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Information on EC 2.7.1.1 - hexokinase and Organism(s) Rattus norvegicus and UniProt Accession P05708
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2.7.1.1 hexokinaseIUBMB 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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Word Map
- 2.7.1.1
- glucose-6-phosphate
-
phosphofructokinase
- glycogen
- fructose
- citrate
- adp
- erythrocyte
- malate
- phosphorylase
- pancreatic
- hypoxia
- islet
- pentose
- creatine
- mellitus
- 2-deoxyglucose
- aldolase
- hyperglycemia
- phosphoglucomutase
-
warburg
-
hypoxia-inducible
- 6-phosphogluconate
-
glut-1
-
voltage-dependent
-
vdacs
- streptozotocin
-
positron
- soleus
-
18f-fdg
- lateralis
- fructose-1,6-bisphosphatase
-
hypoglycemic
- invertase
- 2-deoxy-d-glucose
- fructokinase
-
gluconeogenic
-
insulin-stimulated
-
carboxykinase
- hexoses
-
vastus
-
glycogenolysis
- g6pase
- glycosomes
-
antihyperglycemic
-
phosphoglucose
-
18f-fluorodeoxyglucose
-
fdg-pet
- pharmacology
-
suvmax
- analysis
-
glutaminolysis
-
2,6-bisphosphate
- synthesis
- diagnostics
- industry
- medicine
The taxonomic range for the selected organisms is: Rattus norvegicus
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Reaction Schemes
Synonyms
hexokinase, hexokinase ii, hexokinase 2, hexokinase i, hk ii, hxk, liver glucokinase, hexokinase 1, hexokinase-2, hkdc1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ATP-D-hexose 6-phosphotransferase
-
-
-
-
ATP-dependent hexokinase
-
-
-
-
brain form hexokinase
-
-
-
-
glucokinase
glucose ATP phosphotransferase
-
-
-
-
hexokinase (phosphorylating)
-
-
-
-
hexokinase D
hexokinase PI
-
-
-
-
hexokinase PII
-
-
-
-
hexokinase type I
-
substitutes for glucokinase in hepatomas and in embryonic livers
hexokinase type II
hexokinase type IV
hexokinase type IV glucokinase
-
-
-
-
hexokinase, tumor isozyme
-
-
-
-
HK
-
-
-
-
HK4
HKI
HKII
HXK
-
-
-
-
kinase, hexo- (phosphorylating)
-
-
-
-
muscle form hexokinase
-
-
-
-
glucokinase
-
-
-
-
glucokinase
-
-
hexokinase D
-
-
-
-
hexokinase type II
-
substitutes for glucokinase in hepatomas and in embryonic livers
hexokinase type IV
-
-
-
-
HK4
-
-
-
-
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + D-hexose = ADP + D-hexose 6-phosphate
non-cooperative conditions shows an ordered kinetic mechanism with MgADP as the last product to be released
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
-
-
-
-
PATHWAY SOURCE
PATHWAYS
BRENDA
KEGG
Amino sugar and nucleotide sugar metabolism, Biosynthesis of secondary metabolites, Fructose and mannose metabolism, Galactose metabolism, Glycolysis / Gluconeogenesis, Microbial metabolism in diverse environments, Neomycin, kanamycin and gentamicin biosynthesis, Starch and sucrose metabolism, Streptomycin biosynthesis
-
-, -, -, -, -, -, -, -, -, -, -, -, -, -, -, -
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
9001-51-8
-
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
2-fluoro-2-deoxy-D-glucose + ATP
2-fluoro-2-deoxy-D-glucose 6-phosphate + ADP
-
-
-
?
ATP + 2-deoxy-D-glucose
ADP + 2-deoxy-D-glucose 6-phosphate
-
-
-
-
?
ATP + D-glucose
ADP + D-glucose 6-phosphate
-
-
641070, 641071, 641072, 660949, 660963, 663393, 701997, 702116, 702556, 703129, 704456, 704831, 705268, 705294, 706889
-
-
?
D-glucose + ATP
D-glucose 6-phosphate + ADP
-
glucose metabolism
-
?
D-glucose + ATP
D-glucose 6-phosphate + ADP
-
glucose metabolism
-
?
D-glucose + ATP
D-glucose 6-phosphate + ADP
-
binding of brain enzyme to the outer mitochondrial membrane plays a role in regulation of hexokinase activity in vivo, and thereby of the cerebral glycolytic rate
-
-
?
D-glucose + ATP
D-glucose 6-phosphate + ADP
-
initial catalytic step of the cerebral glucose metabolism, glucose 6-phosphate represents a major regulatory influence on the in vivo activity
-
-
?
additional information
?
-
allosteric regulation of hexokinase I, the functional regulatory glucose 6-phosphate binding site is located in the N-terminal half
-
-
?
additional information
?
-
hexokinase I and hexokinase II are independently regulated, implying that they perform different roles in cardiac glucose regulation
-
-
?
additional information
?
-
hexokinase I and hexokinase II are independently regulated, implying that they perform different roles in cardiac glucose regulation
-
-
?
additional information
?
-
-
ligand binding sites in the N- and C-terminal halves and interactions between these sites
-
-
?
additional information
?
