: 17% and GKRP plus 10 microM sorbitol 6-phosphate: 53%
A379V
mutations is associated with mature-onset diabetes of the young, type 2 (MODY2). Vmax is 65% of maximal activity, Km-value for ATP is 1.5fold higher than wild-type enzyme
A456V
A460R
-
mutation increases the affinity of the enzyme for glucose
A464P/E465G
-
mutant with a helix breaker embedded in the interdomain alpha-helix has a smaller magnitude of phosphate alleviation than the wild type
A53S
-
the mutant shows wild type kinetics, is thermolabile
A8L
-
mutant maintains binding to mitochondrial-like membrane structures
C213R
C220Y
-
inactivating mutation in glucokinase causing maturity-onset diabetes of the young (MODY) subtype glucokinase, characterized by mild fasting hyperglycemia
C233R
C252Y
C457V
-
the mutant enzyme shows a slightly higher glucose level than the wild type and a slightly lower affinity for ATP. The activity of the enzymes at 5 mM glucose is higher than the wild type activity
C5A
mutation abrogates palmitoylation of protein
C5S
mutation abrogates palmitoylation of protein
D158A
-
naturally occurring mutation, activity and kinetics are similar to the wild-type enzyme
D205A
D400Y
-
mutation isolated in a type 2 diabetes patient
D78A/D158A
-
site-directed mutagenesis, highly reduced activity compared to the wild-type enzyme
E256A
the mutation in the L-domain results in enzyme form that does not bind alpha-D-glucose at 200 mM and is essentially catalytically inactive (2.6% relative activity compared to the wild type enzyme)
E256K
the mutation in the L-domain results in enzyme form that does not bind alpha-D-glucose at 200 mM and is essentially catalytically inactive
E265K
E279Q
-
kinetic mutation effects are increased S0.5, decreased kcat
E280A
hexokinase I mutation eliminates hydrogen bonds between monomers of crystallographic dimers, triple mutant E280A/R283A/G284Y: nonaggregating mutant of recombinant hexokinase I, engineered by directed mutation to block dimerization, exhibits wild-type activity
E290A
the mutant 45.9% relative activity compared to the wild type enzyme
E300A
-
mutation isolated in a type 2 diabetes patient
E300K
-
mutant shows kinetics same as wild type and decreased thermostability
E300Q
-
kinetic mutation effect is increased S0.5
E339G
-
kinetic mutation effects are increased S0.5, decreased Hill number, increased Km for ATP, decreased kcat
E339K
crystal structure of E339K glucokinase in complex with glucose is shown. This mutation results in a conformational change of His416, spatially interfering with adenosine-triphosphate (ATP) binding
E356K
-
kinetic mutation effects are decreased S0.5, decreased kcat
E395A
-
mutation isolated in a type 2 diabetes patient
E395G
-
mutation isolated in a type 2 diabetes patient
E397L
-
kinetic mutation effect is decreased thermostability
E442K
kcat(1/sec): 52.6, D-glucose S05 (mM): 5.24, Km (ATP): 1.5 mM, relative inhibition of glucokinase activity through GKRP alone: 14% and GKRP plus 10 microM sorbitol 6-phosphate: 40%
E70K
-
kinetic mutation effects are increased S0.5, decreased Hill number, decreased kcat
F419L
-
inactivating mutation in glucokinase causing maturity-onset diabetes of the young (MODY) subtype glucokinase, characterized by mild fasting hyperglycemia
G175E
-
kinetic mutation effects are increased S0.5, decreased kcat
G175R
-
kinetic mutation effects are increased S0.5, decreased Hill number, decreased kcat
G227A/D158A
-
site-directed mutagenesis, reduced activity compared to the wild-type enzyme
G261R
-
kinetic mutation effects are increased S0.5, increased Hill number, increased Km for ATP, decreased kcat
G264S
-
mutant shows near normal kinetics, mild elevation of S0.5, slight decrease in Hill number, slightly decreased thermostability
G284Y
hexokinase I mutation introduces steric hindrance, triple mutant E280A/R283A/G284Y: nonaggregating mutant of recombinant hexokinase I, engineered by directed mutation to block dimerization, exhibits wild-type activity
G299R
-
kinetic mutation effects are decreased S0.5, decreased Km for ATP, decreased kcat
G2A
mutant protein lacks myristoylation
G2A/C5S
mutation abrogates both myristoylation and palmitoylation of protein
G44S
-
kinetic mutation effects are increased S0.5, decreased Hill number, decreased Km for ATP, decreased kcat
G68K
kcat(1/sec): 43.2, D-glucose S05 (mM): 2.34, Km (ATP): 0.39 mM, relative inhibition of glucokinase activity through GKRP alone: 2% and GKRP plus 10 microM sorbitol 6-phosphate: 20.5%
G80A
-
kinetic mutation effects are increased S0.5, decreased Hill number, decreased kcat
H137R
-
mutant shows wild type kinetics
H380N
-
mutation isolated in a type 2 diabetes patient
H5P
-
mutation abolishes binding to mitochondrial-like membrane structures, and a greater than 4fold decrease in H5P protein levels as compared with wild-type protein levels is found in the cytoplasmic fraction
I348N
-
mutation isolated in a type 2 diabetes patient
I366F
-
inactivating mutation in glucokinase causing maturity-onset diabetes of the young (MODY) subtype glucokinase, characterized by mild fasting hyperglycemia
K102A/D158A
-
site-directed mutagenesis, slightly reduced activity compared to the wild-type enzyme
K140E
kcat(1/sec): 40, D-glucose S05 (mM): 10.8, Km (ATP): 0.35 mM, relative inhibition of glucokinase activity through GKRP alone: 9% and GKRP plus 10 microM sorbitol 6-phosphate: 10.5%
K169A
inactive, Lys169 enhances the binding of glucokinase with both ATP and glucose by serving as a bridge between ATP and glucose, Lys169 directly participates in the glucose phosphorylation as a general acid catalyst
K169N
K414E
K420E
K458R
-
mutation results in an enzyme with lower glucose affinity and lower ATP affinity than the wild type enzyme. Activity of the K458R mutant at 5 mM glucose is lower than the wild type activity
K459L
-
the mutant enzyme shows a slightly higher glucose than the wild type and a slightly lower affinity for ATP. The activity of the enzymes at 5 mM glucose is higher than the wild type activity
K90A/D158A
-
site-directed mutagenesis, 2fold increased activity compared to the wild-type enzyme
L146R
L165F
-
kinetic mutation effects are increased S0.5, decreased Hill number, increased Km for ATP, decreased kcat, decreased thermostability
L301M
-
mutation isolated in a type 2 diabetes patient
L309P
-
kinetic mutation effects are increased S0.5, decreased Hill number, increased Km for ATP, decreased kcat
M197E
