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Information on EC 2.7.1.3 - ketohexokinase
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2.7.1.3 ketohexokinaseIUBMB Comments
D-Sorbose, D-tagatose and 5-dehydro-D-fructose and a number of other ketoses and their analogues can also act as substrates .
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Word Map
- 2.7.1.3
- fructokinase
-
fructose-induced
-
high-fructose
- fructose-1-phosphate
- triokinase
-
fructolytic
-
fructosuria
-
fructose-metabolizing
- medicine
- analysis
The expected taxonomic range for this enzyme is: Eukaryota, Bacteria, Archaea
Synonyms
ketohexokinase, khk-a, khk-c, 
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SYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ATP:D-fructose 1-phosphotransferase
fructokinase
ketohexokinase
ketohexokinase (phosphorylating)
-
-
-
-
KHK
Khk-A
Khk-C
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REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + D-fructose = ADP + D-fructose 1-phosphate
-
-
-
-
ATP + D-fructose = ADP + D-fructose 1-phosphate
random kinetic mechanism with the formation of two dead-end complexes
-
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho group transfer
-
-
-
-
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
ATP:D-fructose 1-phosphotransferase
D-Sorbose, D-tagatose and 5-dehydro-D-fructose and a number of other ketoses and their analogues can also act as substrates [4].
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CAS REGISTRY NUMBER
COMMENTARY
9030-50-6
-
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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
ATP + D-fructose
ADP + D-fructose 1-phosphate
-
specific for beta-furanose anomer
-
-
?
ATP + D-fructose
ADP + D-fructose 1-phosphate
-
except for ATP, other nucleotides such as UTP, CTP, GTP, or ITP can not act as phosphoryl donors
-
-
?
ATP + D-fructose
ADP + D-fructose 1-phosphate
-
except for ATP, other nucleotides such as UTP, CTP, GTP, or ITP can not act as phosphoryl donors
-
-
?
ATP + D-fructose
ADP + D-fructose 1-phosphate
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fructose enters glycolytic metabolism after phosphorylation by ketohexokinase and is converted to fructose-1-phosphate. Fructose-driven glycolytic respiration in Heterocephalus glaber tissues avoids feedback inhibition of glycolysis via phosphofructokinase, allowing continued glycolytic flux independent of cellular energy status and supporting viability
-
-
?
ATP + D-fructose
ADP + D-fructose 1-phosphate
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role in formation of glycoaldehyde
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-
?
ATP + D-fructose
ADP + D-fructose 1-phosphate
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conversion of fructose to glucose in liver homogenates involves the intermediary formation of D-fructose 1-phosphate
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?
additional information
?
-
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the minimum molecule for substrate activity seems to be (2R)-2-hydroxymethyl-3,4-dihydroxytetrahydrofuran
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-
?
additional information
?
-
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specificity of fructokinase is for a tetrahydrofuran ring with beta-D-(or alpha-L-)configuration at position 2, L-configuration at position 3 and either D- or L-configuration at position 4 and 5
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-
?
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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-fructose
ADP + D-fructose 1-phosphate
-
fructose enters glycolytic metabolism after phosphorylation by ketohexokinase and is converted to fructose-1-phosphate. Fructose-driven glycolytic respiration in Heterocephalus glaber tissues avoids feedback inhibition of glycolysis via phosphofructokinase, allowing continued glycolytic flux independent of cellular energy status and supporting viability
-
-
?
ATP + D-fructose
ADP + D-fructose 1-phosphate
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role in formation of glycoaldehyde
-
-
?
ATP + D-fructose
ADP + D-fructose 1-phosphate
-
conversion of fructose to glucose in liver homogenates involves the intermediary formation of D-fructose 1-phosphate
-
?