-
-
isolated catalytically active 51 kDa C-fragment and 52 kDa N-fragment without catalytic activity, both fragments contain discrete binding sites for hexoses and hexose 6-phosphates, one of each pair of sites must be latent in the intact enzyme, the regulatory site binding glucose 6-phosphate is associated with the N-terminal half
-
-
?
additional information
?
-
hexokinase I and hexokinase II are independently regulated, implying that they perform different roles in cardiac glucose regulation
-
-
?
additional information
?
-
hexokinase I and hexokinase II are independently regulated, implying that they perform different roles in cardiac glucose regulation
-
-
?
additional information
?
-
-
the enzyme plays a role in glycogen synthesis and glucose homeostasis
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + D-glucose
ADP + D-glucose 6-phosphate
-
-
-
-
?
D-glucose + ATP
D-glucose 6-phosphate + ADP
-
glucose metabolism
-
?
D-glucose + ATP
D-glucose 6-phosphate + ADP
-
glucose metabolism
-
?
D-glucose + ATP
D-glucose 6-phosphate + ADP
-
binding of brain enzyme to the outer mitochondrial membrane plays a role in regulation of hexokinase activity in vivo, and thereby of the cerebral glycolytic rate
-
-
?
D-glucose + ATP
D-glucose 6-phosphate + ADP
-
initial catalytic step of the cerebral glucose metabolism, glucose 6-phosphate represents a major regulatory influence on the in vivo activity
-
-
?
additional information
?
-
hexokinase I and hexokinase II are independently regulated, implying that they perform different roles in cardiac glucose regulation
-
-
?
additional information
?
-
hexokinase I and hexokinase II are independently regulated, implying that they perform different roles in cardiac glucose regulation
-
-
?
additional information
?
-
hexokinase I and hexokinase II are independently regulated, implying that they perform different roles in cardiac glucose regulation
-
-
?
additional information
?
-
hexokinase I and hexokinase II are independently regulated, implying that they perform different roles in cardiac glucose regulation
-
-
?
additional information
?
-
-
the enzyme plays a role in glycogen synthesis and glucose homeostasis
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1,5-Anhydro-D-glucitol 6-phosphate
hexokinase I, antagonism by phosphate at low concentrations
D-glucose 6-phosphate
product inhibition of hexokinase I, antagonism by phosphate at low concentrations results from competition for a common anion binding site located in the N-terminal half
phenylpyruvic acid
the enzyme decreases the activity of enzyme in the presence and absence of glucose-6-phosphate (G6P) and increases the release of the enzyme from mitochondria
5,5'-dithiobis-(2-nitrobenzoic acid)
-
inactivation, protection by MgADP-, AMP, 2-deoxyglucose, glucose, and mannose probably via binary complex formation, no protection by glucose 6-phosphate, slight protection by MgATP2-
acidic phospholipids
-
irreversible inhibition, binds at the nucleotide-binding site of enzyme, ATP and glucose 6-phosphate protect, effectiveness of various ligands in protection against inhibition, effect of pH and temperature
-
cardiolipin
-
effectiveness of various ligands in protection against inhibition, effect of pH and temperature
Cr(III)-ATP
-
complex of ATP with chromium in the 3+ oxidation state, mixed versus MgATP2-, competitive inhibition versus 2-deoxyglucose
Insulin
-
decreases glucokinase activity at 5.5 mM glucose and at 10 mM glucose. No effect at 2.8 mM glucose or at 20 mM glucose
-
leptin
-
decreases glucokinase activity at all glucose concentrations tested
-
MgADP-
-
product inhibition, mixed type inhibition versus MgATP2-, competitive inhibition versus 2-deoxyglucose
N-acetylglucosamine
-
mixed versus MgATP2-, competitive inhibition versus 2-deoxyglucose
phosphatidylinositol
-
effectiveness of various ligands in protection against inhibition, effect of pH and temperature
1,5-Anhydro-D-glucitol 6-phosphate
-
intact enzyme and catalytically active 51 kDa C fragment of hexokinase
1,5-Anhydro-D-glucitol 6-phosphate
-
HK I and HK I+, the D84A mutant of HK I has 2fold increased Ki, HK I: low millimolar concentrations of phosphate antagonize inhibition by competing for an anion binding site in the N-terminal half of HK I, HK I+: insert abolishes the antagonism of phosphate
D-glucose
-
hexokinase C: above 0.2 mM, inhibition partially relieved by ATP concentrations above 1 mM, inhibition is not pH-dependent
D-glucose 6-phosphate
-
inhibition of HK I, antagonism of inhibition by low millimolar concentrations of phosphate results from competition of this ligands for an anion binding site in the N-terminal half of HK I, mechanism
D-glucose 6-phosphate
-
hexokinase activity is strongly inhibited by high, but physiological, concentrations of glucose 6-phosphate
D-glucose 6-phosphate
-
D-glucose 6-phosphate at physiological concentrations is a potent inhibitor of hexokinase isoforms I and II but not of hexokinase type IV
glucokinase regulatory protein
-
i.e. GKRP, recombinantly expressed in Escherichia coli, inhibition in absence of fructose 6-phosphate or sorbitol 6-phosphate, competitive to D-glucose, fructose 1-phosphate and chloride are reversing the inhibition
-
glucokinase regulatory protein
-
binding of fructose 6-phosphate to glucokinase regulatory protein favors the glucokinase regulatory protein-glucokinas interaction with a negative effect on enzyme activity, while binding of fructose-1-phosphate weakens the glucokinase regulatory protein-glucokinase interaction and releases active glucokinase, the reversible association of glucokinase with glucokinase regulatory protein does more than simply regulate the catalytic activity of glucokinase, it also appears to underlie the intracellular trafficking of glucokinase between cytoplasm and nucleus
-
glucokinase regulatory protein
-
binds glucokinase in the nucleus and inhibits its activity
-
glucokinase regulatory protein
-
competitive inhibitor of glucokinase, in the fasted state, glucokinase is in part sequestered in the nucleus in an inactive state, complexed to a specific regulatory protein, glucokinase regulatory protein
-
glucokinase regulatory protein
-
inhibits competitively GCK activity with D-glucose, inhibition of glucokinase activity by glucokinase regulatory protein in vivo is enhanced by fructose 6-phosphate or sorbitol 6-phosphate
-
palmitoyl-CoA
-
inhibition of enzymes from rat liver, pig liver, Buffo marinus, no inhibition: rat brain, bovine heart, yeast
palmitoyl-CoA
-
inhibitor binds to a site distinct from the catalytic site, noncompetitive to MgATP2-, competitive to glucose, synergistic with N-acetylglucosamine
palmitoyl-CoA
-
glucokinase is inhibited by endogenous long-chain fatty acyl-CoA in islets from omega3-depleted rats
phosphate
-
at higher concentrations, binds to a lower affinity site in the C-terminal half, HK I and HK I+
phosphate
-
intact enzyme: at high concentrations, catalytically active 51 kDa C fragment of hexokinase: also at low concentrations
Regulatory protein
-
inhibition of enzymes from rat liver, pig liver, Buffo marinus, no inhibition: rat brain, bovine heart, yeast
-
Regulatory protein
-
inhibitor binds to a site distinct from the catalytic site, noncompetitive to MgATP2-, competitive to glucose, synergistic with N-acetylglucosamine, phosphate and sulfate decrease inhibition, monovalent anions antagonize inhibition with the following decreasing order of potency: I-, Br-, NO3-, Cl-, F-, acetate
-
additional information
-
not inhibited by 1 mM phosphatidylethanolamine or phosphatidylcholine
-
additional information
-
enzymes from rat brain and bovine heart are not inhibited by palmitoyl-CoA or regulatory protein
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(methylamino)-N-(4-methyl-1,3-thiazol-2-yl)-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]benzamide
-
-
2-amino-5-(1H-imidazol-2-ylsulfanyl)-N-(4-methyl-1,3-thiazol-2-yl)benzamide
-
-
2-amino-5-[(1-methyl-1H-imidazol-2-yl)sulfanyl]-N-(4-methyl-1,3-thiazol-2-yl)benzamide
-
-
2-amino-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]-N-(1,2,4-thiadiazol-5-yl)benzamide
-
-
2-amino-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]-N-(1,3-thiazol-2-yl)benzamide
-
-
2-amino-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]-N-[4-(trifluoromethyl)-1,3-thiazol-2-yl]benzamide
-
-
2-amino-5-[2-[methyl(methylidene)oxido-l6-sulfanyl]phenoxy]-N-(4-methyl-1,3-thiazol-2-yl)benzamide
-
-
2-amino-N-(3-methyl-1,2,4-thiadiazol-5-yl)-5-(pyridin-2-ylsulfanyl)benzamide
-
-
2-amino-N-(3-methyl-1,2,4-thiadiazol-5-yl)-5-(pyridin-3-ylsulfanyl)benzamide
-
-
2-amino-N-(3-methyl-1,2,4-thiadiazol-5-yl)-5-(pyridin-4-ylsulfanyl)benzamide
-
-
2-amino-N-(3-methyl-1,2,4-thiadiazol-5-yl)-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]benzamide
-
-
2-amino-N-(4-methyl-1,3-thiazol-2-yl)-5-(4H-1,2,4-triazol-3-ylsulfanyl)benzamide
-
-
2-amino-N-(4-methyl-1,3-thiazol-2-yl)-5-(pyridin-2-ylsulfanyl)benzamide
-
-
2-amino-N-(4-methyl-1,3-thiazol-2-yl)-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]benzamide
-
-
2-amino-N-(5-methyl-1,3-thiazol-2-yl)-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]benzamide
-
-
2-amino-N-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]benzamide
-
-
ethyl 2-[([2-amino-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]phenyl]carbonyl)amino]-1,3-thiazole-4-carboxylate
-
-
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
-
N-(4-methyl-1,3-thiazol-2-yl)-3-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]benzamide
-
-
N-(4-methyl-1,3-thiazol-2-yl)-5-[(4-methyl-4H-1,2,4-triazol-3-yl)sulfanyl]-2-nitrobenzamide
-
-
RO-28-1675
-
lowers the threshold concentration of D-glucose required for insulin release from 7 mM to 3 mM in pancreatic islets in vivo, reduced blood glucose level in vivo after feeding to type 2 diabetic Goto-Kakizaki rats and supresses endogenous glucose production in ZDF-Gmi rats
additional information
-
the allosteric activator compound A, increases the level of cytoplasmic glucokinase in both isolated rat primary hepatocytes and the liver tissues from rats. Compound A interacts with glucose-bound free GK, thereby impairing the association of glucokinase and glucokinase regulatory protein
-
additional information
-
not affected by 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
-
KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.43 - 0.47
ATP
recombinant wild-type hexokinase I, D84A, D84E and D84K mutants
0.035 - 0.038
D-glucose
recombinant wild-type hexokinase I, D84A, D84E and D84K mutants
additional information
additional information
-
non-cooperative conditions shows an ordered, ternary-complex mechanism with MgADP- as the last product to be released, hyperbolic kinetics with both 2-deoxyglucose and MgATP2-
-
Ki VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
additional information
-
inhibition kinetics, overview
-
0.014
1,5-Anhydro-D-glucitol 6-phosphate
recombinant wild-type hexokinase I
0.018
1,5-Anhydro-D-glucitol 6-phosphate
recombinant D84E mutant hexokinase I
0.028
1,5-Anhydro-D-glucitol 6-phosphate
recombinant D84K mutant hexokinase I
0.033
1,5-Anhydro-D-glucitol 6-phosphate
recombinant D84A mutant hexokinase I
0.01 - 0.02
1,5-Anhydro-D-glucitol 6-phosphate
-
catalytically active 51 kDa C fragment of hexokinase
6
phosphate
-
catalytically active 51 kDa C fragment of hexokinase, versus ATP
60
phosphate
-
catalytically active 51 kDa C fragment of hexokinase, versus glucose
SPECIFIC ACTIVITY [µmol/min/mg]
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
0.57
-
rat hepatocytes treated with adenovirus containing the entire coding sequence of rat liver glucokinase
additional information
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
pI VALUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
in addition to gonadotropes the enzyme is observed in a subpopulation of corticotropes and tyrotropes
-
153-306 times higher overexpression in rat AS-30D hepatoma cells than in normal freshly isolated rat hepatocytes. The enhanced glycolytic flux in fast-growth tumor cells is controlled by an overproduced, but glucose 6-phosphate-inhibited hexokinase
-
hexokinase I: predominant in normal brain, hexokinase II: increased in brain tumors, ethylnitrosourea-induced 36B-10 astrocytic F-344 rat brain tumor cell line
-
the contribution of glucokinase to total glucose-phosphorylating activity is of 12.4% in the brainstem
-
the contribution of glucokinase to total glucose-phosphorylating activity is of 13.3% in the cerebellum
-
153-306 times higher overexpression in rat AS-30D hepatoma cells than in normal freshly isolated rat hepatocytes
-
pancreatic islets of Langerhans cells: hexokinase I and IV mRNA in beta cells, not type II and III, but HK I activity probably originates mainly from contaminating pancreatic exocrine cells
-
key role for hexokinase activity and/or localization to the mitochondria in the regulation of neurite outgrowth in cultured adult sensory neurons
-
Novikoff ascites-hepatoma cells, hexokinases A, B and C, but not D
-
contains 3.6fold the enzyme found in mature erythrocytes, hexokinase type I
-
the presence of glucokinase phosphorylating activity is detected in different brain areas of 21-day-old foetuses with a contribution to the total glucose-phosphorylating activity of between 17.2% and 12.4%
-
the contribution of glucokinase to total glucose-phosphorylating activity is of 15.3% in the cerebral cortex
-
hexokinase II, increased in brain tumors, ethylnitrosourea-induced 36B-10 astrocytic F-344 rat brain tumor cell line
-
enzyme activities increase in the ventromedial hypothalamus as the glucose concentration rises. Enzyme activities in lateral hypothalamus decreases at 2.8 mM and 20 mM glucose
-
three days of dichlorvos administration (20 ng/kg body weight) results in increase of glucokinase mRNA levels and decrease in enzyme activity
-
the rate of glucose phosphorylation in hepatocytes is determined by the subcellular location of glucokinase and by its association with its regulatory protein (GKRP) in the nucleus. Elevated glucose concentrations and precursors of fructose 1-phosphate (e.g., sorbitol) cause dissociation of glucokinase from GKRP and translocation to the cytoplasm. Mechanisms downstream of AMPK activation, involving phosphorylation of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and GKRP are involved in the ATP-independent inhibition of glucose-induced glucokinase translocation by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside in hepatocytes
-
islets of Langerhans cells: hexokinase I and IV mRNA in beta cells, not type II and III, but HK I activity probably originates mainly from contaminating pancreatic exocrine cells
-
three days of dichlorvos administration (20 ng/kg body weight) has no affect on pancreatic glucokinase activity as well as mRNA levels
-
constitutively expressed at a basal rate of 63 pmol/microgram protein/h
-
glucokinase is inhibited by endogenous long-chain fatty acyl-CoA in islets from omega3-depleted rats. Such an inhibition probably participates to the alteration of D-glucose catabolism prevailing in these islets
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
glucose levels higher 5 mM or fructose addition to the medium causes a rapid translocation of glucokinase to a predominant cytoplasmic localization
oleate decreases hexokinase-mitochondrial binding and abolishes insulin-mediated translocation of HK I. Under basal conditions, the fraction of hexokinase I that is mitochondrially bound is 5times greater than for hexokinase II. Insulin and ischemia cause a fourfold increase in hexokinase II binding but only a doubling of hexokinase I binding
-
glucokinase becomes active when it is released from glucokinase regulatory protein and translocates to the cytosol
-
HKII translocates between mitochondria and the cytosol in response to glucose, glucose 6-phosphate and Akt
-
binding of brain enzyme to the outer mitochondrial membrane plays a role in regulation of hexokinase activity in vivo
under basal conditions, the fraction of hexokinase I that is mitochondrially bound is 5times greater than for hexokinase II. Insulin and ischemia cause a fourfold increase in hexokinase II binding but only a doubling of hexokinase I binding
-
key role for hexokinase activity and/or localization to the mitochondria in the regulation of neurite outgrowth in cultured adult sensory neurons
-
HKII translocates between mitochondria and the cytosol in response to glucose, glucose 6-phosphate and Akt
-
glucokinase is mainly localized to the nuclei at glucose concentrations around 5 mM
-
glucokinase regulatory protein causes accumulation of glucokinase in the nucleus
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
metabolism
physiological function
malfunction
-
defect in the activation of glucokinase is potential contributing factor to the dysregulation of hepatic glucose metabolism in type 2 diabetes
malfunction
-
hypoxia-inducible factor (HIF)-1-regulated glycolytic enzyme hexokinase II (HKII) acts as a molecular switch that determines cellular fate by regulating both cytoprotection and induction of apoptosis based on the metabolic state. Together with phosphoprotein enriched in astrocytes (PEA15), HKII inhibits apoptosis after hypoxia. In contrast, HKII accelerates apoptosis in the absence of PEA15 and under glucose deprivation
metabolism
-
HKII promotes glycolysis when bound to mitochondria. Promotes glycogen synthesis when located in the cytosol
physiological function
-
glucokinase acts as a hepatic glucose sensor that permits hepatic metabolism to respond appropriately to changes in plasma glucose concentrations
physiological function
-
in animals with normal levels of glucokinase, glucokinase regulatory protein is mainly localized to the nuclei of hepatocytes. In seven-day old rats, glucokinase regulatory protein is found primarily in the cytoplasm. Varying the level of glucokinase protein has no effect on total cellular glucokinase regulatory protein protein levels
physiological function
in fasted rats, glucokinase activity is specifically increased in the arcuate nucleus but not other regions of the hypothalamus. Pharmacologic and genetic activation of glucokinase in the arcuate nucleus of rodent models increases glucose ingestion, while decreased arcuate nucleus glucokinase activity reduces glucose intake. ATP-sensitive potassium channel and P/Q calcium channel activity are required for glucokinase-mediated glucose intake. Altered glucokinase activity affects release of the orexigenic neurotransmitter neuropeptide Y in response to glucose
physiological function
inhibition of hexokinase-II diminishes, while overexpression of hexokinase-II potentiates autophagy induced by glucose deprivation in cardiomyocyte and noncardiomyocyte cells. Hexokinase-II binds to and inhibits the autophagy suppressor, mTOR complex 1 (TORC1), and this binding is increased by glucose deprivation. Mutating the TOS motif, a scaffold sequence responsible for binding TORC1 substrates, in hexokinase-II blocks its ability to bind to TORC1 and regulate protective autophagy. The transition from glycolysis to autophagy appears to be regulated by a decrease in glucose-6 phosphate
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). HXK1_RAT
918
0
102408
Swiss-Prot
other Location (Reliability: 2)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
100000
52000
98000
additional information
-
retention of the full catalytic activity of rat brain hexokinase C-terminal half supports the suggestion that the 100000 MW hexokinase evolves from an ancestral 50000 MW yeast type hexokinase by a process of gene duplication
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
monomer
CRYSTALLIZATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D84A
HK I mutant with 2fold increased Ki value for the inhibitory 1,5-anhydro-D-glucitol 6-phosphate, mutation diminishes the ability of phosphate to antagonize inhibition, but has no effect on the inhibition by phosphate at higher concentrations
D84E
HK I mutant, slightly increased Ki value for the inhibitory 1,5-anhydro-D-glucitol 6-phosphate, antagonistic effect of phosphate is drastically reduced, no effect on the inhibition by phosphate at higher concentrations
D84K
HK I mutant, increased Ki value for the inhibitory 1,5-anhydro-D-glucitol 6-phosphate, antagonistic effect of phosphate is abolished, slightly decreased Ki value for inhibition by phosphate at higher concentrations
D84A
-
HK I mutant with 2fold increased Ki value for the inhibitory 1,5-anhydro-D-glucitol 6-phosphate, mutation diminishes the ability of phosphate to antagonize inhibition, but has no effect on the inhibition by phosphate at higher concentrations