kcat(1/sec): 17.7, D-glucose S05 (mM): 41.6, Km (ATP): 0.4 mM, relative inhibition of glucokinase activity through GKRP alone: 13.5% and GKRP plus 10 microM sorbitol 6-phosphate: 18.5%
M197I
M197I/A397T
kcat(1/sec): 50.2, D-glucose S05 (mM): 5.81, Km (ATP): 2.71 mM, relative inhibition of glucokinase activity through GKRP alone: 18% and GKRP plus 10 microM sorbitol 6-phosphate: 37%
M197L
kcat(1/sec): 62.6, D-glucose S05 (mM): 4.03, Km (ATP): 1.31 mM, relative inhibition of glucokinase activity through GKRP alone: 15% and GKRP plus 10 microM sorbitol 6-phosphate: 37%
M210K
-
kinetic mutation effects are increased S0.5, decreased Hill number, increased Km for ATP, decreased kcat
M210W
-
kinetic mutation effects are increased S0.5, decreased Hill number, decreased kcat
M224R
-
inactivating mutation in glucokinase causing maturity-onset diabetes of the young (MODY) subtype glucokinase, characterized by mild fasting hyperglycemia
M235V
-
kinetic mutation effects are thermostability, decreased kcat
M235W
-
kinetic mutation effects are increased S0.5, decreased Hill number, decreased Km for ATP, decreased kcat
M298I
-
mutation isolated in a type 2 diabetes patient
M298K
M381G
-
mutation isolated in a type 2 diabetes patient
M402R
-
mutation isolated in a type 2 diabetes patient
N166R
-
increased affinity for glucose and ATP by a factor of 3
N166R-S151-A
-
lowers the KM-value for glucose by a factor of 40 and increases the KM-value for ATP
N204A
the mutation in the L-domain results in enzyme form that does not bind alpha-D-glucose at 200 mM and is essentially catalytically inactive (8.9% relative activity compared to the wild type enzyme)
N231A
the mutant shows 0.03% relative activity compared to the wild type enzyme
P417R
kcat(1/sec): 48.3, D-glucose S05 (mM): 6.59, Km (ATP): 2.08 mM, relative inhibition of glucokinase activity through GKRP alone: 10% and GKRP plus 10 microM sorbitol 6-phosphate: 39%
Q287V
the mutant 57.9% relative activity compared to the wild type enzyme
Q466_H467insHMNLAEQ
-
mutant has a smaller magnitude of phosphate alleviation than the wild type
R275C
-
mutant shows near wild type kinetics
R283A
hexokinase I mutation eliminates hydrogen bonds between monomers of crystallographic dimers, triple mutant E280A/R283A/G284Y: nonaggregating mutant of recombinant hexokinase I, engineered by directed mutation to block dimerization, exhibits wild-type activity
R308K
-
mutation isolated in a type 2 diabetes patient
R308W
-
kinetic mutation effects are increased S0.5, decreased kcat, decreased thermostability
R345X
-
inactivating mutation in glucokinase causing maturity-onset diabetes of the young (MODY) subtype glucokinase, characterized by mild fasting hyperglycemia
R36W
-
kinetic mutation effects are edecreased S0.5, decreased Km for ATP, decreased kcat
R377C
-
kinetic mutation effects are increased S0.5, decreased kcat
R394P
-
mutation isolated in a type 2 diabetes patient
R397S
-
mutation isolated in a type 2 diabetes patient
S127P
-
inactivating mutation in glucokinase causing maturity-onset diabetes of the young (MODY) subtype glucokinase, characterized by mild fasting hyperglycemia
S131P
-
kinetic mutation effects are increased S0.5, increased Km for ATP, decreased kcat
S151A
-
lowers the KM-value for glucose by a factor of 26, increases the KM-value for ATP and decreases the KM-value for mannose and fructose
S151C
-
lowers the KM-value for glucose by a factor of 2, increases the KM-value for ATP and decreases the KM-value for mannose and fructose
S151G
-
lowers the KM-value for glucose by a factor of 40, increases the KM-value for ATP and decreases the KM-value for mannose and fructose
S263P
S336L
S383L
-
kinetic mutation effects are increased S0.5, increased Km for ATP, decreased Hill number, decreased kcat
S398R
-
mutation isolated in a type 2 diabetes patient
S411A
-
site-directed mutagenesis, reduced activity compared to the wild-type enzyme
S411F
-
kinetic mutation effects are decreased S0.5, increased Km for ATP, decreased Hill number, decreased kcat
S411L
-
site-directed mutagenesis, reduced activity compared to the wild-type enzyme
S453L
-
kinetic mutation effects are increased S0.5, increased Km for ATP, decreased Hill number, decreased kcat
S4L
-
mutant maintains binding to mitochondrial-like membrane structures, a greater than 6fold increase in S4L mutant protein is found in the mitochondrial fraction
S64P
kcat(1/sec): 83.3, D-glucose S05 (mM): 2.07, Km (ATP): 0.32 mM, relative inhibition of glucokinase activity through GKRP alone: 5% and GKRP plus 10 microM sorbitol 6-phosphate: 4%
S64R/E67D/S69T
3fold increase in activity, no change in cooperativity
T168G
the mutant shows 9.4% relative activity compared to the wild type enzyme
T206M
-
inactivating mutation in glucokinase causing maturity-onset diabetes of the young (MODY) subtype glucokinase, characterized by mild fasting hyperglycemia
T228A
T228A/D158A
-
site-directed mutagenesis, very highly reduced activity compared to the wild-type enzyme
T228M
-
mutant shows a 9000fold reduced activity
T82A
-
site-directed mutagenesis, highly reduced activity compared to the wild-type enzyme
V182L
V182M
-
kinetic mutation effects are increased S0.5, decreased Hill number, decreased kcat, decreased Km for ATP
V203A
-
kinetic mutation effects are increased S0.5, decreased kcat, increased Km for ATP
V226M
-
kinetic mutation effects are increased S0.5, decreased Hill number, increased Km for ATP, decreased kcat
V367M
-
the mutant shows wild type kinetics
V389L
kcat(1/sec): 67.1, D-glucose S05 (mM): 3.45, Km (ATP): 0.76 mM, relative inhibition of glucokinase activity through GKRP alone: 67% and GKRP plus 10 microM sorbitol 6-phosphate: 75%
V452L
kcat(1/sec): 122, D-glucose S05 (mM): 2.27, Km (ATP): 0.53 mM, relative inhibition of glucokinase activity through GKRP alone: 19% and GKRP plus 10 microM sorbitol 6-phosphate: 38%
V455E
-
kinetic mutation effects are increased S0.5, decreased kcat
V455M
V62E
-
kcat for ATP is 8% of wild-type value
V62F
-
no inhibition by glucokinase regulatory protein. kcat for ATP is 54% of wild-type value
V62K
-
no inhibition by glucokinase regulatory protein. kcat for ATP is 10% of wild-type value
V62L
-
no inhibition by glucokinase regulatory protein. kcat for ATP is 96% of wild-type value
V62Q
-
no inhibition by glucokinase regulatory protein. kcat for ATP is 24% of wild-type value
V62T
-
kcat for ATP is 41% of wild-type value
V91L
kcat(1/sec): 60.6, D-glucose S05 (mM): 1.66, Km (ATP): 0.48 mM, relative inhibition of glucokinase activity through GKRP alone: 6% and GKRP plus 10 microM sorbitol 6-phosphate: 22.5%
