UniProt functional annotation for P35557



	UniProt functional annotation for P35557

UniProt code: P35557.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

Function: Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively) (PubMed:7742312, PubMed:11916951, PubMed:15277402, PubMed:17082186, PubMed:18322640, PubMed:19146401, PubMed:25015100, PubMed:8325892). Compared to other hexokinases, has a weak affinity for D-glucose, and is effective only when glucose is abundant (By similarity). Mainly expressed in pancreatic beta cells and the liver and constitutes a rate-limiting step in glucose metabolism in these tissues (PubMed:18322640, PubMed:25015100, PubMed:8325892, PubMed:11916951, PubMed:15277402). Since insulin secretion parallels glucose metabolism and the low glucose affinity of GCK ensures that it can change its enzymatic activity within the physiological range of glucose concentrations, GCK acts as a glucose sensor in the pancreatic beta cell (By similarity). In pancreas, plays an important role in modulating insulin secretion (By similarity). In liver, helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage (By similarity). Required to provide D-glucose 6-phosphate for the synthesis of glycogen (PubMed:8878425). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (PubMed:7742312). {ECO:0000250|UniProtKB:P17712, ECO:0000250|UniProtKB:P52792, ECO:0000269|PubMed:11916951, ECO:0000269|PubMed:15277402, ECO:0000269|PubMed:17082186, ECO:0000269|PubMed:18322640, ECO:0000269|PubMed:19146401, ECO:0000269|PubMed:25015100, ECO:0000269|PubMed:7742312, ECO:0000269|PubMed:8325892, ECO:0000269|PubMed:8878425}.

Catalytic activity: Reaction=ATP + D-hexose = ADP + D-hexose 6-phosphate + H(+); Xref=Rhea:RHEA:22740, ChEBI:CHEBI:4194, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:61567, ChEBI:CHEBI:456216; EC=2.7.1.1; Evidence={ECO:0000269|PubMed:11916951, ECO:0000269|PubMed:15277402, ECO:0000269|PubMed:17082186, ECO:0000269|PubMed:18322640, ECO:0000269|PubMed:19146401, ECO:0000269|PubMed:25015100, ECO:0000269|PubMed:8325892}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22741; Evidence={ECO:0000269|PubMed:11916951, ECO:0000269|PubMed:15277402, ECO:0000269|PubMed:17082186, ECO:0000269|PubMed:18322640, ECO:0000269|PubMed:19146401, ECO:0000269|PubMed:25015100, ECO:0000269|PubMed:8325892};

Catalytic activity: Reaction=ATP + D-fructose = ADP + D-fructose 6-phosphate + H(+); Xref=Rhea:RHEA:16125, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:37721, ChEBI:CHEBI:61527, ChEBI:CHEBI:456216; EC=2.7.1.1; Evidence={ECO:0000269|PubMed:7742312}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16126; Evidence={ECO:0000269|PubMed:7742312};

Catalytic activity: Reaction=ATP + D-glucose = ADP + D-glucose 6-phosphate + H(+); Xref=Rhea:RHEA:17825, ChEBI:CHEBI:4167, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:61548, ChEBI:CHEBI:456216; EC=2.7.1.1; Evidence={ECO:0000269|PubMed:7742312}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17826; Evidence={ECO:0000269|PubMed:7742312};

Catalytic activity: Reaction=ATP + D-mannose = ADP + D-mannose 6-phosphate + H(+); Xref=Rhea:RHEA:11028, ChEBI:CHEBI:4208, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:58735, ChEBI:CHEBI:456216; EC=2.7.1.1; Evidence={ECO:0000269|PubMed:7742312}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11029; Evidence={ECO:0000269|PubMed:7742312};

Activity regulation: Subject to allosteric regulation (PubMed:15016359). Low glucose and high fructose-6-phosphate triggers association with the inhibitor GCKR followed by sequestration in the nucleus (PubMed:10456334). {ECO:0000269|PubMed:10456334, ECO:0000269|PubMed:15016359}.

Pathway: Carbohydrate metabolism; hexose metabolism. {ECO:0000305|PubMed:7742312}.

Pathway: Carbohydrate degradation; glycolysis; D-glyceraldehyde 3- phosphate and glycerone phosphate from D-glucose: step 1/4. {ECO:0000305|PubMed:7742312}.

Subunit: Monomer (PubMed:15016359, PubMed:19362831, PubMed:23957911). Interacts with MIDN; the interaction occurs preferentially at low glucose levels and results in inhibition of hexokinase activity (PubMed:24187134). Interacts with GCKR; leading to sequestration in the nucleus (PubMed:10456334). {ECO:0000269|PubMed:10456334, ECO:0000269|PubMed:15016359, ECO:0000269|PubMed:19362831, ECO:0000269|PubMed:23957911, ECO:0000269|PubMed:24187134}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:10456334, ECO:0000269|PubMed:24187134}. Nucleus {ECO:0000269|PubMed:10456334, ECO:0000269|PubMed:24187134}. Mitochondrion {ECO:0000250|UniProtKB:P17712}. Note=Under low glucose concentrations, GCK associates with GCKR and the inactive complex is recruited to the hepatocyte nucleus. {ECO:0000269|PubMed:10456334}.