F199A
mutation in mTOR signaling motif. While overexpressed wild-type enzyme associates with mTOR and raptor, mutant F199A does not show association above control levels
L309R/N313Y
-
significantly reduced interaction with glucokinase regulatory protein
L355R/N350Y
-
mutant has a fivefold-higher binding affinity for glucokinase regulatory protein than wild-type glucokinase
L58R/N204Y
-
10fold reduced interaction with glucokinase regulatory protein. Mutant lacks glucose-dependent translocation by glucokinase regulatory protein
GENERAL STABILITY
ORGANISM
UNIPROT
LITERATURE
storage of purified enzyme in D-glucose-containing phosphate buffer enhances its stability
-
STORAGE STABILITY
ORGANISM
UNIPROT
LITERATURE
-20°C, purified enzyme, in the presence of glucose, glycerol and thiol-reducing agents, stable
-
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
intact hexokinase I, isolation of a catalytically active 51 kDa C fragment and a 52 kDa N fragment without catalytic activity
-
recombinant N-terminally His6-tagged hepatic enzyme from Escherichia coli by nickel affinity chromatography to over 90% purity
-
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
cDNAs coding for hexokinases II and III are cloned, hexokinase II is expressed in Pichia pastoris and hexokinase III in Schizosaccharomyces pombe
-
expression of the N-terminally His6-tagged hepatic enzyme in Escherichia coli
-
HK I+, a modified form of HK I with a centrally located polyalanine insert, and D84A mutants of HK I and HK I+ are expressed in M+R42 cells
-
HKI and HKII linked to YFP are expressed in CHO-cells to track their subcellular location in real time and their mobilization in response to substrates
-
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
biotin increases glucokinase expression, inhibition of soluble guanylate cyclase or protein kinase G signalling suppresses biotin-induced glucokinase expression, inhibition of insulin secretion with diazoxide or nifedipine prevents biotin-stimulated glucokinase mRNA increase
-
in the liver, expression of glucokinase is strictly dependent on the presence of insulin, insulin induction of glucokinase in hepatocytes is suppressed by the inhibitors of phosphoinositide 3-kinase, wortmannin, and LY294002
-
tissue mRNA levels are increased following a single neutral protamine Hagadorn insulin injection, basal glucokinase gene expression is elevated by precedent insulin dosing
-
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
-
given the combined prominent role of glucokinase on insulin secretion and hepatic glucose metabolism where the GK-GKRP mechanism is involved, activation of glucokinase has a new therapeutic potential in the treatment of type 2 diabetes
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Easterby, J.S.; Qadri, S.S.
Hexokinase type II from rat skeletal muscle
Methods Enzymol.
90
11-15
1982
Rattus norvegicus
-
Nakashima, R.A.; Paggi, M.G.; Scott, L.J.; Pedersen, P.L.
Purification and characterization of a bindable form of mitochondrial bound hexokinase from the highly glycolytic AS-30D rat hepatoma cell line
Cancer Res.
48
913-919
1988
Rattus norvegicus
Hashimoto, M.; Wilson, J.E.
Kinetic and regulatory properties of HK I+, a modified form of the type I isozyme of mammalian hexokinase in which interactions between the N- and C-terminal halves have been disrupted
Arch. Biochem. Biophys.
399
109-115
2002
Rattus norvegicus
Serafini, G.; Magnani, M.; Stocchi, V.; Dacha, M.; Forniani, G.
Rat red blood cell hexokinase purification, properties and age-dependence
Mol. Cell. Biochem.
69
179-185
1986
Rattus norvegicus
Vandercammen, A.; Van Schaftingen, E.
Competitive inhibition of liver glucokinase by its regulatory protein
Eur. J. Biochem.
200
545-551
1991
Bos taurus, Rhinella marina, Rattus norvegicus, Sus scrofa
Nemat-Gorgani, M.; Wilson, J.E.
Acidic phospholipids may inhibit rat brain hexokinase by interaction at the nucleotide binding site
Arch. Biochem. Biophys.
236
220-227
1985
Rattus norvegicus
Radojkovic, J.; Ureta, T.
Hexokinase isoenzymes from the Novikoff hepatoma. Purification, kinetic and structural characterization, with emphasis on hexokinase C
Biochem. J.
242
895-903
1987
Rattus norvegicus
White, T.K.; Wilson, J.E.
Isolation and characterization of the discrete N- and C-terminal halves of rat brain hexokinase: retention of full catalytic activity in the isolated C-terminal half
Arch. Biochem. Biophys.
274
375-393
1989
Rattus norvegicus
Sui, D.; Wilson, J.E.
Purification of the type II and type III isozymes of rat hexokinase, expressed in yeast
Protein Expr. Purif.
24
83-89
2002
Rattus norvegicus
Schuit, F.; Moens, K.; Heimberg, H.; Pipeleers, D.
Cellular origin of hexokinase in pancreatic islets
J. Biol. Chem.
274
32803-32809
1999
Rattus norvegicus
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
Sebastian, S.; Wilson, J.E.; Mulichak, A.; Garavito, R.M.
Allosteric regulation of type I hexokinase: A site-directed mutational study indicating location of the functional glucose 6-phosphate binding site in the N-terminal half of the enzyme
Arch. Biochem. Biophys.
362
203-210
1999
Rattus norvegicus (P05708)
Tu, J.; Tuch, B.E.
Glucose regulates the maximal velocities of glucokinase and glucose utilization in the immature fetal rat pancreatic islet
Diabetes
45
1068-1075
1996
Rattus norvegicus
Takeuchi, H.; Inoue, Y.; Ishihara, H.; Oka, Y.
Overexpression of either liver type or pancreatic beta cell type glucokinase via recombinant adenovirus enhances glucose oxidation in isolated rat hepatocytes
FEBS Lett.
393
60-64
1996
Rattus norvegicus
Roncero, I.; Alvarez, E.; Vazquez, P.; Blazquez, E.
Functional glucokinase isoforms are expressed in rat brain
J. Neurochem.
74
1848-1857
2000
Rattus norvegicus
Monasterio, O.; Cardenas, M.L.
Kinetic studies of rat liver hexokinase D ('glucokinase') in non-co-operative conditions show an ordered mechanism with MgADP as the last product to be released
Biochem. J.
371
29-38
2003
Rattus norvegicus
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
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
Southworth, R.; Davey, K.A.; Warley, A.; Garlick, P.B.
A reevaluation of the roles of hexokinase I and II in the heart
Am. J. Physiol. Heart Circ. Physiol.
292
H378-H386
2007
Rattus norvegicus (P05708), Rattus norvegicus (P27881)
Zelent, D.; Najafi, H.; Odili, S.; Buettger, C.; Weik-Collins, H.; Li, C.; Doliba, N.; Grimsby, J.; Matschinsky, F.M.
Glucokinase and glucose homeostasis: proven concepts and new ideas
Biochem. Soc. Trans.
33
306-310
2005
Rattus norvegicus
Baltrusch, S.; Francini, F.; Lenzen, S.; Tiedge, M.
Interaction of glucokinase with the liver regulatory protein is conferred by leucine-asparagine motifs of the enzyme
Diabetes
54
2829-2837
2005
Rattus norvegicus
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
Futamura, M.; Hosaka, H.; Kadotani, A.; Shimazaki, H.; Sasaki, K.; Ohyama, S.; Nishimura, T.; Eiki, J.; Nagata, Y.
An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism
J. Biol. Chem.
281
37668-37674
2006
Rattus norvegicus
Sanz, C.; Roncero, I.; Vazquez, P.; Navas, M.A.; Blazquez, E.
Effects of glucose and insulin on glucokinase activity in rat hypothalamus
J. Endocrinol.
193
259-267
2007
Rattus norvegicus
Sorenson, R.L.; Stout, L.E.; Brelje, T.C.; Jetton, T.L.; Matschinsky, F.M.
Immunohistochemical evidence for the presence of glucokinase in the gonadotropes and thyrotropes of the anterior pituitary gland of rat and monkey
J. Histochem. Cytochem.
55
555-566
2007
Macaca fascicularis, Rattus norvegicus
Romero-Navarro, G.; Lopez-Aceves, T.; Rojas-Ochoa, A.; Fernandez Mejia, C.
Effect of dichlorvos on hepatic and pancreatic glucokinase activity and gene expression, and on insulin mRNA levels
Life Sci.
78
1015-1020
2006
Rattus norvegicus
Mukhtar, M.H.; Payne, V.A.; Arden, C.; Harbottle, A.; Khan, S.; Lange, A.J.; Agius, L.
Inhibition of glucokinase translocation by AMP-activated protein kinase is associated with phosphorylation of both GKRP and 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
Am. J. Physiol. Regul. Integr. Comp. Physiol.
294
R766-R774
2008
Rattus norvegicus
Zhang, Y.; Bulur, N.; Peltier, S.; Carpentier, Y.A.; Malaisse, W.J.; Sener, A.
Long-chain fatty acyl-coenzyme A-induced inhibition of glucokinase in pancreatic islets from rats depleted in long-chain polyunsaturated omega3 fatty acids
Cell Biochem. Funct.
26
233-237
2008
Rattus norvegicus
Bertram, L.S.; Black, D.; Briner, P.H.; Chatfield, R.; Cooke, A.; Fyfe, M.C.; Murray, P.J.; Naud, F.; Nawano, M.; Procter, M.J.; Rakipovski, G.; Rasamison, C.M.; Reynet, C.; Schofield, K.L.; Shah, V.K.; Spindler, F.; Taylor, A.; Turton, R.; Williams, G.M.; Wong-Kai-In, P.; Yasuda, K.
SAR, pharmacokinetics, safety, and efficacy of glucokinase activating 2-(4-sulfonylphenyl)-N-thiazol-2-ylacetamides: discovery of PSN-GK1
J. Med. Chem.
51
4340-4345
2008
Rattus norvegicus
Wang, Z.; Gardiner, N.J.; Fernyhough, P.
Blockade of hexokinase activity and binding to mitochondria inhibits neurite outgrowth in cultured adult rat sensory neurons
Neurosci. Lett.
434
6-11
2008
Rattus norvegicus
Zhuravliova, E.; Barbakadze, T.; Zaalishvili, E.; Chipashvili, M.; Koshoridze, N.; Mikeladze, D.
Social isolation in rats inhibits oxidative metabolism, decreases the content of mitochondrial K-Ras and activates mitochondrial hexokinase
Behav. Brain Res.
205
377-383
2009
Rattus norvegicus
Agius, L.
Glucokinase and molecular aspects of liver glycogen metabolism
Biochem. J.
414
1-18
2008
Homo sapiens, Mus musculus, Rattus norvegicus
Nishimura, T.; Iino, T.; Mitsuya, M.; Bamba, M.; Watanabe, H.; Tsukahara, D.; Kamata, K.; Sasaki, K.; Ohyama, S.; Hosaka, H.; Futamura, M.; Nagata, Y.; Eiki, J.
Identification of novel and potent 2-amino benzamide derivatives as allosteric glucokinase activators
Bioorg. Med. Chem. Lett.
19
1357-1360
2009
Rattus norvegicus
Iynedjian, P.B.
Molecular physiology of mammalian glucokinase
Cell. Mol. Life Sci.
66
27-42
2009
Rattus norvegicus
Wei, P.; Shi, M.; Barnum, S.; Cho, H.; Carlson, T.; Fraser, J.D.
Effects of glucokinase activators GKA50 and LY2121260 on proliferation and apoptosis in pancreatic INS-1 beta cells
Diabetologia
52
2142-2150
2009
Rattus norvegicus
Cifuentes, D.; Martinez-Pons, C.; Garcia-Rocha, M.; Galina, A.; Ribas de Pouplana, L.; Guinovart, J.J.
Hepatic glycogen synthesis in the absence of glucokinase: the case of embryonic liver
J. Biol. Chem.
283
5642-5649
2008
Rattus norvegicus
Polakof, S.; Miguez, J.M.; Soengas, J.L.
A hepatic protein modulates glucokinase activity in fish and avian liver: a comparative study
J. Comp. Physiol. B
179
643-652
2009
Carassius auratus, Cyprinus carpio, Gallus gallus, Oncorhynchus mykiss, Rattus norvegicus
Genabai, N.K.; Vavaiya, K.V.; Briski, K.P.
Adaptation of glucokinase gene expression in the rat dorsal vagal complex in a model for recurrent intermediate insulin-induced hypoglycemia: impact of gender
J. Mol. Neurosci.
37
80-85
2009
Rattus norvegicus
Roncero, I.; Sanz, C.; Alvarez, E.; Vazquez, P.; Barrio, P.A.; Blazquez, E.
Glucokinase and glucokinase regulatory proteins are functionally coexpressed before birth in the rat brain
J. Neuroendocrinol.
21
973-981
2009
Rattus norvegicus
Vilches-Flores, A.; Tovar, A.R.; Marin-Hernandez, A.; Rojas-Ochoa, A.; Fernandez-Mejia, C.
Biotin increases glucokinase expression via soluble guanylate cyclase/protein kinase G, adenosine triphosphate production and autocrine action of insulin in pancreatic rat islets
J. Nutr. Biochem.
21
606-612
2009
Rattus norvegicus
Hiskett, E.K.; Suwitheechon, O.U.; Lindbloom-Hawley, S.; Boyle, D.L.; Schermerhorn, T.
Lack of glucokinase regulatory protein expression may contribute to low glucokinase activity in feline liver
Vet. Res. Commun.
33
227-240
2009
Canis lupus familiaris, Felis catus, Rattus norvegicus
John, S.; Weiss, J.N.; Ribalet, B.
Subcellular localization of hexokinases I and II directs the metabolic fate of glucose
PLoS ONE
6
e17674
2011
Rattus norvegicus
Mergenthaler, P.; Kahl, A.; Kamitz, A.; van Laak, V.; Stohlmann, K.; Thomsen, S.; Klawitter, H.; Przesdzing, I.; Neeb, L.; Freyer, D.; Priller, J.; Collins, T.J.; Megow, D.; Dirnagl, U.; Andrews, D.W.; Meisel, A.
Mitochondrial hexokinase II (HKII) and phosphoprotein enriched in astrocytes (PEA15) form a molecular switch governing cellular fate depending on the metabolic state
Proc. Natl. Acad. Sci. USA
109
1518-1523
2012
Rattus norvegicus
Jin, L.; Guo, T.; Li, Z.; Lei, Z.; Li, H.; Mao, Y.; Wang, X.; Zhou, N.; Zhang, Y.; Hu, R.; Zhang, X.; Niu, G.; Irwin, D.M.; Tan, H.
Role of glucokinase in the subcellular localization of glucokinase regulatory protein
Int. J. Mol. Sci.
16
7377-7393
2015
Mus musculus, Rattus norvegicus
Hussain, S.; Richardson, E.; Ma, Y.; Holton, C.; De Backer, I.; Buckley, N.; Dhillo, W.; Bewick, G.; Zhang, S.; Carling, D.; Bloom, S.; Gardiner, J.
Glucokinase activity in the arcuate nucleus regulates glucose intake
J. Clin. Invest.
125
337-349
2015
Rattus norvegicus (P17712)
Roberts, D.J.; Tan-Sah, V.P.; Ding, E.Y.; Smith, J.M.; Miyamoto, S.
Hexokinase-II positively regulates glucose starvation-induced autophagy through TORC1 inhibition
Mol. Cell
53
521-533
2014
Rattus norvegicus (P27881)
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