W167F
the mutant exhibits 24fold reduction in catalytic efficiency
W167F/W257F
-
W99 kcat values are markedly lowered compared to wild-type, Km (ATP) increased compared to wild-type, kcat only moderately increased in the presence of glucokinase activator drug
W168A
-
kinetic mutation effects are increased S0.5, decreased Hill number, increased Km for ATP
W168P
-
kinetic mutation effects are increased S0.5, decreased Hill number, increased Km for ATP, decreased kcat
W206M
-
kinetic mutation effects are increased S0.5, decreased Hill number, decreased kcat
W209M
-
kinetic mutation effects are decreased S0.5, increased Km for ATP, decreased kcat
W228A
-
kinetic mutation effects are decreased S0.5, decreased Hill number
W257F
the mutant exhibits slightly reduced affinity for D-glucose
W257R
-
kinetic mutation effects are decreased S0.5, decreased kcat
W65I
-
kinetic mutation effects are decreased S0.5, decreased Hill number, increased Km for ATP, decreased kcat
W99F
the mutant shows a small increase in both affinity and catalytic efficiency
W99L
-
kinetic mutation effects are decreased S0.5, increased kcat
W99R/W167F
-
W257 kcat values are markedly lowered compared to wild-type, Km (ATP) increased compared to wild-type
W99R/W257F
-
W167 kcat values onlye weakly lowered compared to wild-type, Km (ATP) weakly increased compared to wild-type, kcat increased in the presence of glucokinase activator drug
Y108C
-
kinetic mutation effects are increased S0.5, decreased Hill number, decreased Km for ATP, decreased kcat
Y214A
kcat(1/sec): 117, D-glucose S05 (mM): 1.41, Km (ATP): 0.92 mM, relative inhibition of glucokinase activity through GKRP alone: 24% and GKRP plus 10 microM sorbitol 6-phosphate: 53%
Y214A/V452A
kcat(1/sec): 23.1, D-glucose S05 (mM): 0.55, Km (ATP): 1.42 mM, relative inhibition of glucokinase activity through GKRP alone: 11.5% and GKRP plus 10 microM sorbitol 6-phosphate: 20%
Y214C
Y215A
Y273X
-
inactivating mutation in glucokinase causing maturity-onset diabetes of the young (MODY) subtype glucokinase, characterized by mild fasting hyperglycemia
additional information
TEMPERATURE STABILITY
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
34
Tm-value, wild-type enzyme
42
Tm-value, wild-type enzyme, addition of glucose
40
-
stabilization by D-glucose and glycerol is limited since thermal glucokinase denaturation above 40 °C is irreversible even in their presence
42.5
-
wild-type enzyme is more stable than mutant enzyme V62M
44
-
5 mM Tris-HCl, pH 7.2, 9% v/v glycerol, 3 mM 2-mercaptoethanol, 20 min, about 30% loss of activity, glucose protects
48 - 52
half-life of 5-7 min at 50°C, the transition temperatures for the wild type enzyme are 48.4°C and 51.6°C in the absence and presence of saturating glucose (100 mM), respectively
additional information
-
glucose protects against inactivation at higher temperatures
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
glucose binding enhances the stability of the wild-type enzyme and the single mutant D657A of the C-domain, but it does not increase the stability of the D209A mutant of the N-domain
the interaction of HK2 with the mitochondria through its N-half is proposed to facilitate higher stability on the mitochondria
the N-domain of HK2 regulates the stability of the whole enzyme in contrast with the C-domain
D-glucose protects against inactivation at higher temperatures
-
D-glucose stabilizes the enzyme through a specific, ligand induced intramolecular transition from an open to a closed conformation
-
glycerol increases the stability
-
glycerol, 9-15% v/v, stabilizes
-
phosphate stabilizes the wild-type monomer of hexokinase I relative to the dimer, D-glucose 6-phosphate stabilizes the dimer relative to the monomer
stability depends on the presence of 1 mM D-glucose, 3 mM mercaptoethanol, and 9% v/v glycerol
-
sulfhydryl protecting agents, e.g. DTT or 2-mercaptoethanol, required for optimum stability
-
ORGANIC SOLVENT
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
Glycerol
-
glycerol causes large functional changes and increases stability as a result of generalized restructuring of surface water of glucokinase by an indirect mechanism and these changes can occur with minimal perturbation of the protein folding structure and with preservation of the unique cooperative kinetics of the enzyme whereas D-glucose stabilizes the enzyme through a specific, ligand induced intramolecular transition from an open to a closed conformation
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
recombinant enzyme
120fold: recombinant carboxyl-domain of hexokinase type III, partial: hexokinase type III from lymphocytes
-
13fold
-
from blood: 175000fold, from heart: 1700fold
-
from erythrocytes: 110000fold, and from heart
-
glutathione S-transferase (GST)-GlkB fusion proteins, wild-type and mutant
glutathione Sepharose column chromatography, Sephadex G-25 gel filtration
HisTrap column chromatography and Superose 6 gel filtration
-
Ni-NTA column chromatography
-
Ni-NTA column chromatography, Hitrap Q FF column chromatography, and Superdex 200 gel filtration
-
Ni-NTA resin column chromatography
nickel and FLAG affinity column chromatography and gel filtration
-
partial, from adult and fetal erythrocytes, 1000-2000fold
-
phenyl-Sepharose column chromatography, ammonium sulfate precipitation, Q-Sepharose column chromatography, glutathione-Sepharose 4B column chromatography
recombinant
-
recombinant enzyme
-
recombinant FLAG-tagged hepatic wild-type and mutant enzymes from Escherichia coli strain DH5 alpha by ion exchange and glucosamine affinity chromatography, and gel filtration
recombinant full-length HK I, truncate form lacking the first 11 amino acids named HK-11aa, 50 kDa C-terminal half containing the catalytic domain
-
recombinant hexokinase I expressed in Escherichia coli BL21(DE3)
-
recombinant N-terminally His6-tagged pancreatic enzyme from Escherichia coli by nickel affinity chromatography to over 90% purity
-
recombinant wild-type and mutant enzymes from Escherichia coli to homogeneity
-
recombinant wild-type and nondimerizing mutant hexokinase I, expressed in Escherichia coli ZSC13
soluble hexokinase type I with 2 unseparated subtypes, 11600fold
-
using Ni-NTA chromatography
using Ni-NTA chromatography followed by ion-exchange chromatography on a HiTrap Q FF column and gel filtration on a Superdex 200 column
wild type, mutant V62M, and E300K GST-glucokinase proteins
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