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METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Cs+
CsCl
-
the enzyme is maximally active in the presence of 1.2 M KCl. Activity in the presence of RbCl and CsCl is similar to that observed in the presence of KCl
K+
KCl
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the enzyme is maximally active in the presence of 1.2 M KCl. Activity in the presence of RbCl and CsCl is similar to that observed in the presence of KCl
Li+
-
absolute requirement for both monovalent and divalent cations, when Mg2+ fills the requirement for divalent cation, K+ and Rb+ are the most active monovalent cations, NH4+, Na+, Cs+ and Li+ are decreasingly active
Mg2+
Na+
NaCl
-
stimulates, yields 50% of the activity observed in equimolar KCl
NH4+
Rb+
RbCl
-
the enzyme is maximally active in the presence of 1.2 M KCl. Activity in the presence of RbCl and CsCl is similar to that observed in the presence of KCl
Cs+
-
absolute requirement for both monovalent and divalent cations, when Mg2+ fills the requirement for divalent cation, K+ and Rb+ are the most active monovalent cations, NH4+, Na+, Cs+ and Li+ are decreasingly active
K+
-
absolute requirement for both monovalent and divalent cations, when Mg2+ fills the requirement for divalent cation, K+ and Rb+ are the most active monovalent cations
Mg2+
-
absolute requirement for both monovalent and divalent cations, for optimal activity the concentration of Mg2+ must equal or exceed the concentration of ATP
Mg2+
-
most active at a Mg2+ concentration of 1 mM. Mg2+ can not be replaced by Mn2+. ATP/Mg2+ in the ratio of 1:2 forms the actual substrate for ketohexokinase activity
Na+
-
absolute requirement for both monovalent and divalent cations, when Mg2+ fills the requirement for divalent cation, K+ and Rb+ are the most active monovalent cations, NH4+, Na+, Cs+ and Li+ are decreasingly active
NH4+
-
absolute requirement for both monovalent and divalent cations, when Mg2+ fills the requirement for divalent cation, K+ and Rb+ are the most active monovalent cations, NH4+, Na+, Cs+ and Li+ are decreasingly active
Rb+
-
absolute requirement for both monovalent and divalent cations, when Mg2+ fills the requirement for divalent cation, K+ and Rb+ are the most active monovalent cations, NH4+, Na+, Cs+ and Li+ are decreasingly active
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INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(4-aminopiperidin-1-yl)-N8-(cyclopropylmethyl)-N4-(2-methylphenyl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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2-ethyl-7-(3-hydroxy-3-methylpyrrolidin-1-yl)-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile
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2-[(3R)-3-aminopiperidin-1-yl]-N8-(cyclopropylmethyl)-N4-[2-(methylsulfanyl)phenyl]pyrimido[5,4-d]pyrimidine-4,8-diamine
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2-[(3S)-3-aminopiperidin-1-yl]-N8-(cyclopropylmethyl)-N4-[2-(methylsulfanyl)phenyl]pyrimido[5,4-d]pyrimidine-4,8-diamine
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2-[3-(aminomethyl)azetidin-1-yl]-N8-(cyclopropylmethyl)-N4-[2-(methylsulfanyl)phenyl]pyrimido[5,4-d]pyrimidine-4,8-diamine
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2-[4-(aminomethyl)piperidin-1-yl]-N8-(cyclopropylmethyl)-N4-(2-methylphenyl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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2-[4-(aminomethyl)piperidin-1-yl]-N8-(cyclopropylmethyl)-N4-[2-(methylsulfanyl)phenyl]pyrimido[5,4-d]pyrimidine-4,8-diamine
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6-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-2-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile
6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile
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6-[4-(2-hydroxyethyl)piperazin-1-yl]-4-[3-(hydroxymethyl)piperidin-1-yl]-2-(trifluoromethyl)pyridine-3-carbonitrile
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7-[(3R)-3-hydroxy-3-methylpyrrolidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile
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7-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile
D-Fructose 1-phosphate
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competitive against D-fructose, noncompetitive to MgATP2-
N4-(2-bromophenyl)-N8-cyclopropyl-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N4-(2-chlorophenyl)-N8-cyclopropyl-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N4-(2-methylphenyl)-2-(piperazin-1-yl)-N8-(1,3-thiazol-2-ylmethyl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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-
N4-(2-methylphenyl)-2-(piperazin-1-yl)-N8-(prop-2-yn-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N4-(2-methylphenyl)-2-(piperazin-1-yl)-N8-(tetrahydrothiophen-2-ylmethyl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N4-(2-methylphenyl)-2-(piperazin-1-yl)-N8-propylpyrimido[5,4-d]pyrimidine-4,8-diamine
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N4-cyclohexyl-N8-cyclopropyl-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N4-[2-(methylsulfanyl)phenyl]-2-(piperazin-1-yl)-N8-(1,3-thiazol-2-ylmethyl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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-