Disease: Maturity-onset diabetes of the young 2 (MODY2) [MIM:125851]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269|PubMed:10588527, ECO:0000269|PubMed:10694920, ECO:0000269|PubMed:11106831, ECO:0000269|PubMed:11372010, ECO:0000269|PubMed:1303265, ECO:0000269|PubMed:1464666, ECO:0000269|PubMed:1502186, ECO:0000269|PubMed:16965331, ECO:0000269|PubMed:17573900, ECO:0000269|PubMed:18322640, ECO:0000269|PubMed:19884385, ECO:0000269|PubMed:22611063, ECO:0000269|PubMed:25015100, ECO:0000269|PubMed:8168652, ECO:0000269|PubMed:8325892, ECO:0000269|PubMed:8446612, ECO:0000269|PubMed:8495817, ECO:0000269|PubMed:8878425, ECO:0000269|PubMed:9049484, ECO:0000269|PubMed:9662401}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Familial hyperinsulinemic hypoglycemia 3 (HHF3) [MIM:602485]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. {ECO:0000269|PubMed:11916951, ECO:0000269|PubMed:12941786, ECO:0000269|PubMed:15277402, ECO:0000269|PubMed:17082186, ECO:0000269|PubMed:19884385, ECO:0000269|PubMed:20375417, ECO:0000269|PubMed:28247534, ECO:0000269|PubMed:9435328}. Note=The disease is caused by variants affecting the gene represented in this entry.

Disease: Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:1360036}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.

Disease: Diabetes mellitus, permanent neonatal, 1 (PNDM1) [MIM:606176]: An autosomal recessive form of permanent neonatal diabetes mellitus, a type of diabetes characterized by onset of persistent hyperglycemia within the first six months of life. Initial clinical manifestations include intrauterine growth retardation, hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive. {ECO:0000269|PubMed:11372010, ECO:0000269|PubMed:25015100}. Note=The disease is caused by variants affecting the gene represented in this entry.

Similarity: Belongs to the hexokinase family. {ECO:0000255|PROSITE- ProRule:PRU01084, ECO:0000305}.

Sequence caution: Sequence=AAA67541.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; Sequence=AAA67542.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



Function:		Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively) (PubMed:7742312, PubMed:11916951, PubMed:15277402, PubMed:17082186, PubMed:18322640, PubMed:19146401, PubMed:25015100, PubMed:8325892). Compared to other hexokinases, has a weak affinity for D-glucose, and is effective only when glucose is abundant (By similarity). Mainly expressed in pancreatic beta cells and the liver and constitutes a rate-limiting step in glucose metabolism in these tissues (PubMed:18322640, PubMed:25015100, PubMed:8325892, PubMed:11916951, PubMed:15277402). Since insulin secretion parallels glucose metabolism and the low glucose affinity of GCK ensures that it can change its enzymatic activity within the physiological range of glucose concentrations, GCK acts as a glucose sensor in the pancreatic beta cell (By similarity). In pancreas, plays an important role in modulating insulin secretion (By similarity). In liver, helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage (By similarity). Required to provide D-glucose 6-phosphate for the synthesis of glycogen (PubMed:8878425). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (PubMed:7742312). {ECO:0000250\|UniProtKB:P17712, ECO:0000250\|UniProtKB:P52792, ECO:0000269\|PubMed:11916951, ECO:0000269\|PubMed:15277402, ECO:0000269\|PubMed:17082186, ECO:0000269\|PubMed:18322640, ECO:0000269\|PubMed:19146401, ECO:0000269\|PubMed:25015100, ECO:0000269\|PubMed:7742312, ECO:0000269\|PubMed:8325892, ECO:0000269\|PubMed:8878425}.