compared with untransfected LoVo cells, LoVo cells transfected with pGenesil-1-HK II plasmids show significant decrease in the cellular ATP contents and Ki67 expression, and obvious increase in the apoptosis indexes
expression in Escherichia coli
expression in Escherichia coli using Champion pET SUMO expression system
the full encoding sequence for human type II hexokinase is cloned into the Escherichia coli expression vector pET 21b and expressed as a C-terminally hexahistidine-tagged protein in the BL21 strain. The IPTG-induced HXK II approximately accounts for 17% of the total Escherichia coli proteins, and 81% of hexahistidine-tagged HXK II exists in inclusion bodies. The production of soluble recombinant HXK II protein, in the functionally active form, is improved by low temperature, and the osmotic stress expression method. When expressed at 18°C, about 83% of HXK II-6His exists in the soluble fraction, which amounts to a 4.1fold yield over that expressed at 37°C. The soluble form of hexahistidine-tagged enzyme is also highly produced in the presence of 1 M sorbitol under the standard condition (37°C), which indicates that temperature downshift and low water potentials are required to improve the yield of active recombinant HXK II protein
a synthetic gene, encoding hexokinase I from brain, is expressed in Escherichia coli BL21(DE3) under the control of the bacteriophage T7 promoter
-
carboxyl-domain of hexokinase type III is cloned, sequenced and overexpressed in Escherichia coli XL1-Blue as a glutathione S-transferase fusion protein, recombinant protein is catalytically active
-
cDNA encoding hexokinase I is cloned and expressed in Escherichia coli BL21(DE3), amino acid sequence
-
cloning and overexpression of a full-length HK I, a truncate form lacking the first 11 amino acids named HK-11aa, and of the 50 kDa C-terminal half containing the catalytic domain in Escherichia coli BL21(DE3)
-
expressed in Escherichia coli as a GST-fusion protein
expressed in Escherichia coli as a GST-tagged fusion protein
-
expressed in Escherichia coli as a His-tagged fusion protein
expressed in Escherichia coli BL21(DE3) cells
expressed in Escherichia coli strain M15
expressed in Saccharomyces cerevisiae strain DBY1315
-
expression in Escherichia coli
-
expression in Escherichia coli BL21
-
expression of hepatic wild-type and mutant enzymes in Escherichia coli strain DH5 alpha as FLAG-tagged proteins
expression of mutant enzymes in Escherichia coli
-
expression of the N-terminally His6-tagged pancreatic enzyme in Escherichia coli
-
expression of wild-type and mutant enzymes in Escherichia coli BL21(DE3)
-
full-length cDNA encoding brain hexokinase I is cloned, expression of wild-type and nondimerizing mutant hexokinase I in Escherichia coli ZSC13
glutathione S-transferase (GST)-GlkB fusion proteins
transfection of U-2OS cell
-
wild type and mutant enzymes are expressed as N-terminal hexa-histidine tagged polypeptides in glucokinase-deficient Escherichia coli K-12 strain BM5340(DE3)
-
wild type, mutant V62M,and G72R recombinant full-length human beta-cell glucokinases are expressed in Escherichia coli BL21(DE3) cells
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
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
in contrast to normal brain and low-grade gliomas, which express predominantly HK1, human glioblastoma multiforme show show increased HK2 expression
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY hide
LITERATURE
medicine
HK II gene can act as a crucial therapeutic target for slowing colon cancer growth
analysis
-
detection of glucose-induced conformational change in hexokinase II using fluorescence complementation assay
diagnostics
-
increased proportion of hexokinase II is used as a marker for brain tumors
medicine
pharmacology
-
enzyme is a target for activator drug design in therapy of type 2 diabetes mellitus
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Liu, F.; Dong, Q.; Myers, A.M.; Fromm, H.J.
Expression of human brain hexokinase in Escherichia coli: Purification and characterization of the expressed enzyme
Biochem. Biophys. Res. Commun.
177
305-311
1991
Homo sapiens
Manually annotated by BRENDA team
Haritos, A.A.; Rosemeyer, M.A.
Purification and physical properties of hexokinase from human erythrocytes
Biochim. Biophys. Acta
873
335-339
1986
Homo sapiens
Manually annotated by BRENDA team
Siebenlist, K.R.; Taketa, F.
Inhibition of red cell and yeast hexokinase by triethyltin bromide [(C2H5)3SnBr]
Biochem. Biophys. Res. Commun.
95
758-764
1980
Saccharomyces cerevisiae, Homo sapiens
Manually annotated by BRENDA team
Haritos, A.A.; Rosemeyer, M.A.
The purification and properties of human hexokinase
Biochem. Soc. Trans.
9
245
1981
Homo sapiens
-
Manually annotated by BRENDA team
Stocchi, V.; Magnani, M.; Canestrari, F.; Dacha, M.; Fornaini, G.
Multiple forms of human red blood cell hexokinase. Preparation, characterization, and age dependence
J. Biol. Chem.
257
2357-2364
1982
Homo sapiens
Manually annotated by BRENDA team
Magnani, M.; Stocchi, V.; Serafini, G.; Chiarantini, L.; Fornaini, G.
Purification, properties, and evidence for two subtypes of human placenta hexokinase type I
Arch. Biochem. Biophys.
260
388-399
1988
Homo sapiens
Manually annotated by BRENDA team
Rijksen, G.; Staal, G.E.J.; Beks, P.J.; Streefkerk, M.; Akkerman, J.W.N.
Compartmentation of hexokinase in human blood cells. Characterization of soluble and particulate enzymes
Biochim. Biophys. Acta
719
431-437
1982
Homo sapiens
Manually annotated by BRENDA team
Aleshin, A.E.; Zeng, C.; Bourenkov, G.P.; Bartunik, H.D.; Fromm, H.J.; Honzatko, R.B.
The mechanism of regulation of hexokinase: New insights from the crystal structure of recombinant human brain hexokinase complexed with glucose and glucose-6-phosphate
Structure
6
39-50
1998
Homo sapiens
Manually annotated by BRENDA team
Aleshin, A.E.; Fromm, H.J.; Honzatko, R.B.
Multiple crystal forms of hexokinase I: New insights regarding conformational dynamics, subunit interactions, and membrane association
FEBS Lett.
434
42-46
1998
Homo sapiens
Manually annotated by BRENDA team
Aleshin, A.E.; Malfois, M.; Liu, X.; Kim, C.S.; Fromm, H.J.; Honzatko, R.B.; Koch, M.H.J.; Svergun, D.I.
Nonaggregating mutant of recombinant human hexokinase I exhibits wild-type kinetics and rod-like conformations in solution
Biochemistry
38
8359-8366
1999
Homo sapiens (P19367), Homo sapiens
Manually annotated by BRENDA team
Muzi, M.; Freeman, S.D.; Burrows, R.C.; Wiseman, R.W.; Link, J.M.; Krohn, K.A.; Graham, M.M.; Spence, A.M.
Kinetic characterization of hexokinase isoenzymes from glioma cells: Implications for FDG imaging of human brain tumors
Nucl. Med. Biol.
28
107-116
2001
Bos taurus, Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Palma, F.; Agostini, D.; Mason, P.; Dacha, M.; Piccoli, G.; Biagiarelli, B.; Fiorani, M.; Stocchi, V.
Purification and characterization of the carboxyl-domain of human hexokinase type III expressed as fusion protein
Mol. Cell. Biochem.
155
23-29
1996
Homo sapiens
Manually annotated by BRENDA team
Bianchi, M.; Serafini, G.; Bartolucci, E.; Giammarini, C.; Magnani, M.
Enzymatic properties of overexpressed human hexokinase fragments
Mol. Cell. Biochem.
189
185-193
1998
Homo sapiens
Manually annotated by BRENDA team
Sener, A.; Malaisse, W.J.
Kinetics and specificity of human B-cell glucokinase: relevance to hexose-induced insulin release
Biochim. Biophys. Acta
1312
73-78
1996
Homo sapiens
Manually annotated by BRENDA team
Xu, L.Z.; Harrison, R.W.; Weber, I.T.; Pilkis, S.J.
Human beta-cell glucokinase. Dual role of Ser-151 in catalysis and hexose affinity
J. Biol. Chem.
270
9939-9946
1995
Homo sapiens
Manually annotated by BRENDA team
Marotta, D.E.; Anand, G.R.; Anderson, T.A.; Miller, S.P.; Okar, D.A.; Levitt, D.G.; Lange, A.J.
Identification and characterization of the ATP-binding site in human pancreatic glucokinase
Arch. Biochem. Biophys.
436
23-31
2005
Homo sapiens
Manually annotated by BRENDA team
Brocklehurst, K.J.; Davies, R.A.; Agius, L.
Differences in regulatory properties between human and rat glucokinase regulatory protein
Biochem. J.
378
693-697
2004
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Grimsby, J.; Sarabu, R.; Corbett, W.L.; Haynes, N.E.; Bizzarro, F.T.; Coffey, J.W.; Guertin, K.R.; Hilliard, D.W.; Kester, R.F.; Mahaney, P.E.; Marcus, L.; Qi, L.; Spence, C.L.; Tengi, J.; Magnuson, M.A.; Chu, C.A.; Dvorozniak, M.T.; Matschinsky, F.M.; Grippo, J.F.
Allosteric activators of glucokinase: potential role in diabetes therapy
Science
301
370-373
2003
Homo sapiens, Mus musculus, Rattus norvegicus
Manually annotated by BRENDA team
Kamata, K.; Mitsuya, M.; Nishimura, T.; Eiki, J.; Nagata, Y.
Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase
Structure
12
429-438
2004
Homo sapiens (P35557)
Manually annotated by BRENDA team
Heredia, V.V.; Thomson, J.; Nettleton, D.; Sun, S.
Glucose-induced conformational changes in glucokinase mediate allosteric regulation: transient kinetic analysis
Biochemistry
45
7553-7562
2006
Homo sapiens
Manually annotated by BRENDA team
Kim, Y.B.; Kalinowski, S.S.; Marcinkeviciene, J.
A pre-steady state analysis of ligand binding to human glucokinase: evidence for a preexisting equilibrium
Biochemistry
46
1423-1431
2007
Homo sapiens
Manually annotated by BRENDA team
Jeong, E.J.; Park, K.; Joung, H.A.; Lee, C.S.; Seol, D.W.; Chung, B.H.; Kim, M.
Detection of glucose-induced conformational change in hexokinase II using fluorescence complementation assay
Biotechnol. Lett.
29
797-802
2007
Homo sapiens
Manually annotated by BRENDA team
Marin-Hernandez, A.; Rodriguez-Enriquez, S.; Vital-Gonzalez, P.A.; Flores-Rodriguez, F.L.; Macias-Silva, M.; Sosa-Garrocho, M.; Moreno-Sanchez, R.
Determining and understanding the control of glycolysis in fast-growth tumor cells. Flux control by an over-expressed but strongly product-inhibited hexokinase
FEBS J.
273
1975-1988
2006
Homo sapiens, Rattus norvegicus
Manually annotated by BRENDA team
Gloyn, A.L.; Odili, S.; Zelent, D.; Buettger, C.; Castleden, H.A.; Steele, A.M.; Stride, A.; Shiota, C.; Magnuson, M.A.; Lorini, R.; dAnnunzio, G.; Stanley, C.A.; Kwagh, J.; van Schaftingen, E.; Veiga-da-Cunha, M.; Barbetti, F.; Dunten, P.; Han, Y.; Grimsby, J.; Taub, R.; Ellard, S.; Hattersley, A.T.
Insights into the structure and regulation of glucokinase from a novel mutation (V62M), which causes maturity-onset diabetes of the young
J. Biol. Chem.
280
14105-14113
2005
Homo sapiens
Manually annotated by BRENDA team
Bjorkhaug, L.; Molnes, J.; Sovik, O.; Njolstad, P.R.; Flatmark, T.
Allosteric activation of human glucokinase by free polyubiquitin chains and its ubiquitin-dependent cotranslational proteasomal degradation
J. Biol. Chem.
282
22757-22764
2007
Homo sapiens
Manually annotated by BRENDA team
Tsai, H.J.
Function of interdomain alpha-helix in human brain hexokinase: covalent linkage and catalytic regulation between N- and C-terminal halves
J. Biomed. Sci.
14
195-202
2007
Homo sapiens
Manually annotated by BRENDA team
Pedelini, L.; Garcia-Gimeno, M.A.; Marina, A.; Gomez-Zumaquero, J.M.; Rodriguez-Bada, P.; Lopez-Enriquez, S.; Soriguer, F.C.; Cuesta-Munoz, A.L.; Sanz, P.
Structure-function analysis of the alpha5 and the alpha13 helices of human glucokinase: description of two novel activating mutations
Protein Sci.
14
2080-2086
2005
Homo sapiens
Manually annotated by BRENDA team
Zelent, B.; Odili, S.; Buettger, C.; Shiota, C.; Grimsby, J.; Taub, R.; Magnuson, M.A.; Vanderkooi, J.M.; Matschinsky, F.M.
Sugar binding to recombinant wild-type and mutant glucokinase monitored by kinetic measurement and tryptophan fluorescence
Biochem. J.
413
269-280
2008
Homo sapiens
Manually annotated by BRENDA team
Peng, Q.; Zhou, Q.; Zhou, J.; Zhong, D.; Pan, F.; Liang, H.
Stable RNA interference of hexokinase II gene inhibits human colon cancer LoVo cell growth in vitro and in vivo
Cancer Biol. Ther.