N4-[2-(methylsulfanyl)phenyl]-2-(piperazin-1-yl)-N8-(pyridin-2-ylmethyl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N4-[2-(methylsulfanyl)phenyl]-2-(piperazin-1-yl)-N8-(thiophen-2-ylmethyl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N4-[2-(methylsulfanyl)phenyl]-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N8-(2-cyclopropylethyl)-N4-[2-(methylsulfanyl)phenyl]-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N8-(2-methoxyethyl)-N4-[2-(methylsulfanyl)phenyl]-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N8-(cyclobutylmethyl)-N4-[2-(methylsulfanyl)phenyl]-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N8-(cyclopropylmethyl)-2-(1,4-diazepan-1-yl)-N4-(2-methylphenyl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N8-(cyclopropylmethyl)-2-(4-iminopiperidin-1-yl)-N4-(2-methylphenyl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N8-(cyclopropylmethyl)-2-(4-methylpiperazin-1-yl)-N4-[2-(methylsulfanyl)phenyl]pyrimido[5,4-d]pyrimidine-4,8-diamine
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N8-(cyclopropylmethyl)-2-[4-[(dimethylamino)methyl]piperidin-1-yl]-N4-[2-(methylsulfanyl)phenyl]pyrimido[5,4-d]pyrimidine-4,8-diamine
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-
N8-(cyclopropylmethyl)-N2-methyl-N2-[2-(methylamino)ethyl]-N4-[2-(methylsulfanyl)phenyl]pyrimido[5,4-d]pyrimidine-2,4,8-triamine
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N8-(cyclopropylmethyl)-N4-(2-methylphenyl)-2-(4-methylpiperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-(cyclopropylmethyl)-N4-(2-methylphenyl)-2-(morpholin-4-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-benzyl-N4-(2-methylphenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclohexyl-N4-(2-methylphenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclopropyl-2-(piperazin-1-yl)-N4-[2-(propan-2-yl)phenyl]pyrimido[5,4-d]pyrimidine-4,8-diamine
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-
N8-cyclopropyl-2-(piperazin-1-yl)-N4-[2-[(trifluoromethyl)sulfanyl]phenyl]pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclopropyl-N4-(2-cyclopropylphenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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-
N8-cyclopropyl-N4-(2-ethoxyphenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclopropyl-N4-(2-ethylphenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclopropyl-N4-(2-fluorophenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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-
N8-cyclopropyl-N4-(2-methoxyphenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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-
N8-cyclopropyl-N4-(2-methylphenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclopropyl-N4-(3-methylphenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclopropyl-N4-phenyl-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclopropyl-N4-[2-(ethylsulfanyl)phenyl]-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclopropyl-N4-[2-(methylsulfanyl)phenyl]-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclopropyl-N4-[2-(methylsulfonyl)phenyl]-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclopropyl-N4-[3-(methylsulfanyl)phenyl]-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-cyclopropyl-N4-[4-(methylsulfanyl)phenyl]-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
-
-
N8-ethyl-N4-(2-methylphenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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-
N8-hexyl-N4-(2-methylphenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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N8-methyl-N4-(2-methylphenyl)-2-(piperazin-1-yl)pyrimido[5,4-d]pyrimidine-4,8-diamine
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[(3R)-1-(5-methyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)piperidin-3-yl]methanol
-
6-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-2-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile
nonbasic moderately potent and highly selective ketohexokinase inhibitor
6-[(3S,4S)-3,4-dihydroxypyrrolidin-1-yl]-2-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-4-(trifluoromethyl)pyridine-3-carbonitrile
nonbasic moderately potent and highly selective ketohexokinase inhibitor with favorable ADME and safety profiles and good exposure in rats
7-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile
-
7-[(3S)-3-hydroxy-3-methylpyrrolidin-1-yl]-5-(trifluoromethyl)-1H-pyrrolo[3,2-b]pyridine-6-carbonitrile
-
additional information
-
extracts of Angelica archangelica, Garcinia mangostana, Petroselinum crispum, and Scutellaria baicalensis exhibit ketohexokinase inhibitory activity and block fructose-induced ATP depletion and fructose-induced elevation in triglyerides and uric acid
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additional information
-
the phosphorylation of D-fructose by ketohexokinase is resistant to inhibition by D-mannoheptulose
-
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DISEASE
TITLE OF PUBLICATION
LINK TO PUBMED
Carcinogenesis
Prognostic Impact of Metabolism Reprogramming Markers Acetyl-CoA Synthetase 2 Phosphorylation and Ketohexokinase-A Expression in Non-Small-Cell Lung Carcinoma.