Catalytic activity:		Reaction=ATP + D-hexose = ADP + D-hexose 6-phosphate + H(+); Xref=Rhea:RHEA:22740, ChEBI:CHEBI:4194, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:61567, ChEBI:CHEBI:456216; EC=2.7.1.1; Evidence={ECO:0000269\|PubMed:11916951, ECO:0000269\|PubMed:15277402, ECO:0000269\|PubMed:17082186, ECO:0000269\|PubMed:18322640, ECO:0000269\|PubMed:19146401, ECO:0000269\|PubMed:25015100, ECO:0000269\|PubMed:8325892}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22741; Evidence={ECO:0000269\|PubMed:11916951, ECO:0000269\|PubMed:15277402, ECO:0000269\|PubMed:17082186, ECO:0000269\|PubMed:18322640, ECO:0000269\|PubMed:19146401, ECO:0000269\|PubMed:25015100, ECO:0000269\|PubMed:8325892};
Catalytic activity:		Reaction=ATP + D-fructose = ADP + D-fructose 6-phosphate + H(+); Xref=Rhea:RHEA:16125, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:37721, ChEBI:CHEBI:61527, ChEBI:CHEBI:456216; EC=2.7.1.1; Evidence={ECO:0000269\|PubMed:7742312}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16126; Evidence={ECO:0000269\|PubMed:7742312};
Catalytic activity:		Reaction=ATP + D-glucose = ADP + D-glucose 6-phosphate + H(+); Xref=Rhea:RHEA:17825, ChEBI:CHEBI:4167, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:61548, ChEBI:CHEBI:456216; EC=2.7.1.1; Evidence={ECO:0000269\|PubMed:7742312}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17826; Evidence={ECO:0000269\|PubMed:7742312};
Catalytic activity:		Reaction=ATP + D-mannose = ADP + D-mannose 6-phosphate + H(+); Xref=Rhea:RHEA:11028, ChEBI:CHEBI:4208, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:58735, ChEBI:CHEBI:456216; EC=2.7.1.1; Evidence={ECO:0000269\|PubMed:7742312}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:11029; Evidence={ECO:0000269\|PubMed:7742312};
Activity regulation:		Subject to allosteric regulation (PubMed:15016359). Low glucose and high fructose-6-phosphate triggers association with the inhibitor GCKR followed by sequestration in the nucleus (PubMed:10456334). {ECO:0000269\|PubMed:10456334, ECO:0000269\|PubMed:15016359}.
Pathway:		Carbohydrate metabolism; hexose metabolism. {ECO:0000305\|PubMed:7742312}.
Pathway:		Carbohydrate degradation; glycolysis; D-glyceraldehyde 3- phosphate and glycerone phosphate from D-glucose: step 1/4. {ECO:0000305\|PubMed:7742312}.
Subunit:		Monomer (PubMed:15016359, PubMed:19362831, PubMed:23957911). Interacts with MIDN; the interaction occurs preferentially at low glucose levels and results in inhibition of hexokinase activity (PubMed:24187134). Interacts with GCKR; leading to sequestration in the nucleus (PubMed:10456334). {ECO:0000269\|PubMed:10456334, ECO:0000269\|PubMed:15016359, ECO:0000269\|PubMed:19362831, ECO:0000269\|PubMed:23957911, ECO:0000269\|PubMed:24187134}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:10456334, ECO:0000269\|PubMed:24187134}. Nucleus {ECO:0000269\|PubMed:10456334, ECO:0000269\|PubMed:24187134}. Mitochondrion {ECO:0000250\|UniProtKB:P17712}. Note=Under low glucose concentrations, GCK associates with GCKR and the inactive complex is recruited to the hepatocyte nucleus. {ECO:0000269\|PubMed:10456334}.
Disease:		Maturity-onset diabetes of the young 2 (MODY2) [MIM:125851]: A form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease. {ECO:0000269\|PubMed:10588527, ECO:0000269\|PubMed:10694920, ECO:0000269\|PubMed:11106831, ECO:0000269\|PubMed:11372010, ECO:0000269\|PubMed:1303265, ECO:0000269\|PubMed:1464666, ECO:0000269\|PubMed:1502186, ECO:0000269\|PubMed:16965331, ECO:0000269\|PubMed:17573900, ECO:0000269\|PubMed:18322640, ECO:0000269\|PubMed:19884385, ECO:0000269\|PubMed:22611063, ECO:0000269\|PubMed:25015100, ECO:0000269\|PubMed:8168652, ECO:0000269\|PubMed:8325892, ECO:0000269\|PubMed:8446612, ECO:0000269\|PubMed:8495817, ECO:0000269\|PubMed:8878425, ECO:0000269\|PubMed:9049484, ECO:0000269\|PubMed:9662401}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Familial hyperinsulinemic hypoglycemia 3 (HHF3) [MIM:602485]: Most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur. {ECO:0000269\|PubMed:11916951, ECO:0000269\|PubMed:12941786, ECO:0000269\|PubMed:15277402, ECO:0000269\|PubMed:17082186, ECO:0000269\|PubMed:19884385, ECO:0000269\|PubMed:20375417, ECO:0000269\|PubMed:28247534, ECO:0000269\|PubMed:9435328}. Note=The disease is caused by variants affecting the gene represented in this entry.
Disease:		Diabetes mellitus, non-insulin-dependent (NIDDM) [MIM:125853]: A multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269\|PubMed:1360036}. Note=Disease susceptibility is associated with variants affecting the gene represented in this entry.
Disease:		Diabetes mellitus, permanent neonatal, 1 (PNDM1) [MIM:606176]: An autosomal recessive form of permanent neonatal diabetes mellitus, a type of diabetes characterized by onset of persistent hyperglycemia within the first six months of life. Initial clinical manifestations include intrauterine growth retardation, hyperglycemia, glycosuria, osmotic polyuria, severe dehydration, and failure to thrive. {ECO:0000269\|PubMed:11372010, ECO:0000269\|PubMed:25015100}. Note=The disease is caused by variants affecting the gene represented in this entry.
Similarity:		Belongs to the hexokinase family. {ECO:0000255\|PROSITE- ProRule:PRU01084, ECO:0000305}.
Sequence caution:		Sequence=AAA67541.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305}; Sequence=AAA67542.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};