7
1128-1135
2008
Homo sapiens (P52789), Homo sapiens
Manually annotated by BRENDA team
Christesen, H.B.; Tribble, N.D.; Molven, A.; Siddiqui, J.; Sandal, T.; Brusgaard, K.; Ellard, S.; Nj?lstad, P.R.; Alm, J.; Brock Jacobsen, B.; Hussain, K.; Gloyn, A.L.
Activating glucokinase (GCK) mutations as a cause of medically responsive congenital hyperinsulinism: prevalence in children and characterisation of a novel GCK mutation
Eur. J. Endocrinol.
159
27-34
2008
Homo sapiens
Manually annotated by BRENDA team
Anderka, O.; Boyken, J.; Aschenbach, U.; Batzer, A.; Boscheinen, O.; Schmoll, D.
Biophysical characterization of the interaction between hepatic glucokinase and its regulatory protein - impact of physiological and pharmacological effectors
J. Biol. Chem.
283
31333-31340
2008
Homo sapiens
Manually annotated by BRENDA team
Estalella, I.; Garcia-Gimeno, M.A.; Marina, A.; Castano, L.; Sanz, P.
Biochemical characterization of novel glucokinase mutations isolated from Spanish maturity-onset diabetes of the young (MODY2) patients
J. Hum. Genet.
53
460-466
2008
Homo sapiens (Q53Y25)
Manually annotated by BRENDA team
Jeong, E.J.; Park, K.; Yi, S.Y.; Kang, H.J.; Chung, S.J.; Lee, C.S.; Chung, J.W.; Seol, D.W.; Chung, B.H.; Kim, M.
Stress-governed expression and purification of human type II hexokinase in Escherichia coli
J. Microbiol. Biotechnol.
17
638-643
2007
Homo sapiens (P52789), Homo sapiens
Manually annotated by BRENDA team
Agius, L.
Glucokinase and molecular aspects of liver glycogen metabolism
Biochem. J.
414
1-18
2008
Homo sapiens, Mus musculus, Rattus norvegicus
Manually annotated by BRENDA team
Riera, A.; Ahuatzi, D.; Herrero, P.; Garcia-Gimeno, M.A.; Sanz, P.; Moreno, F.
Human pancreatic beta-cell glucokinase: subcellular localization and glucose repression signalling function in the yeast cell
Biochem. J.
415
233-239
2008
Homo sapiens
Manually annotated by BRENDA team
Veiga-da-Cunha, M.; Sokolova, T.; Opperdoes, F.; Van Schaftingen, E.
Evolution of vertebrate glucokinase regulatory protein from a bacterial N-acetylmuramate 6-phosphate etherase
Biochem. J.
423
323-332
2009
Homo sapiens, Xenopus laevis
Manually annotated by BRENDA team
Ralph, E.C.; Thomson, J.; Almaden, J.; Sun, S.
Glucose modulation of glucokinase activation by small molecules
Biochemistry
47
5028-5036
2008
Homo sapiens
Manually annotated by BRENDA team
Sun, S.
Biochemical characterization of MODY2 glucokinase variants V62M and G72R reveals reduced enzymatic activities relative to wild-type
Biochemistry
48
2514-2521
2009
Homo sapiens (P35557), Homo sapiens
Manually annotated by BRENDA team
Antoine, M.; Boutin, J.A.; Ferry, G.
Binding kinetics of glucose and allosteric activators to human glucokinase reveal multiple conformational states
Biochemistry
48
5466-5482
2009
Homo sapiens
Manually annotated by BRENDA team
Larion, M.; Miller, B.G.
23-Residue C-terminal alpha-helix governs kinetic cooperativity in monomeric human glucokinase
Biochemistry
48
6157-6165
2009
Homo sapiens
Manually annotated by BRENDA team
Pfefferkorn, J.A.; Lou, J.; Minich, M.L.; Filipski, K.J.; He, M.; Zhou, R.; Ahmed, S.; Benbow, J.; Perez, A.G.; Tu, M.; Litchfield, J.; Sharma, R.; Metzler, K.; Bourbonais, F.; Huang, C.; Beebe, D.A.; Oates, P.J.
Pyridones as glucokinase activators: identification of a unique metabolic liability of the 4-sulfonyl-2-pyridone heterocycle
Bioorg. Med. Chem. Lett.
19
3247-3252
2009
Homo sapiens
Manually annotated by BRENDA team
Zhang, L.; Li, H.; Zhu, Q.; Liu, J.; Chen, L.; Leng, Y.; Jiang, H.; Liu, H.
Benzamide derivatives as dual-action hypoglycemic agents that inhibit glycogen phosphorylase and activate glucokinase
Bioorg. Med. Chem.
17
7301-7312
2009
Homo sapiens
Manually annotated by BRENDA team
Ahn, K.J.; Kim, J.; Yun, M.; Park, J.H.; Lee, J.D.
Enzymatic properties of the N- and C-terminal halves of human hexokinase II
BMB Rep.
42
350-355
2009
Homo sapiens
Manually annotated by BRENDA team
Christesen, H.B.; Brusgaard, K.; Beck Nielsen, H.; Brock Jacobsen, B.
Non-insulinoma persistent hyperinsulinaemic hypoglycaemia caused by an activating glucokinase mutation: hypoglycaemia unawareness and attacks
Clin. Endocrinol. (Oxf.)
68
747-755
2008
Homo sapiens
Manually annotated by BRENDA team
Grimsby, J.; Berthel, S.J.; Sarabu, R.
Glucokinase activators for the potential treatment of type 2 diabetes
Curr. Top. Med. Chem.
8
1524-1532
2008
Homo sapiens
Manually annotated by BRENDA team
Coghlan, M.; Leighton, B.
Glucokinase activators in diabetes management
Expert Opin. Investig. Drugs
17
145-167
2008
Homo sapiens
Manually annotated by BRENDA team
Molnes, J.; Bjorkhaug, L.; Sovik, O.; Njolstad, P.R.; Flatmark, T.
Catalytic activation of human glucokinase by substrate binding: residue contacts involved in the binding of D-glucose to the super-open form and conformational transitions
FEBS J.
275
2467-2481
2008
Homo sapiens (P35557), Homo sapiens
Manually annotated by BRENDA team
Beer, N.L.; Tribble, N.D.; McCulloch, L.J.; Roos, C.; Johnson, P.R.; Orho-Melander, M.; Gloyn, A.L.
The P446L variant in GCKR associated with fasting plasma glucose and triglyceride levels exerts its effect through increased glucokinase activity in liver
Hum. Mol. Genet.
18
4081-4088
2009
Homo sapiens
Manually annotated by BRENDA team
Osbak, K.K.; Colclough, K.; Saint-Martin, C.; Beer, N.L.; Bellanne-Chantelot, C.; Ellard, S.; Gloyn, A.L.
Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia
Hum. Mutat.
30
1512-1526
2009
Homo sapiens
Manually annotated by BRENDA team
Zhang, J.; Li, C.; Shi, T.; Chen, K.; Shen, X.; Jiang, H.
Lys169 of human glucokinase is a determinant for glucose phosphorylation: implication for the atomic mechanism of glucokinase catalysis
PLoS ONE
4
e6304
2009
Homo sapiens (P19367)
Manually annotated by BRENDA team
Petit, P.; Antoine, M.; Ferry, G.; Boutin, J.A.; Lagarde, A.; Gluais, L.; Vincentelli, R.; Vuillard, L.
The active conformation of human glucokinase is not altered by allosteric activators
Acta Crystallogr. Sect. D
67
929-935
2011
Homo sapiens (P35557)
Manually annotated by BRENDA team
Zelent, B.; Odili, S.; Buettger, C.; Zelent, D.K.; Chen, P.; Fenner, D.; Bass, J.; Stanley, C.; Laberge, M.; Vanderkooi, J.M.; Sarabu, R.; Grimsby, J.; Matschinsky, F.M.
Mutational analysis of allosteric activation and inhibition of glucokinase
Biochem. J.
440
203-215
2011
Homo sapiens (P35557)
Manually annotated by BRENDA team
Bourbonais, F.J.; Chen, J.; Huang, C.; Zhang, Y.; Pfefferkorn, J.A.; Landro, J.A.
Modulation of glucokinase by glucose, small-molecule activator and glucokinase regulatory protein: steady-state kinetic and cell-based analysis
Biochem. J.
441
881-887
2012
Homo sapiens
Manually annotated by BRENDA team
Zelent, B.; Buettger, C.; Grimsby, J.; Sarabu, R.; Vanderkooi, J.M.; Wand, A.J.; Matschinsky, F.M.
Thermal stabilty of glucokinase (GK) as influenced by the substrate glucose, an allosteric glucokinase activator drug (GKA) and the osmolytes glycerol and urea
Biochim. Biophys. Acta
1824
769-784
2012
Homo sapiens
Manually annotated by BRENDA team
Li, F.; Zhu, Q.; Zhang, Y.; Feng, Y.; Leng, Y.; Zhang, A.
Design, synthesis, and pharmacological evaluation of N-(4-mono and 4,5-disubstituted thiazol-2-yl)-2-aryl-3-(tetrahydro-2H-pyran-4-yl)propanamides as glucokinase activators
Bioorg. Med. Chem.
18
3875-3884
2010
Homo sapiens
Manually annotated by BRENDA team
Mao, W.; Ning, M.; Liu, Z.; Zhu, Q.; Leng, Y.; Zhang, A.
Design, synthesis, and pharmacological evaluation of benzamide derivatives as glucokinase activators
Bioorg. Med. Chem.
20
2982-2991
2012
Homo sapiens
Manually annotated by BRENDA team
Molnes, J.; Teigen, K.; Aukrust, I.; Bjorkhaug, L.; Sovik, O.; Flatmark, T.; Njolstad, P.R.
Binding of ATP at the active site of human pancreatic glucokinase--nucleotide-induced conformational changes with possible implications for its kinetic cooperativity
FEBS J.
278
2372-2386
2011
Homo sapiens
Manually annotated by BRENDA team
Liu, Q.; Shen, Y.; Liu, S.; Weng, J.; Liu, J.
Crystal structure of E339K mutated human glucokinase reveals changes in the ATP binding site
FEBS Lett.
585
1175-1179
2011
Homo sapiens (P35557)
Manually annotated by BRENDA team
Wolf, A.; Agnihotri, S.; Micallef, J.; Mukherjee, J.; Sabha, N.; Cairns, R.; Hawkins, C.; Guha, A.
Hexokinase 2 is a key mediator of aerobic glycolysis and promotes tumor growth in human glioblastoma multiforme
J. Exp. Med.
208
313-326
2011
Homo sapiens
Manually annotated by BRENDA team
Larion, M.; Salinas, R.; Bruschweiler-Li, L.; Miller, B.; Brschweiler, R.
Order-disorder transitions govern kinetic cooperativity and allostery of monomeric human glucokinase
PLoS Biol.
10
e1001452
2012
Homo sapiens
Manually annotated by BRENDA team
Bowler, J.; Hervert, K.; Kearley, M.; Miller, B.
Small-molecule allosteric activation of human glucokinase in the absence of glucose
ACS Med. Chem. Lett.
4
580-584
2013
Homo sapiens
Manually annotated by BRENDA team
Lin, H.; Zeng, J., Xie, R.; Schulz, M.J.; Tedesco, R.; Qu, J.; Erhard, K.F.; Mack, J.F.; Raha, K.; Rendina, A.R.; Szewczuk, L.M.; Kratz, P.M.; Jurewicz, A.J.; Cecconie, T.; Martens, S.; McDevitt, P.J.; Martin, J.D.; Chen, S.B.; Jiang, Y.; Nickels, L.; Schwartz, B.J.; Smallwood, A.; Zhao, B.; Campobasso, N.; Qian, Y.; Briand, J.; Rominger, C.M.; Oleykowski, C.; Hardwicke, M.A.; Luengo, J.I.
Discovery of a novel 2,6-disubstituted glucosamine series of potent and selective hexokinase 2 inhibitors
ACS Med. Chem. Lett.
7
217-22
2015
Homo sapiens (P19367), Homo sapiens (P52789)
Manually annotated by BRENDA team
Dransfield, P.J.; Pattaropong, V.; Lai, S.; Fu, Z.; Kohn, T.J.; Du, X.; Cheng, A.; Xiong, Y.; Komorowski, R.; Jin, L.; Conn, M.; Tien, E.; DeWolf, W.E.; Hinklin, R.J.; Aicher, T.D.; Kraser, C.F.; Boyd, S.A.; Voegtli, W.C.; Condroski, K.R.; Veniant-Ellison, M.; Medina, J.C.; Houze, J.; Coward, P.
Novel series of potent glucokinase activators leading to the discovery of AM-2394
ACS Med. Chem. Lett.
7
714-718
2016
Homo sapiens (P52789)
Manually annotated by BRENDA team
Zhuo, B.; Li, Y.; Li, Z.; Qin, H.; Sun, Q.; Zhang, F.; Shen, Y.; Shi, Y.; Wang, R.
PI3K/Akt signaling mediated Hexokinase-2 expression inhibits cell apoptosis and promotes tumor growth in pediatric osteosarcoma
Biochem. Biophys. Res. Commun.
464
401-406
2015
Homo sapiens
Manually annotated by BRENDA team
Kumar, S.; Parameswaran, S.; Sharma, R.K.
Novel myristoylation of the sperm-specific hexokinase 1 isoform regulates its atypical localization
Biol. Open
4
1679-1687
2015
Homo sapiens (P19367)
Manually annotated by BRENDA team
Bryan, N.; Raisch, K.
Identification of a mitochondrial-binding site on the N-terminal end of hexokinase II
Biosci. Rep.
35
e00205
2015
Homo sapiens
Manually annotated by BRENDA team
Sen, S.; Kaminiski, R.; Deshmane, S.; Langford, D.; Khalili, K.; Amini, S.; Datta, P.K.
Role of hexokinase-1 in the survival of HIV-1-infected macrophages
Cell Cycle
14
980-989
2015
Homo sapiens
Manually annotated by BRENDA team
Ermakova, E.
Structural insight into the glucokinase-ligands interactions. Molecular docking study
Comput. Biol. Chem.
64
281-296
2016
Homo sapiens (P35557)
Manually annotated by BRENDA team
Yellapu, N.; Mahto, M.K.; Valasani, K.R.; Sarma, P.V.; Matcha, B.
Mutations in exons 10 and 11 of human glucokinase result in conformational variations in the active site of the structure contributing to poor substrate binding - explains hyperglycemia in type 2 diabetic patients
J. Biomol. Struct. Dyn.
33
820-833
2015
Homo sapiens
Manually annotated by BRENDA team
Pandurangan, M.; Enkhtaivan, G.; Kim, D.H.
Homobrassinolide induced conformational changes in hexokinase: a possible mechanism for its antidiabetic potential
J. Mol. Recognit.
29
276-280
2016
Homo sapiens (P35557), Homo sapiens
Manually annotated by BRENDA team
Martinez, J.A.; Larion, M.; Conejo, M.S.; Porter, C.M.; Miller, B.G.
Role of connecting loop I in catalysis and allosteric regulation of human glucokinase
Protein Sci.
23
915-922
2014
Homo sapiens (P35557), Homo sapiens
Manually annotated by BRENDA team
Milanes, J.E.; Suryadi, J.; Abendroth, J.; Van Voorhis, W.C.; Barrett, K.F.; Dranow, D.M.; Phan, I.Q.; Patrick, S.L.; Rozema, S.D.; Khalifa, M.M.; Golden, J.E.; Morris, J.C.
Enzymatic and structural characterization of the Naegleria fowleri glucokinase
Antimicrob. Agents Chemother.
63
e02410-18
2019
Homo sapiens (P35557)
Manually annotated by BRENDA team
Heneberg, P.
Redox regulation of hexokinases
Antioxid. Redox Signal.
30
415-442
2019
Oryctolagus cuniculus, Trypanosoma brucei, Mus musculus (P17710), Homo sapiens (P19367), Homo sapiens (P52789), Homo sapiens (P52790), Plasmodium falciparum (Q02155)
Manually annotated by BRENDA team
Casey, A.K.; Miller, B.G.
Kinetic Basis of carbohydrate-mediated inhibition of human glucokinase by the glucokinase regulatory protein
Biochemistry
55
2899-2902
2016
Homo sapiens
Manually annotated by BRENDA team
Tesinsky, M.; Simcikova, D.; Heneberg, P.
First evidence of changes in enzyme kinetics and stability of glucokinase affected by somatic cancer-associated variations
Biochim. Biophys. Acta Proteins Proteom.
1867
213-218
2019
Homo sapiens
Manually annotated by BRENDA team
Cornish-Bowden, A.
Zacharias Dische and the discovery of feedback inhibition A landmark paper published in the forerunner of Biochimie
Biochimie
182
120-130
2021
Homo sapiens
Manually annotated by BRENDA team
Liu, Y.; Li, M.; Zhang, Y.; Wu, C.; Yang, K.; Gao, S.; Zheng, M.; Li, X.; Li, H.; Chen, L.
Structure based discovery of novel hexokinase 2 inhibitors
Bioorg. Chem.
96
103609
2020
Homo sapiens (P52789), Homo sapiens
Manually annotated by BRENDA team
Nawaz, M.H.; Ferreira, J.C.; Nedyalkova, L.; Zhu, H.; Carrasco-Lopez, C.; Kirmizialtin, S.; Rabeh, W.M.
The catalytic inactivation of the N-half of human hexokinase 2 and structural and biochemical characterization of its mitochondrial conformation
Biosci. Rep.
38
BSR20171666
2018
Homo sapiens (P52789), Homo sapiens
Manually annotated by BRENDA team
Dische, Z.
Sur l'interdependance des divers enzymes du systeme glycolytique et sur la regulation automatique de leur activite dans les cellules
Bull. Soc. Chim. Biol.
23
1140-1148
1941
Homo sapiens
-
Manually annotated by BRENDA team
Wang, Z.; Shi, X.; Zhang, H.; Yu, L.; Cheng, Y.; Zhang, H.; Zhang, H.; Zhou, J.; Chen, J.; Shen, X.; Duan, W.
Discovery of cycloalkyl-fused N-thiazol-2-yl-benzamides as tissue non-specific glucokinase activators Design, synthesis, and biological evaluation
Eur. J. Med. Chem.
139
128-152
2017
Homo sapiens
Manually annotated by BRENDA team
Bao, F.; Yang, K.; Wu, C.; Gao, S.; Wang, P.; Chen, L.; Li, H.
New natural inhibitors of hexokinase 2 (HK2) Steroids from Ganoderma sinense
Fitoterapia
125
123-129
2018
Homo sapiens (P52789)
Manually annotated by BRENDA team
Aljamal, J.; Badawneh, M.
In vitro inhibition of human erythrocyte hexokinase by various hyperglycemic drugs
J. Biochem. Mol. Toxicol.
31
e21910
2017
Homo sapiens (P19367), Homo sapiens
Manually annotated by BRENDA team
Khan, M.W.; Ding, X.; Cotler, S.J.; Clarke, M.; Layden, B.T.
Studies on the tissue localization of HKDC1, a putative novel fifth hexokinase, in humans
J. Histochem. Cytochem.
66
385-392
2018
Homo sapiens (Q2TB90), Homo sapiens
Manually annotated by BRENDA team
Roh, J.I.; Kim, Y.; Oh, J.; Kim, Y.; Lee, J.; Lee, J.; Chun, K.H.; Lee, H.W.
Hexokinase 2 is a molecular bridge linking telomerase and autophagy
PLoS ONE
13
e0193182
2018
Homo sapiens (P52789)
Manually annotated by BRENDA team
Simcikova, D.; Heneberg, P.
Identification of alkaline pH optimum of human glucokinase because of ATP-mediated bias correction in outcomes of enzyme assays
Sci. Rep.
9
11422
2019
Homo sapiens (P35557), Homo sapiens
Manually annotated by BRENDA team
Yin, X.; Choudhury, M.; Kang, J.H.; Schaefbauer, K.J.; Jung, M.Y.; Andrianifahanana, M.; Hernandez, D.M.; Leof, E.B.
Hexokinase 2 couples glycolysis with the profibrotic actions of TGF-beta
Sci. Signal.
12
eaax4067
2019
Mus musculus (O08528), Mus musculus, Homo sapiens (P52789), Homo sapiens
Manually annotated by BRENDA team