Carcinoma
KHK-A promotes the proliferation of oesophageal squamous cell carcinoma through the up-regulation of PRPS1.
Carcinoma
The expression of ketohexokinase is diminished in human clear cell type of renal cell carcinoma.
Carcinoma, Hepatocellular
A splicing switch from ketohexokinase-C to ketohexokinase-A drives hepatocellular carcinoma formation.
Carcinoma, Renal Cell
The expression of ketohexokinase is diminished in human clear cell type of renal cell carcinoma.
Diabetes Mellitus
Endogenous fructose is correlated with urinary albumin creatinine ratios and uric acid in type 2 diabetes mellitus.
Diabetes Mellitus, Type 2
Endogenous fructose is correlated with urinary albumin creatinine ratios and uric acid in type 2 diabetes mellitus.
Esophageal Squamous Cell Carcinoma
KHK-A promotes the proliferation of oesophageal squamous cell carcinoma through the up-regulation of PRPS1.
Fatty Liver
Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.
Fatty Liver
Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis.
Fructose Intolerance
Expression of rat liver ketohexokinase in yeast results in fructose intolerance.
Glioma
Ketohexokinase is involved in fructose utilization and promotes tumor progression in glioma.
Hepatitis
Science letters: Proteomic analysis of differentially expressed proteins in mice with concanavalin A-induced hepatitis.
Hyperoxaluria
Calciuria, oxaluria and phosphaturia after ingestion of glucose, xylitol and sorbitol in two population groups with different stone-risk profiles.
Hypoglycemia
Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice.
ketohexokinase deficiency
Properties of normal and mutant recombinant human ketohexokinases and implications for the pathogenesis of essential fructosuria.
Liver Diseases
Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis.
Metabolic Syndrome
Short-term fructose ingestion affects the brain independently from establishment of metabolic syndrome.
Neoplasms
Ketohexokinase is involved in fructose utilization and promotes tumor progression in glioma.
Neoplasms
KHK-A promotes the proliferation of oesophageal squamous cell carcinoma through the up-regulation of PRPS1.
Neoplasms
Prognostic Impact of Metabolism Reprogramming Markers Acetyl-CoA Synthetase 2 Phosphorylation and Ketohexokinase-A Expression in Non-Small-Cell Lung Carcinoma.
Neoplasms
The expression of ketohexokinase is diminished in human clear cell type of renal cell carcinoma.
Non-alcoholic Fatty Liver Disease
Ketohexokinase inhibition improves NASH by reducing fructose-induced steatosis and fibrogenesis.
Obesity
Inhibitors of Ketohexokinase: Discovery of Pyrimidinopyrimidines with Specific Substitution that Complements the ATP-Binding Site.
Obesity
Pyrimidinopyrimidine inhibitors of ketohexokinase: Exploring the ring C2 group that interacts with Asp-27B in the ligand binding pocket.
Proteinuria
IL-6/STAT3 signaling activation exacerbates high fructose-induced podocyte hypertrophy by ketohexokinase-A-mediated tristetraprolin down-regulation.
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KM VALUE [mM]
SUBSTRATE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE