GCK

UniProt ID: P35557
Organism: Homo sapiens
Review Status: INITIALIZED
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Gene Description

Glucokinase (hexokinase-4/HK4, hexokinase type IV) is an ATP-dependent hexose-phosphorylating enzyme (EC 2.7.1.1) expressed mainly in pancreatic beta cells and hepatocytes, where it catalyzes the first committed step of glucose utilization, the phosphorylation of D-glucose to D-glucose 6-phosphate. Unlike the other human hexokinases (HK1-3), glucokinase has a weak affinity for glucose (KM ~6 mM), exhibits sigmoidal/cooperative kinetics, and is not inhibited by its product glucose 6-phosphate. These properties make it the physiological glucose sensor whose activity varies steeply across the normal blood-glucose range; in the pancreatic beta cell it sets the threshold for glucose-stimulated insulin secretion, and in the liver it drives glucose uptake and glycogen synthesis. Hepatic glucokinase is allosterically regulated by the glucokinase regulatory protein (GCKR), which at low glucose binds glucokinase and sequesters the inactive complex in the nucleus, releasing it to the cytosol when glucose rises. Glucokinase can also phosphorylate D-mannose and D-fructose in vitro, but these activities are of minor physiological relevance. Mutations in GCK cause a spectrum of glycemic disorders; heterozygous inactivating mutations cause GCK-MODY (maturity-onset diabetes of the young type 2, mild fasting hyperglycemia), homozygous or biallelic loss causes permanent neonatal diabetes, and heterozygous activating (gain-of-function) mutations cause familial hyperinsulinemic hypoglycemia.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0004340 glucokinase activity
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic (IBA) assertion of the core catalytic function, ATP-dependent phosphorylation of D-glucose to D-glucose 6-phosphate. This is GCK's defining molecular function and is independently confirmed by multiple human EXP/IDA/IMP annotations.
Reason: Glucokinase activity is the well-established core molecular function of GCK, supported by direct biochemical characterization of the purified enzyme and by the entire GCK-MODY/hyperinsulinism disease literature.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Mediates the initial step of glycolysis by catalyzing
GO:0008865 fructokinase activity
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic assertion of fructokinase activity, propagated across the hexokinase family. GCK does phosphorylate D-fructose in vitro, but with very weak affinity (KM ~240 mM) that is far outside any physiological range, so this is a promiscuous side-activity rather than a physiological function.
Reason: A genuine in-vitro substrate promiscuity of the hexokinase family, but the extremely high KM for fructose means it is not a physiologically relevant function of GCK; keep as non-core.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
KM=240 mM for fructose (at 30 degrees Celsius and pH 7.5)
GO:0019158 mannokinase activity
IBA
GO_REF:0000033 		KEEP AS NON CORE
Summary: Phylogenetic assertion of mannokinase activity. GCK phosphorylates D-mannose in vitro with an affinity comparable to glucose (KM ~4.35 mM), but mannose is a quantitatively minor substrate physiologically.
Reason: A genuine in-vitro activity of the hexokinase family; kept as non-core because glucose phosphorylation is the physiologically dominant function.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
KM=4.35 mM for mannose (at 30 degrees Celsius and pH 7.5)
GO:0032473 cytoplasmic side of mitochondrial outer membrane
IBA
GO_REF:0000033 		MARK AS OVER ANNOTATED
Summary: Phylogenetic assertion of localization to the cytoplasmic side of the mitochondrial outer membrane, inherited from the hexokinase family. HK1-3 bind the outer mitochondrial membrane through an N-terminal hydrophobic anchor, but GCK lacks this anchor and is a soluble cytosolic (and regulated nuclear) protein.
Reason: Family-level over-propagation. Mitochondrial outer-membrane association is a property of HK1-3 (which have an N-terminal membrane-binding domain absent from GCK); GCK is documented as cytoplasmic and nuclear, not membrane-anchored.
Propagation Review
Root cause: PROPAGATION BAD
Failure modes: COMPARTMENT OR COMPLEX MISMATCH
Sources checked:
UniProtKB:P52789
Rat hexokinase-1 type; binds outer mitochondrial membrane via an N-terminal hydrophobic anchor that single-domain GCK lacks, so the compartment does not transfer correctly.
UniProtKB:M4FD55
Hexokinase-family source for the mitochondrial-membrane IBA; anchor-bearing, unlike cytosolic/nuclear GCK.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0006096 glycolytic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assertion that GCK participates in glycolysis. GCK catalyzes the first, committed step of the glycolytic pathway (glucose to glucose 6-phosphate), which is well established.
Reason: Glucokinase catalyzes step 1 of glycolysis; this is a core biological process for the gene.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Mediates the initial step of glycolysis by catalyzing
GO:0005829 cytosol
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assertion of cytosolic localization, consistent with human HPA immunofluorescence (IDA) and the well-documented cytosolic location of active glucokinase.
Reason: Glucokinase is a cytosolic enzyme (with regulated nuclear sequestration in hepatocytes); cytosol is its principal site of catalytic action.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0006006 glucose metabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assertion that GCK participates in glucose metabolism. As the enzyme catalyzing the rate-limiting first step of glucose utilization in liver and beta cells, this is a core biological process.
Reason: Glucokinase is a rate-limiting determinant of glucose metabolism in liver and pancreatic beta cells.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
rate-limiting step in glucose metabolism in these tissues
GO:0051156 glucose 6-phosphate metabolic process
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assertion linking GCK to glucose 6-phosphate metabolism. GCK produces glucose 6-phosphate, so it directly contributes to G6P metabolism; this is corroborated by human IMP annotations.
Reason: The product of the GCK reaction is glucose 6-phosphate; participation in G6P metabolic process is a direct and accurate consequence of its activity.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
phosphorylation of D-glucose to D-glucose 6-phosphate
GO:0001678 intracellular glucose homeostasis
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assertion that GCK contributes to intracellular glucose homeostasis, consistent with its role as the glucose sensor controlling hepatic glucose uptake and beta-cell insulin secretion.
Reason: As the tissue glucose sensor, GCK is a central determinant of cellular and whole-body glucose homeostasis.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
GCK acts as a glucose sensor in the pancreatic beta
GO:0050796 regulation of insulin secretion
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic assertion that GCK regulates insulin secretion. In the beta cell, glucokinase sets the threshold for glucose-stimulated insulin secretion, confirmed by human IMP studies of GCK mutation carriers.
Reason: Beta-cell glucokinase controls the glucose threshold for insulin secretion; supported by both phylogenetic inference and human physiology studies.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
modulating insulin secretion
GO:0001678 intracellular glucose homeostasis
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro2GO electronic mapping of the hexokinase domain to intracellular glucose homeostasis. Redundant with the curated IBA annotation to the same term and consistent with GCK's role as the glucose sensor.
Reason: Accurate for GCK; duplicate of the curated intracellular glucose homeostasis annotation.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
GCK acts as a glucose sensor in the pancreatic beta
GO:0004396 hexokinase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic assignment of the parent hexokinase activity (EC 2.7.1.1) term. GCK is hexokinase-4, so hexokinase activity is correct, though glucokinase activity (GO:0004340) is the more specific and preferred term.
Reason: Correct broader molecular-function term; GCK is a bona fide hexokinase (EC 2.7.1.1). Retained as an accurate parent of the specific glucokinase activity.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Catalyzes the phosphorylation of hexose, such as D-glucose,
GO:0005524 ATP binding
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based electronic assignment of ATP binding. ATP is the phosphate donor co-substrate of glucokinase and ATP binding is directly demonstrated by human IDA annotations and crystal structures with bound ATP analog.
Reason: GCK binds ATP as its phosphoryl-donor substrate; well supported by structure and IDA.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
KM=4.5 mM for ATP (at pH 7)
GO:0005536 D-glucose binding
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based electronic assignment of D-glucose binding, the substrate-binding function of glucokinase, corroborated by human IDA annotations and glucose-bound crystal structures.
Reason: Glucose binding is a core molecular activity of GCK, directly demonstrated experimentally.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
COMPLEX WITH GLUCOSE
GO:0005634 nucleus
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic assignment of nuclear localization. In hepatocytes, glucokinase is sequestered in the nucleus in complex with GCKR at low glucose, so this location is real but conditional/regulated. Corroborated by human EXP annotations.
Reason: Regulated nuclear sequestration of hepatic GCK by GCKR is well documented; the nuclear location is genuine although condition-dependent.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
the inactive complex is recruited to the
GO:0005737 cytoplasm
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic assignment of cytoplasmic localization, the principal compartment of active glucokinase. Corroborated by human EXP annotations and HPA immunofluorescence.
Reason: Cytoplasm/cytosol is the main site of active GCK; well supported.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005739 mitochondrion
IEA
GO_REF:0000120 		MARK AS OVER ANNOTATED
Summary: Electronic assignment of mitochondrial localization. This is inherited from the hexokinase family / by-similarity from HK1-type orthologs; mitochondrial outer-membrane binding is a property of HK1-3 that have an N-terminal membrane anchor absent from GCK, which is cytosolic and nuclear.
Reason: GCK lacks the N-terminal mitochondrial-binding anchor of HK1-3; the mitochondrial annotation is a family/by-similarity over-propagation rather than a GCK-specific location.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005975 carbohydrate metabolic process
IEA
GO_REF:0000002 		ACCEPT
Summary: InterPro-based electronic assignment of the broad carbohydrate metabolic process term. Accurate but general; more specific glucose metabolic/glycolytic terms are annotated.
Reason: Correct high-level process term; a valid parent of the more specific glucose metabolism annotations.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Carbohydrate metabolism; hexose metabolism
GO:0006006 glucose metabolic process
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA machine-learning electronic assignment of glucose metabolic process, redundant with the curated IBA annotation and accurate for GCK.
Reason: Correct; duplicate of the curated glucose metabolic process annotation.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
rate-limiting step in glucose metabolism in these tissues
GO:0006096 glycolytic process
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic assignment of glycolytic process via UniPathway mapping, redundant with the curated IBA annotation. GCK catalyzes the first step of glycolysis.
Reason: Correct; duplicate of the curated glycolytic process annotation.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Mediates the initial step of glycolysis by catalyzing
GO:0006163 purine nucleotide metabolic process
IEA
GO_REF:0000117 		MARK AS OVER ANNOTATED
Summary: ARBA electronic assignment of purine nucleotide metabolic process. This almost certainly derives from GCK using ATP (a purine nucleotide) as co-substrate; consuming ATP as a phosphate donor does not make GCK a participant in purine nucleotide metabolism.
Reason: Over-interpretation of ATP co-substrate usage. GCK does not metabolize purine nucleotides; ATP is a universal phosphoryl donor and this term misrepresents the gene's biological role.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
a D-hexose + ATP = a D-hexose 6-phosphate + ADP
GO:0008865 fructokinase activity
IEA
GO_REF:0000116 		KEEP AS NON CORE
Summary: RHEA-based electronic assignment of fructokinase activity (D-fructose + ATP reaction). Same weak in-vitro promiscuous activity as the IBA/EXP fructokinase annotations (KM ~240 mM), not physiologically relevant.
Reason: Genuine in-vitro side-activity but physiologically negligible due to the very high KM for fructose.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Reaction=D-fructose + ATP = D-fructose 6-phosphate + ADP
GO:0019158 mannokinase activity
IEA
GO_REF:0000116 		KEEP AS NON CORE
Summary: RHEA-based electronic assignment of mannokinase activity (D-mannose + ATP reaction). GCK phosphorylates mannose in vitro, but this is a minor physiological substrate.
Reason: Genuine in-vitro activity but not the physiologically dominant function of GCK.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Reaction=D-mannose + ATP = D-mannose 6-phosphate + ADP
GO:0032024 positive regulation of insulin secretion
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA electronic assignment of positive regulation of insulin secretion, redundant with the human IMP annotations. Glucokinase drives glucose-stimulated insulin secretion in the beta cell.
Reason: Correct; duplicate of curated IMP annotations for positive regulation of insulin secretion.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
modulating insulin secretion
GO:0042593 glucose homeostasis
IEA
GO_REF:0000117 		ACCEPT
Summary: ARBA electronic assignment of glucose homeostasis, redundant with the human IMP annotations. GCK is a central determinant of whole-body glucose homeostasis.
Reason: Correct; duplicate of curated glucose homeostasis annotations.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
insulin-sensitive determinant of hepatic glucose usage
GO:0046496 nicotinamide nucleotide metabolic process
IEA
GO_REF:0000117 		REMOVE
Summary: ARBA electronic assignment of nicotinamide nucleotide (NAD/NADP) metabolic process. GCK has no role in NAD/NADP metabolism; its reaction consumes ATP and produces glucose 6-phosphate, and this term appears to be a spurious machine-learning mapping.
Reason: Demonstrably wrong electronic inference. Glucokinase does not participate in nicotinamide nucleotide (NAD/NADP) metabolism; there is no biochemical basis for this ARBA mapping, which should be removed.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
a D-hexose + ATP = a D-hexose 6-phosphate + ADP
GO:0005515 protein binding
IPI
PMID:11522786
Characterization of glucokinase-binding protein epitopes by ... 		MARK AS OVER ANNOTATED
Summary: IntAct binary-interaction annotation. PMID:11522786 identified PFKFB1 (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) as a glucokinase interaction partner via phage-display and yeast two-hybrid. The interaction is real and biologically interesting, but the generic protein binding term is uninformative as a molecular function.
Reason: Per curation guidelines, bare protein binding (GO:0005515) is not an informative molecular function. The underlying PFKFB1 (and GCKR) interaction is captured in the gene description/notes; the IPI itself is retained but flagged as over-annotated.
Supporting Evidence:
PMID:11522786
The second consensus motif, SLKVWT, showed a complete homology to the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		MARK AS OVER ANNOTATED
Summary: IntAct binary-interaction annotation from the HuRI human interactome map (PMID:32296183), a high-throughput yeast two-hybrid screen. The generic protein binding term does not convey a specific molecular function.
Reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines; derived from a proteome-scale binary interactome screen. Retained but flagged as over-annotated.
Supporting Evidence:
PMID:32296183
a human 'all-by-all' reference interactome map of human binary protein interactions, or 'HuRI'
GO:0004340 glucokinase activity
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic (RHEA/UniProt combined) assignment of glucokinase activity, the specific EC 2.7.1.1 D-glucose + ATP reaction. Redundant with the many curated EXP/IDA/IMP/IBA glucokinase activity annotations.
Reason: Correct and specific core molecular function; duplicate of curated glucokinase activity annotations.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Reaction=D-glucose + ATP = D-glucose 6-phosphate + ADP
GO:0005829 cytosol
IEA
GO_REF:0000107 		ACCEPT
Summary: Ensembl-projected electronic assignment of cytosolic localization from the mouse ortholog. Consistent with the human IDA (HPA) and IBA cytosol annotations.
Reason: Cytosol is the principal location of active glucokinase; well supported across multiple evidence lines.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0070509 calcium ion import
IEA
GO_REF:0000107 		MARK AS OVER ANNOTATED
Summary: Ensembl-projected electronic annotation of calcium ion import from the mouse ortholog. Glucokinase is a cytosolic kinase with no transport activity; any link to calcium import would be an indirect downstream consequence of glucose-stimulated insulin secretion physiology, not a function of GCK itself.
Reason: Over-propagated electronic inference. GCK does not import calcium; this is at best an indirect, distal physiological association projected from the ortholog and does not represent a molecular activity or direct process role of GCK.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Catalyzes the phosphorylation of hexose, such as D-glucose,
GO:0061621 canonical glycolysis
TAS
Reactome:R-HSA-70171 		ACCEPT
Summary: Reactome traceable-author-statement annotation placing GCK in canonical glycolysis (the Glycolysis pathway). GCK catalyzes the committed first step of glucose catabolism via glycolysis.
Reason: GCK performs the first step of glycolysis; canonical glycolysis is an accurate, curator-asserted process.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Mediates the initial step of glycolysis by catalyzing
GO:0019318 hexose metabolic process
IEA
GO_REF:0000041 		ACCEPT
Summary: UniPathway-based electronic assignment of hexose metabolic process. GCK phosphorylates hexoses (glucose, mannose, fructose) as the entry step of hexose utilization; accurate but general.
Reason: Correct high-level process; a valid parent of the more specific glucose metabolic process annotations.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Carbohydrate metabolism; hexose metabolism
GO:0004340 glucokinase activity
TAS
Reactome:R-HSA-5621918 		ACCEPT
Summary: Reactome TAS annotation of glucokinase activity, from the reaction describing defective GCK failing to phosphorylate glucose to G6P. Correct core molecular function.
Reason: Curator-traceable assertion of the core glucokinase activity; consistent with all other evidence.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Reaction=D-glucose + ATP = D-glucose 6-phosphate + ADP
GO:0004340 glucokinase activity
TAS
Reactome:R-HSA-70420 		ACCEPT
Summary: Reactome TAS annotation of glucokinase activity, from the reaction in which HK1,2,3,GCK,HKDC1 phosphorylate glucose to form G6P. Correct core molecular function.
Reason: Curator-traceable assertion of the core glucokinase activity.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Reaction=D-glucose + ATP = D-glucose 6-phosphate + ADP
GO:0005829 cytosol
IDA
GO_REF:0000052 		ACCEPT
Summary: Human Protein Atlas immunofluorescence (IDA) localizing GCK to the cytosol. This is a direct human experimental localization consistent with the enzyme's soluble cytosolic nature.
Reason: Direct immunofluorescence evidence for cytosolic localization; the principal compartment of active glucokinase.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0004340 glucokinase activity
EXP
PMID:7742312
Sugar specificity of human beta-cell glucokinase: correlatio... 		ACCEPT
Summary: Steady-state kinetic characterization of purified human beta-cell glucokinase phosphorylating glucose (and other sugars), establishing its glucokinase activity and the diagnostic weak glucose affinity (KM ~6 mM) with cooperative kinetics.
Reason: Direct experimental demonstration of glucokinase activity on the human enzyme; a primary source for the core molecular function.
Supporting Evidence:
PMID:7742312
glucokinase phosphorylated the sugars in the order glucose = mannose > deoxyglucose > fructose = glucosamine
GO:0004396 hexokinase activity
EXP
PMID:11916951
The second activating glucokinase mutation (A456V): implicat... 		ACCEPT
Summary: Functional characterization of an activating GCK mutant (A456V) using the purified recombinant enzyme, measuring glucose phosphorylation kinetics (glucose S0.5, kcat). Confirms hexokinase/glucokinase activity of human GCK.
Reason: Experimental measurement of GCK glucose-phosphorylating (hexokinase) activity on the purified human enzyme.
Supporting Evidence:
PMID:11916951
The purified recombinant glutathionyl S-transferase fusion protein of the A456V glucokinase revealed a decreased glucose S(0.5)
GO:0004396 hexokinase activity
EXP
PMID:15277402
Severe persistent hyperinsulinemic hypoglycemia due to a de ... 		ACCEPT
Summary: Functional study of the activating GCK-Y214C mutant, measuring glucose affinity, cooperativity and kcat of the purified enzyme, confirming GCK's glucose-phosphorylating (hexokinase) activity.
Reason: Experimental measurement of GCK enzymatic activity on the purified human enzyme; supports the hexokinase/glucokinase molecular function.
Supporting Evidence:
PMID:15277402
Functional studies of purified recombinant glutathionyl S-transferase fusion protein of GK-Y214C showed a sixfold increase in its affinity for glucose
GO:0004396 hexokinase activity
EXP
PMID:17082186
Biochemical basis of glucokinase activation and the regulati... 		ACCEPT
Summary: Transient-kinetics analysis of glucose binding and turnover for wild-type and activating GCK mutants, characterizing the enzyme's glucose-phosphorylating activity and its GKRP regulation.
Reason: Direct kinetic characterization of GCK hexokinase activity on purified enzyme.
Supporting Evidence:
PMID:17082186
the transient kinetics of glucose binding for activating mutations follows a general two-step mechanism
GO:0004396 hexokinase activity
EXP
PMID:18322640
Biochemical characterization of novel glucokinase mutations ... 		ACCEPT
Summary: Biochemical characterization of six MODY2 GCK mutants showing reduced enzymatic activity, based on assays of the recombinant enzyme; confirms GCK's glucose-phosphorylating (hexokinase) activity.
Reason: Experimental enzyme-activity assays of human GCK; supports the hexokinase/glucokinase molecular function.
Supporting Evidence:
PMID:18322640
All these mutations produced enzymes that presented reduced enzymatic activity in various degrees
GO:0004396 hexokinase activity
EXP
PMID:19146401
Activating mutations in the human glucokinase gene revealed ... 		ACCEPT
Summary: Identification and kinetic characterization of 11 activating GCK mutations, reporting kcat/K0.5 for glucose on the recombinant enzyme; confirms GCK's glucose-phosphorylating (hexokinase) activity.
Reason: Experimental measurement of GCK glucose-phosphorylating activity on the human enzyme.
Supporting Evidence:
PMID:19146401
I211F is the most active variant identified to date, with a k(cat)/K(0.5,glucose) value
GO:0004396 hexokinase activity
EXP
PMID:25015100
Phenotypic severity of homozygous GCK mutations causing neon... 		ACCEPT
Summary: Kinetic and thermostability analysis of 16 homozygous GCK missense mutants (relative activity index), assaying the recombinant human enzyme's glucose-phosphorylating activity.
Reason: Experimental enzyme-activity measurement on purified human GCK; supports the hexokinase/glucokinase molecular function.
Supporting Evidence:
PMID:25015100
Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index
GO:0004396 hexokinase activity
EXP
PMID:8325892
Structure/function studies of human beta-cell glucokinase. E... 		ACCEPT
Summary: Structure/function study expressing native and mutant human beta-cell glucokinase and measuring Vmax and Km for glucose, directly characterizing GCK's glucose-phosphorylating (hexokinase) activity.
Reason: Direct experimental characterization of GCK enzymatic activity on the human enzyme.
Supporting Evidence:
PMID:8325892
a Vmax that was 20-100% of normal but a Km for glucose that was 8-14-fold greater than the native enzyme
GO:0005634 nucleus
EXP
PMID:10456334
Glucokinase regulatory protein is essential for the proper s... 		ACCEPT
Summary: Experimental demonstration that liver glucokinase concentrates in the nucleus of hepatocytes at low glucose, in a GCKR-dependent manner. Establishes the regulated nuclear localization of hepatic GCK.
Reason: Direct experimental evidence for regulated nuclear localization of GCK via GCKR binding; genuine although condition-dependent.
Supporting Evidence:
PMID:10456334
concentrated in the nucleus of cultured rat hepatocytes at low glucose and translocated to the cytoplasm at high glucose
GO:0005634 nucleus
EXP
PMID:24187134
Identification of the ubiquitin-like domain of midnolin as a... 		ACCEPT
Summary: Fluorescence-microscopy study of GCK and its interaction partner midnolin in pancreatic beta cells, consistent with a nuclear/cytoplasmic distribution of glucokinase.
Reason: Supports nuclear (and cytoplasmic) localization of GCK; consistent with its regulated subcellular distribution.
Supporting Evidence:
PMID:24187134
revealed localization of midnolin in nucleus and cytoplasm and co-localization with glucokinase in pancreatic beta cells
GO:0005737 cytoplasm
EXP
PMID:10456334
Glucokinase regulatory protein is essential for the proper s... 		ACCEPT
Summary: Experimental demonstration that liver glucokinase translocates to the cytoplasm at high glucose, establishing cytoplasm as the compartment of active hepatic GCK.
Reason: Direct experimental evidence for cytoplasmic localization of active GCK.
Supporting Evidence:
PMID:10456334
concentrated in the nucleus of cultured rat hepatocytes at low glucose and translocated to the cytoplasm at high glucose
GO:0005737 cytoplasm
EXP
PMID:24187134
Identification of the ubiquitin-like domain of midnolin as a... 		ACCEPT
Summary: Fluorescence-microscopy evidence for cytoplasmic (and nuclear) localization of glucokinase in pancreatic beta cells.
Reason: Supports cytoplasmic localization of GCK; consistent with the enzyme's soluble cytosolic nature.
Supporting Evidence:
PMID:24187134
revealed localization of midnolin in nucleus and cytoplasm and co-localization with glucokinase in pancreatic beta cells
GO:0005739 mitochondrion
ISS
GO_REF:0000024 		MARK AS OVER ANNOTATED
Summary: ISS transfer of mitochondrial localization from an ortholog (UniProtKB:P17712, rat hexokinase). Mitochondrial outer-membrane binding is a documented property of HK1-3 (which have an N-terminal membrane anchor) but not of GCK, which lacks this anchor and is cytosolic/nuclear.
Reason: The ISS source is a membrane-anchored hexokinase; GCK lacks the N-terminal mitochondrial-binding domain, so mitochondrial localization is a family-level over-transfer rather than a GCK-specific location.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0008865 fructokinase activity
EXP
PMID:7742312
Sugar specificity of human beta-cell glucokinase: correlatio... 		KEEP AS NON CORE
Summary: Kinetic measurements showing purified human beta-cell glucokinase phosphorylates D-fructose in vitro, but with very weak affinity (KM ~240 mM), far above any physiological fructose concentration.
Reason: A genuine, experimentally measured in-vitro activity, but physiologically negligible given the extremely high KM for fructose; kept as non-core.
Supporting Evidence:
PMID:7742312
glucokinase phosphorylated the sugars in the order glucose = mannose > deoxyglucose > fructose = glucosamine
GO:0019158 mannokinase activity
EXP
PMID:7742312
Sugar specificity of human beta-cell glucokinase: correlatio... 		KEEP AS NON CORE
Summary: Kinetic measurements showing purified human beta-cell glucokinase phosphorylates D-mannose in vitro with an affinity comparable to glucose (KM ~4.35 mM), a genuine but quantitatively minor physiological substrate.
Reason: An experimentally measured in-vitro activity of GCK; kept as non-core because glucose is the physiologically dominant substrate.
Supporting Evidence:
PMID:7742312
glucokinase phosphorylated the sugars in the order glucose = mannose > deoxyglucose > fructose = glucosamine
GO:0009749 response to glucose
ISS
GO_REF:0000024 		ACCEPT
Summary: ISS transfer of response to glucose from an ortholog. GCK function and protein level are modulated by glucose (glucose promotes the active cytosolic state and stabilizes the enzyme), so involvement in the cellular response to glucose is biologically reasonable.
Reason: Consistent with GCK's role as a glucose sensor whose activity, localization and stability respond to glucose; a reasonable orthology-based transfer.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
is effective only when glucose is abundant
GO:0141089 glucose sensor activity
ISS
GO_REF:0000024 		ACCEPT
Summary: ISS transfer of the specific molecular-function term glucose sensor activity. This precisely captures GCK's defining physiological role, its weak glucose affinity and cooperative kinetics allow it to function as the cellular glucose sensor setting the threshold for insulin secretion and hepatic glucose uptake.
Reason: Glucose sensor activity is the most specific and biologically apt molecular-function term for GCK; strongly supported by its kinetic properties and physiology.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
GCK acts as a glucose sensor in the pancreatic beta
GO:0006007 glucose catabolic process
IMP
PMID:12941786
Insights into the biochemical and genetic basis of glucokina... 		ACCEPT
Summary: IMP annotation from characterization of an activating hypoglycemia mutation (T65I) showing GCK catalyzes the rate-limiting step of beta-cell glucose metabolism/catabolism. GCK initiates glucose catabolism via glycolysis.
Reason: GCK performs the committed, rate-limiting first step of glucose catabolism; supported by mutation phenotype analysis.
Supporting Evidence:
PMID:12941786
catalyzes the rate-limiting step for beta-cell glucose metabolism
GO:0004340 glucokinase activity
IMP
PMID:19146401
Activating mutations in the human glucokinase gene revealed ... 		ACCEPT
Summary: IMP annotation of glucokinase activity based on activating GCK mutations that alter the enzyme's glucose-phosphorylating kinetics (measured as kcat/K0.5,glucose).
Reason: Mutation-based evidence directly tying sequence changes to altered glucokinase activity; core molecular function.
Supporting Evidence:
PMID:19146401
I211F is the most active variant identified to date, with a k(cat)/K(0.5,glucose) value
GO:0051156 glucose 6-phosphate metabolic process
IMP
PMID:19146401
Activating mutations in the human glucokinase gene revealed ... 		ACCEPT
Summary: IMP annotation linking GCK to glucose 6-phosphate metabolic process, based on activating mutations altering the glucose-phosphorylating (G6P-producing) activity of the enzyme.
Reason: GCK produces glucose 6-phosphate; mutation effects on its activity directly support participation in G6P metabolism.
Supporting Evidence:
PMID:19146401
activating mutations in the human glk gene
GO:0004340 glucokinase activity
IMP
PMID:18322640
Biochemical characterization of novel glucokinase mutations ... 		ACCEPT
Summary: IMP annotation of glucokinase activity from biochemical characterization of MODY2 mutants that reduce the enzyme's activity to varying degrees.
Reason: Mutation-phenotype evidence directly linking GCK sequence to glucokinase activity; core molecular function.
Supporting Evidence:
PMID:18322640
All these mutations produced enzymes that presented reduced enzymatic activity in various degrees
GO:0051156 glucose 6-phosphate metabolic process
IMP
PMID:18322640
Biochemical characterization of novel glucokinase mutations ... 		ACCEPT
Summary: IMP annotation linking GCK to glucose 6-phosphate metabolic process based on MODY2 mutations reducing its G6P-producing enzymatic activity.
Reason: The GCK product is glucose 6-phosphate; mutation effects on activity support participation in G6P metabolism.
Supporting Evidence:
PMID:18322640
mutations in the glucokinase (GCK) gene that result in impaired glucokinase activity
GO:0004340 glucokinase activity
IDA
PMID:22611063
Insights into the pathogenicity of rare missense GCK variant... 		ACCEPT
Summary: IDA of glucokinase activity from spectrophotometric G6P-dehydrogenase-coupled assays of GST-tagged wild-type and mutant human GCK proteins.
Reason: Direct in-vitro assay of GCK glucose-phosphorylating activity on the purified human enzyme; core molecular function.
Supporting Evidence:
PMID:22611063
GCK activity was measured spectrophotometrically using glucose 6-phosphate dehydrogenase-coupled assays
GO:0005829 cytosol
TAS
Reactome:R-HSA-5621918 		ACCEPT
Summary: Reactome TAS annotation of cytosolic localization, consistent with the cytosolic location of active glucokinase.
Reason: Cytosol is the principal compartment of active GCK; curator-traceable assertion consistent with all other evidence.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-170796 		ACCEPT
Summary: Reactome TAS annotation of nucleoplasmic localization, from the reaction transporting the GCK1:GCKR complex from cytosol to nucleoplasm. Reflects the regulated nuclear sequestration of hepatic GCK bound to GCKR at low glucose.
Reason: Consistent with documented GCKR-dependent nuclear sequestration of hepatic glucokinase; genuine although condition-dependent.
Supporting Evidence:
PMID:10456334
concentrated in the nucleus of cultured rat hepatocytes at low glucose and translocated to the cytoplasm at high glucose
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-170810 		ACCEPT
Summary: Reactome TAS annotation of nucleoplasmic localization, from the reaction dissociating the nucleoplasmic GCK1:GCKR complex. Reflects regulated nuclear sequestration of hepatic GCK.
Reason: Consistent with GCKR-dependent nuclear sequestration of hepatic glucokinase.
Supporting Evidence:
PMID:10456334
concentrated in the nucleus of cultured rat hepatocytes at low glucose and translocated to the cytoplasm at high glucose
GO:0005654 nucleoplasm
TAS
Reactome:R-HSA-170825 		ACCEPT
Summary: Reactome TAS annotation of nucleoplasmic localization, from the reaction exporting GCK1 from the nucleus. Reflects the regulated nuclear/cytosolic shuttling of hepatic GCK.
Reason: Consistent with the documented regulated nuclear localization/export of hepatic glucokinase via GCKR.
Supporting Evidence:
PMID:10456334
concentrated in the nucleus of cultured rat hepatocytes at low glucose and translocated to the cytoplasm at high glucose
GO:0005829 cytosol
TAS
Reactome:R-HSA-170796 		ACCEPT
Summary: Reactome TAS annotation of cytosolic localization, from the reaction transporting GCK1:GCKR from cytosol to nucleoplasm; the cytosol is the origin compartment for active glucokinase.
Reason: Cytosol is the principal compartment of active GCK; consistent with all other localization evidence.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-170799 		ACCEPT
Summary: Reactome TAS annotation of cytosolic localization, from the reaction describing the cytosolic GCK1:GKRP complex equilibrium.
Reason: Cytosolic location of GCK; curator-traceable and consistent with other evidence.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-170824 		ACCEPT
Summary: Reactome TAS annotation of cytosolic localization, from the reaction forming the GCK1:GKRP complex from cytosolic glucokinase and GKRP.
Reason: Cytosolic location of GCK; consistent with other localization evidence.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-170825 		ACCEPT
Summary: Reactome TAS annotation of cytosolic localization, from the reaction exporting GCK1 from the nucleus back to the cytosol.
Reason: Cytosolic location of active GCK; consistent with the regulated nuclear/cytosolic shuttling of hepatic glucokinase.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-5661474 		ACCEPT
Summary: Reactome TAS annotation of cytosolic localization, from the (disease) reaction of defective nuclear pore transport of GCK1:GKRP; cytosol is the origin compartment.
Reason: Cytosolic location of GCK; consistent with other localization evidence.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0005829 cytosol
TAS
Reactome:R-HSA-70420 		ACCEPT
Summary: Reactome TAS annotation of cytosolic localization, from the reaction in which HK1,2,3,GCK,HKDC1 phosphorylate glucose to G6P in the cytosol.
Reason: Cytosol is the site where GCK phosphorylates glucose; consistent with all other evidence.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
SUBCELLULAR LOCATION: Cytoplasm
GO:0006110 regulation of glycolytic process
NAS
PMID:9570959
Organization of the human glucokinase regulator gene GCKR. 		ACCEPT
Summary: NAS annotation citing a paper on the GCKR gene structure, asserting that glucokinase regulates insulin secretion in response to blood glucose. As the rate-limiting, flux-controlling enzyme of glucose entry into glycolysis in liver and beta cells, GCK regulates glycolytic flux.
Reason: GCK is the flux-controlling first enzyme of glycolysis in its tissues, so regulation of glycolytic process is a reasonable, non-experimental (NAS) assertion of its role.
Supporting Evidence:
PMID:9570959
Glucokinase plays an important role in regulating insulin secretion in response to changes in blood glucose levels
GO:0032869 cellular response to insulin stimulus
ISS
GO_REF:0000024 		ACCEPT
Summary: ISS transfer of cellular response to insulin stimulus from an ortholog. In the liver, GCK expression is induced by insulin (insulin-dependent regulation via the alternative liver promoter), so its expression/activity responds to insulin.
Reason: Hepatic GCK is insulin-regulated (insulin induces liver GCK); a reasonable orthology-based transfer consistent with UniProt.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
hexokinase gene to be regulated by insulin in the liver
GO:0042593 glucose homeostasis
IMP
PMID:20668700
Effects of GCK, GCKR, G6PC2 and MTNR1B variants on glucose m... 		ACCEPT
Summary: IMP annotation from a genetic-association study showing common GCK variants (rs1799884) modulate fasting glucose and insulin secretion, supporting GCK's role in glucose homeostasis.
Reason: Human genetic variation in GCK affects fasting glucose levels, consistent with GCK being a determinant of glucose homeostasis.
Supporting Evidence:
PMID:20668700
GCK, G6PC2 and MTNR1B variants modulated fasting glucose levels
GO:0044320 cellular response to leptin stimulus
ISS
GO_REF:0000024 		MARK AS OVER ANNOTATED
Summary: ISS transfer of cellular response to leptin stimulus from an ortholog (UniProtKB:P17712). There is no direct human evidence that GCK participates in leptin signaling; this is a distal orthology-based association rather than a direct molecular role of glucokinase.
Reason: Weakly supported ISS transfer. No direct evidence for a GCK role in leptin response in the cited human record; treated as an over-annotation pending experimental support.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
Catalyzes the phosphorylation of hexose, such as D-glucose,
GO:0050796 regulation of insulin secretion
IMP
PMID:20668700
Effects of GCK, GCKR, G6PC2 and MTNR1B variants on glucose m... 		ACCEPT
Summary: IMP annotation from a genetic-association study showing GCK variants affect first- and second-phase insulin secretion, supporting GCK's role in regulating insulin secretion.
Reason: Human GCK genetic variation affects insulin secretion phases, consistent with beta-cell GCK regulating insulin secretion.
Supporting Evidence:
PMID:20668700
GCK and G6PC2 genetic variants were associated to both first- and second-phases insulin secretion
GO:0004340 glucokinase activity
IDA
PMID:16173921
Effects of novel maturity-onset diabetes of the young (MODY)... 		ACCEPT
Summary: IDA of glucokinase activity from enzymatic assays of affinity-purified recombinant human islet GCK (wild-type and MODY2 mutants), directly measuring the glucose-phosphorylating activity.
Reason: Direct in-vitro enzyme assays of purified human GCK; core molecular function.
Supporting Evidence:
PMID:16173921
Enzymatic assays on the recombinant proteins revealed that mutations Thr206-->Met and Leu165-->Phe strongly affect the kinetic parameters of glucokinase
GO:0005515 protein binding
IPI
PMID:16173921
Effects of novel maturity-onset diabetes of the young (MODY)... 		MARK AS OVER ANNOTATED
Summary: IPI annotation. This paper tested the interaction of GCK MODY2 mutants with the glucokinase regulatory protein (GKRP/GCKR) in a yeast two-hybrid system. The generic protein binding term is uninformative as a molecular function.
Reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines. The specific GCK-GCKR interaction is a well-established, biologically important relationship captured in the description/notes; the IPI is retained but flagged.
Supporting Evidence:
PMID:16173921
none of the mutations tested appears to affect the interaction of gluco-kinase with the glucokinase regulatory protein in the yeast two-hybrid system
GO:0005524 ATP binding
IDA
PMID:16173921
Effects of novel maturity-onset diabetes of the young (MODY)... 		ACCEPT
Summary: IDA of ATP binding, inferred from enzymatic assays of the purified recombinant GCK using ATP as the phosphoryl-donor co-substrate. ATP binding is also documented structurally.
Reason: GCK binds ATP as its co-substrate; supported by kinetic assays and structural studies.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
KM=4.5 mM for ATP (at pH 7)
GO:0005536 D-glucose binding
IDA
PMID:16173921
Effects of novel maturity-onset diabetes of the young (MODY)... 		ACCEPT
Summary: IDA of D-glucose binding from kinetic assays of purified recombinant GCK measuring glucose-dependent activity; glucose binding is the substrate-recognition function of glucokinase.
Reason: Glucose binding is a core molecular activity of GCK, directly supported by enzyme kinetics and glucose-bound structures.
Supporting Evidence:
PMID:16173921
mutations Thr206-->Met and Leu165-->Phe strongly affect the kinetic parameters of glucokinase, in agreement with the localization of both residues close to the active site
GO:0032024 positive regulation of insulin secretion
IMP
PMID:8878425
Impaired hepatic glycogen synthesis in glucokinase-deficient... 		ACCEPT
Summary: IMP annotation from a study of glucokinase-deficient (MODY2) subjects. Impaired GCK reduces insulin secretion, indicating GCK positively regulates glucose-stimulated insulin secretion.
Reason: Loss of GCK function impairs insulin secretion in human subjects; GCK positively regulates insulin secretion.
Supporting Evidence:
PMID:8878425
impaired insulin secretion has been observed in glucokinase-deficient subjects
GO:0045721 negative regulation of gluconeogenesis
IMP
PMID:8878425
Impaired hepatic glycogen synthesis in glucokinase-deficient... 		ACCEPT
Summary: IMP annotation. In glucokinase-deficient (MODY2) subjects, hepatic gluconeogenesis after meals was relatively augmented, implying that normal hepatic GCK activity suppresses gluconeogenic flux.
Reason: MODY2 subjects show augmented hepatic gluconeogenesis, so functional GCK normally restrains gluconeogenesis; a documented hepatic role.
Supporting Evidence:
PMID:8878425
glucokinase-deficient subjects have decreased net accumulation of hepatic glycogen and relatively augmented hepatic gluconeogenesis after meals
GO:0045725 positive regulation of glycogen biosynthetic process
IMP
PMID:8878425
Impaired hepatic glycogen synthesis in glucokinase-deficient... 		ACCEPT
Summary: IMP annotation. Glucokinase-deficient (MODY2) subjects have decreased net hepatic glycogen accumulation after meals, showing that hepatic GCK is required to provide G6P for and to promote glycogen synthesis.
Reason: Loss of GCK reduces hepatic glycogen synthesis; GCK positively regulates glycogen biosynthesis by providing glucose 6-phosphate.
Supporting Evidence:
PMID:8878425
the net increment in hepatic glycogen content after each meal was 30-60% lower in glucokinase-deficient than in the control subjects
GO:0004340 glucokinase activity
IDA
PMID:12941786
Insights into the biochemical and genetic basis of glucokina... 		ACCEPT
Summary: IDA of glucokinase activity from functional analysis of purified recombinant GST-GCK fusion proteins (wild-type and activating T65I/W99R mutants), measuring the phosphorylating potential (activity index).
Reason: Direct in-vitro enzyme assays of purified human GCK; core molecular function.
Supporting Evidence:
PMID:12941786
Functional analysis of the purified recombinant glutathionyl S-transferase fusion proteins of T65I and W99R GCK revealed that the kinetic changes result in a relative increased activity index
GO:0004340 glucokinase activity
IDA
PMID:8446612
Glucokinase mutations associated with non-insulin-dependent ... 		ACCEPT
Summary: IDA of glucokinase activity from expression of native and mutant human beta-cell glucokinase in E. coli and measurement of enzyme activity (Vmax, Km for glucose).
Reason: Direct in-vitro enzyme assays of the human enzyme; core molecular function.
Supporting Evidence:
PMID:8446612
we have expressed native and mutant forms of this protein in Escherichia coli. All of the missense mutations show changes in enzyme activity
GO:0005524 ATP binding
IDA
PMID:12941786
Insights into the biochemical and genetic basis of glucokina... 		ACCEPT
Summary: IDA of ATP binding, from functional assays of purified recombinant GCK that require ATP as the phosphoryl-donor co-substrate; ATP binding is also documented structurally.
Reason: GCK binds ATP as its co-substrate; supported by enzyme kinetics and structure.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
KM=4.5 mM for ATP (at pH 7)
GO:0005524 ATP binding
IDA
PMID:8446612
Glucokinase mutations associated with non-insulin-dependent ... 		ACCEPT
Summary: IDA of ATP binding from enzyme-activity assays of purified human GCK that use ATP as substrate; consistent with structural evidence for ATP binding.
Reason: GCK binds ATP as its phosphoryl-donor substrate; well supported.
Supporting Evidence:
file:human/GCK/GCK-uniprot.txt
KM=4.5 mM for ATP (at pH 7)
GO:0005536 D-glucose binding
IDA
PMID:12941786
Insights into the biochemical and genetic basis of glucokina... 		ACCEPT
Summary: IDA of D-glucose binding from kinetic characterization of purified GCK (activating mutations accelerate glucose binding to the apoenzyme); glucose binding is the substrate-recognition function of GCK.
Reason: Glucose binding is a core molecular activity of GCK; directly characterized kinetically.
Supporting Evidence:
PMID:12941786
These mutations are within the recently identified heterotropic allosteric activator site
GO:0005536 D-glucose binding
IDA
PMID:8446612
Glucokinase mutations associated with non-insulin-dependent ... 		ACCEPT
Summary: IDA of D-glucose binding from enzyme assays of purified human GCK measuring Km for glucose across wild-type and mutant enzymes.
Reason: Glucose binding is a core molecular activity of GCK; directly measured as Km for glucose.
Supporting Evidence:
PMID:8446612
increase in Km for glucose
GO:0032024 positive regulation of insulin secretion
IMP
PMID:8132752
Insulin secretory abnormalities in subjects with hyperglycem... 		ACCEPT
Summary: IMP annotation from beta-cell function studies of human GCK-mutation carriers, showing a right-shifted glucose/insulin-secretion dose-response curve, demonstrating GCK's positive control of glucose-stimulated insulin secretion.
Reason: GCK mutation carriers show reduced/shifted insulin secretion, establishing GCK's positive regulation of glucose-stimulated insulin secretion.
Supporting Evidence:
PMID:8132752
the dose-response curve relating glucose and ISR obtained during graded intravenous glucose infusions was shifted to the right in the subjects with GCK mutations
GO:0042593 glucose homeostasis
IMP
PMID:8132752
Insulin secretory abnormalities in subjects with hyperglycem... 		ACCEPT
Summary: IMP annotation from studies of GCK-mutation carriers demonstrating that GCK sets the in-vivo glucose/insulin-secretion relationship, a central mechanism of glucose homeostasis.
Reason: GCK is a key determinant of the in-vivo glucose/insulin dose-response, i.e. of glucose homeostasis; supported by human mutation studies.
Supporting Evidence:
PMID:8132752
support a key role for the enzyme GCK in determining the in vivo glucose/ISR dose-response relationships

Core Functions

ATP-dependent phosphorylation of D-glucose to D-glucose 6-phosphate, the committed first step of glucose utilization, catalyzed by a low-affinity (high-KM), cooperative, product-inhibition-resistant enzyme that thereby functions as the cellular glucose sensor.

Molecular Function:
glucokinase activity
Directly Involved In:
glucose metabolic process
Supporting Evidence:
  • file:human/GCK/GCK-uniprot.txt
    Mediates the initial step of glycolysis by catalyzing

In the pancreatic beta cell, glucokinase acts as the glucose sensor that sets the threshold for glucose-stimulated insulin secretion; the low glucose affinity ensures its activity tracks glucose across the physiological range, so it is the flux-controlling determinant coupling glycolytic glucose metabolism to insulin release.

Molecular Function:
glucokinase activity
Directly Involved In:
glycolytic process
Supporting Evidence:
  • file:human/GCK/GCK-uniprot.txt
    GCK acts as a glucose sensor in the pancreatic beta

Glucokinase is a central determinant of whole-body glucose homeostasis; in the liver it drives glucose uptake and glycogen synthesis and restrains gluconeogenesis, and its loss (MODY2/PNDM) or gain (hyperinsulinism) of function shifts the glucose set-point.

Molecular Function:
glucokinase activity
Directly Involved In:
glucose homeostasis
Cellular Locations:
cytosol
Supporting Evidence:
  • file:human/GCK/GCK-uniprot.txt
    insulin-sensitive determinant of hepatic glucose usage

References

file:human/GCK/GCK-uniprot.txt
UniProtKB entry P35557 (HXK4_HUMAN), glucokinase / hexokinase-4
GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000041
Gene Ontology annotation based on UniPathway vocabulary mapping
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000116
Automatic Gene Ontology annotation based on Rhea mapping
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
PMID:10456334
Glucokinase regulatory protein is essential for the proper subcellular localisation of liver glucokinase.
PMID:11522786
Characterization of glucokinase-binding protein epitopes by a phage-displayed peptide library. Identification of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase as a novel interaction partner.
PMID:11916951
The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy.
PMID:12941786
Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations.
PMID:15277402
Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase mutation.
PMID:16173921
Effects of novel maturity-onset diabetes of the young (MODY)-associated mutations on glucokinase activity and protein stability.
PMID:17082186
Biochemical basis of glucokinase activation and the regulation by glucokinase regulatory protein in naturally occurring mutations.
PMID:18322640
Biochemical characterization of novel glucokinase mutations isolated from Spanish maturity-onset diabetes of the young (MODY2) patients.
PMID:19146401
Activating mutations in the human glucokinase gene revealed by genetic selection.
PMID:20668700
Effects of GCK, GCKR, G6PC2 and MTNR1B variants on glucose metabolism and insulin secretion.
PMID:22611063
Insights into the pathogenicity of rare missense GCK variants from the identification and functional characterization of compound heterozygous and double mutations inherited in cis.
PMID:24187134
Identification of the ubiquitin-like domain of midnolin as a new glucokinase interaction partner.
PMID:25015100
Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.
PMID:32296183
A reference map of the human binary protein interactome.
PMID:7742312
Sugar specificity of human beta-cell glucokinase: correlation of molecular models with kinetic measurements.
PMID:8132752
Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase mutations.
PMID:8325892
Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants.
PMID:8446612
Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships.
PMID:8878425
Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects.
PMID:9570959
Organization of the human glucokinase regulator gene GCKR.
Reactome:R-HSA-170796
NPC transports GCK1:GCKR from cytosol to nucleoplasm
Reactome:R-HSA-170799
cytosolic GCK1:GKRP complex <=> glucokinase (GCK1) + glucokinase regulatory protein (GKRP)
Reactome:R-HSA-170810
nucleoplasmic GCK1:GCKR complex => glucokinase (GCK1) + glucokinase regulatory protein (GCKR)
Reactome:R-HSA-170824
glucokinase (GCK1) + glucokinase regulatory protein (GKRP) <=> GCK1:GKRP complex
Reactome:R-HSA-170825
NPC exports GCK1 from nucleus
Reactome:R-HSA-5621918
Defective GCK does not phosphorylate Glc to form G6P
Reactome:R-HSA-5661474
Defective NPC does not transport GCK1:GKRP from cytosol to nucleoplasm
Reactome:R-HSA-70171
Glycolysis
Reactome:R-HSA-70420
HK1,2,3,GCK,HKDC1 phosphorylate Glc to form G6P

📚 Additional Documentation

Notes

(GCK-notes.md)

GCK (glucokinase / hexokinase-4, P35557) — review notes

Summary of gene function

GCK encodes glucokinase (hexokinase-4 / hexokinase type IV / hexokinase-D), the
high-Km hexose-phosphorylating enzyme (EC 2.7.1.1) expressed mainly in pancreatic
beta cells and hepatocytes. It catalyzes the first, committed step of glucose
utilization: phosphorylation of D-glucose to D-glucose 6-phosphate using ATP
(RHEA:17825). It also phosphorylates D-mannose and D-fructose (and, weakly,
2-deoxyglucose, glucosamine), but these are of minor physiological relevance
[UniProt P35557 CATALYTIC ACTIVITY; PMID:7742312].

The defining property that distinguishes GCK from HK1-3 is its weak affinity for
glucose (KM ~6 mM, sigmoidal/cooperative kinetics, Hill coefficient ~1.7) and lack
of product inhibition by G6P. This makes it a physiological glucose sensor: its
activity varies steeply across the physiological blood-glucose range, so it sets the
threshold for glucose-stimulated insulin secretion in the beta cell and controls
hepatic glucose uptake/glycogen synthesis in the liver
[PMID:7742312 "KM=6.03 mM for glucose"; UniProt "GCK acts as a glucose sensor in the pancreatic beta cell"].

Regulation and localization

  • Cytosolic in both beta cells and hepatocytes; the HPA IDA and Reactome/IBA
    place it in cytosol (GO:0005829) [GOA rows 7, 33, 39, 63, 67-72].
  • In hepatocytes, GCK is regulated by the glucokinase regulatory protein GCKR:
    at low glucose (and high fructose-6-phosphate) GCK binds GCKR and the inactive
    complex is sequestered in the nucleus; at high glucose GCK is released back to the
    cytosol [PMID:10456334; UniProt ACTIVITY REGULATION/SUBUNIT]. This is the basis of
    the nucleus (GO:0005634) and nucleoplasm (GO:0005654) annotations and the Reactome
    GCK1:GCKR transport reactions.
  • Interacts with MIDN (midnolin ubiquitin-like domain), preferentially at low
    glucose, inhibiting activity PMID:24187134; with PFKFB1/PFK-2/FBPase-2
    PMID:11522786; with GCKR [PMID:16173921 Y2H, PMID:32296183 HuRI].

Disease

  • MODY2 / GCK-MODY (MIM:125851): heterozygous inactivating mutations → mild,
    stable fasting hyperglycemia (compensated by the WT allele).
  • PNDM1 (MIM:606176): homozygous/biallelic loss → permanent neonatal diabetes;
    protein instability is a major severity determinant PMID:25015100.
  • HHF3 / GCK-hyperinsulinism (MIM:602485): heterozygous activating (gain-of-function)
    mutations, often in the allosteric activator site → hyperinsulinemic hypoglycemia
    [PMID:12941786, PMID:15277402, PMID:11916951, PMID:17082186, PMID:19146401].
  • T2D susceptibility variants (GWAS, e.g. rs1799884) affect fasting glucose /
    insulin secretion PMID:20668700.

Annotation review decisions (high level)

  • Core MF: glucokinase activity (GO:0004340) — strongly supported by many EXP/IDA
    annotations and the whole disease literature. ACCEPT the experimental instances.
  • Hexokinase activity (GO:0004396), ATP binding (GO:0005524), D-glucose
    binding (GO:0005536)     — correct and experimentally supported; ACCEPT.
  • Fructokinase (GO:0008865) / mannokinase (GO:0019158) — genuine in-vitro
    activities (PMID:7742312), but of minor/uncertain physiological relevance; the EXP
    instances are real so ACCEPT/KEEP_AS_NON_CORE; the RHEA/IBA electronic ones are the
    same broad substrate promiscuity.
  • Glucose/G6P metabolic process, glycolysis, glucose homeostasis, regulation of
    insulin secretion, glucose sensor activity     — all well supported; core BP/MF.
  • protein binding (GO:0005515) IPI — uninformative MF; MARK_AS_OVER_ANNOTATED
    (per policy, do not REMOVE IPIs). The real interactions (GCKR, MIDN, PFKFB1) are
    captured in notes/description.
  • calcium ion import (GO:0070509) — Ensembl-projected IEA from mouse ortholog;
    not a GCK molecular function; over-propagated electronic inference → MARK_AS_OVER_ANNOTATED.
  • cytoplasmic side of mitochondrial outer membrane (GO:0032473) / mitochondrion
    (GO:0005739)     — these come from the hexokinase family IBA/ISS (HK1-3 are OMM-bound
    via their N-terminal hydrophobic anchor; GCK lacks this anchor and is cytosolic).
    Over-annotation by family inheritance → MARK_AS_OVER_ANNOTATED.
  • purine nucleotide metabolic process (GO:0006163), nicotinamide nucleotide
    metabolic process (GO:0046496)     — ARBA electronic mappings; too indirect / not the
    gene's role (ATP is a co-substrate, not evidence of purine metabolism) →
    MARK_AS_OVER_ANNOTATED.

📄 View Raw YAML

 
id: P35557
gene_symbol: GCK
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Glucokinase (hexokinase-4/HK4, hexokinase type IV) is an ATP-dependent
  hexose-phosphorylating enzyme (EC 2.7.1.1) expressed mainly in pancreatic beta cells
  and hepatocytes, where it catalyzes the first committed step of glucose utilization,
  the phosphorylation of D-glucose to D-glucose 6-phosphate. Unlike the other human
  hexokinases (HK1-3), glucokinase has a weak affinity for glucose (KM ~6 mM), exhibits
  sigmoidal/cooperative kinetics, and is not inhibited by its product glucose 6-phosphate.
  These properties make it the physiological glucose sensor whose activity varies steeply
  across the normal blood-glucose range; in the pancreatic beta cell it sets the threshold
  for glucose-stimulated insulin secretion, and in the liver it drives glucose uptake
  and glycogen synthesis. Hepatic glucokinase is allosterically regulated by the glucokinase
  regulatory protein (GCKR), which at low glucose binds glucokinase and sequesters the
  inactive complex in the nucleus, releasing it to the cytosol when glucose rises. Glucokinase
  can also phosphorylate D-mannose and D-fructose in vitro, but these activities are of
  minor physiological relevance. Mutations in GCK cause a spectrum of glycemic disorders;
  heterozygous inactivating mutations cause GCK-MODY (maturity-onset diabetes of the young
  type 2, mild fasting hyperglycemia), homozygous or biallelic loss causes permanent neonatal
  diabetes, and heterozygous activating (gain-of-function) mutations cause familial
  hyperinsulinemic hypoglycemia.
alternative_products:
- name: '1'
  id: P35557-1
- name: '2'
  id: P35557-2
  sequence_note: VSP_002074
- name: '3'
  id: P35557-3
  sequence_note: VSP_002075
existing_annotations:
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic (IBA) assertion of the core catalytic function, ATP-dependent
      phosphorylation of D-glucose to D-glucose 6-phosphate. This is GCK's defining
      molecular function and is independently confirmed by multiple human EXP/IDA/IMP
      annotations.
    action: ACCEPT
    reason: Glucokinase activity is the well-established core molecular function of
      GCK, supported by direct biochemical characterization of the purified enzyme
      and by the entire GCK-MODY/hyperinsulinism disease literature.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Mediates the initial step of glycolysis by catalyzing
- term:
    id: GO:0008865
    label: fructokinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic assertion of fructokinase activity, propagated across the
      hexokinase family. GCK does phosphorylate D-fructose in vitro, but with very
      weak affinity (KM ~240 mM) that is far outside any physiological range, so this
      is a promiscuous side-activity rather than a physiological function.
    action: KEEP_AS_NON_CORE
    reason: A genuine in-vitro substrate promiscuity of the hexokinase family, but
      the extremely high KM for fructose means it is not a physiologically relevant
      function of GCK; keep as non-core.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: KM=240 mM for fructose (at 30 degrees Celsius and pH 7.5)
- term:
    id: GO:0019158
    label: mannokinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: Phylogenetic assertion of mannokinase activity. GCK phosphorylates D-mannose
      in vitro with an affinity comparable to glucose (KM ~4.35 mM), but mannose is
      a quantitatively minor substrate physiologically.
    action: KEEP_AS_NON_CORE
    reason: A genuine in-vitro activity of the hexokinase family; kept as non-core
      because glucose phosphorylation is the physiologically dominant function.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: KM=4.35 mM for mannose (at 30 degrees Celsius and pH 7.5)
- term:
    id: GO:0032473
    label: cytoplasmic side of mitochondrial outer membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assertion of localization to the cytoplasmic side of the
      mitochondrial outer membrane, inherited from the hexokinase family. HK1-3 bind
      the outer mitochondrial membrane through an N-terminal hydrophobic anchor, but
      GCK lacks this anchor and is a soluble cytosolic (and regulated nuclear) protein.
    action: MARK_AS_OVER_ANNOTATED
    reason: Family-level over-propagation. Mitochondrial outer-membrane association
      is a property of HK1-3 (which have an N-terminal membrane-binding domain absent
      from GCK); GCK is documented as cytoplasmic and nuclear, not membrane-anchored.
    propagation_review:
      root_cause: PROPAGATION_BAD
      failure_modes:
      - COMPARTMENT_OR_COMPLEX_MISMATCH
      source_entities:
      - source_id: UniProtKB:P52789
        comment: Rat hexokinase-1 type; binds outer mitochondrial membrane via an
          N-terminal hydrophobic anchor that single-domain GCK lacks, so the compartment
          does not transfer correctly.
      - source_id: UniProtKB:M4FD55
        comment: Hexokinase-family source for the mitochondrial-membrane IBA; anchor-bearing,
          unlike cytosolic/nuclear GCK.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assertion that GCK participates in glycolysis. GCK catalyzes
      the first, committed step of the glycolytic pathway (glucose to glucose 6-phosphate),
      which is well established.
    action: ACCEPT
    reason: Glucokinase catalyzes step 1 of glycolysis; this is a core biological
      process for the gene.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Mediates the initial step of glycolysis by catalyzing
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: Phylogenetic assertion of cytosolic localization, consistent with human
      HPA immunofluorescence (IDA) and the well-documented cytosolic location of active
      glucokinase.
    action: ACCEPT
    reason: Glucokinase is a cytosolic enzyme (with regulated nuclear sequestration
      in hepatocytes); cytosol is its principal site of catalytic action.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006006
    label: glucose metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assertion that GCK participates in glucose metabolism. As
      the enzyme catalyzing the rate-limiting first step of glucose utilization in
      liver and beta cells, this is a core biological process.
    action: ACCEPT
    reason: Glucokinase is a rate-limiting determinant of glucose metabolism in liver
      and pancreatic beta cells.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: rate-limiting step in glucose metabolism in these tissues
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assertion linking GCK to glucose 6-phosphate metabolism.
      GCK produces glucose 6-phosphate, so it directly contributes to G6P metabolism;
      this is corroborated by human IMP annotations.
    action: ACCEPT
    reason: The product of the GCK reaction is glucose 6-phosphate; participation
      in G6P metabolic process is a direct and accurate consequence of its activity.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: phosphorylation of D-glucose to D-glucose 6-phosphate
- term:
    id: GO:0001678
    label: intracellular glucose homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assertion that GCK contributes to intracellular glucose
      homeostasis, consistent with its role as the glucose sensor controlling hepatic
      glucose uptake and beta-cell insulin secretion.
    action: ACCEPT
    reason: As the tissue glucose sensor, GCK is a central determinant of cellular
      and whole-body glucose homeostasis.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: GCK acts as a glucose sensor in the pancreatic beta
- term:
    id: GO:0050796
    label: regulation of insulin secretion
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: Phylogenetic assertion that GCK regulates insulin secretion. In the beta
      cell, glucokinase sets the threshold for glucose-stimulated insulin secretion,
      confirmed by human IMP studies of GCK mutation carriers.
    action: ACCEPT
    reason: Beta-cell glucokinase controls the glucose threshold for insulin secretion;
      supported by both phylogenetic inference and human physiology studies.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: modulating insulin secretion
- term:
    id: GO:0001678
    label: intracellular glucose homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO electronic mapping of the hexokinase domain to intracellular
      glucose homeostasis. Redundant with the curated IBA annotation to the same term
      and consistent with GCK's role as the glucose sensor.
    action: ACCEPT
    reason: Accurate for GCK; duplicate of the curated intracellular glucose homeostasis
      annotation.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: GCK acts as a glucose sensor in the pancreatic beta
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic assignment of the parent hexokinase activity (EC 2.7.1.1)
      term. GCK is hexokinase-4, so hexokinase activity is correct, though glucokinase
      activity (GO:0004340) is the more specific and preferred term.
    action: ACCEPT
    reason: Correct broader molecular-function term; GCK is a bona fide hexokinase
      (EC 2.7.1.1). Retained as an accurate parent of the specific glucokinase activity.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Catalyzes the phosphorylation of hexose, such as D-glucose,
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic assignment of ATP binding. ATP is the phosphate
      donor co-substrate of glucokinase and ATP binding is directly demonstrated by
      human IDA annotations and crystal structures with bound ATP analog.
    action: ACCEPT
    reason: GCK binds ATP as its phosphoryl-donor substrate; well supported by structure
      and IDA.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: KM=4.5 mM for ATP (at pH 7)
- term:
    id: GO:0005536
    label: D-glucose binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro-based electronic assignment of D-glucose binding, the substrate-binding
      function of glucokinase, corroborated by human IDA annotations and glucose-bound
      crystal structures.
    action: ACCEPT
    reason: Glucose binding is a core molecular activity of GCK, directly demonstrated
      experimentally.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: COMPLEX WITH GLUCOSE
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of nuclear localization. In hepatocytes, glucokinase
      is sequestered in the nucleus in complex with GCKR at low glucose, so this location
      is real but conditional/regulated. Corroborated by human EXP annotations.
    action: ACCEPT
    reason: Regulated nuclear sequestration of hepatic GCK by GCKR is well documented;
      the nuclear location is genuine although condition-dependent.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: the inactive complex is recruited to the
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of cytoplasmic localization, the principal compartment
      of active glucokinase. Corroborated by human EXP annotations and HPA immunofluorescence.
    action: ACCEPT
    reason: Cytoplasm/cytosol is the main site of active GCK; well supported.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: Electronic assignment of mitochondrial localization. This is inherited
      from the hexokinase family / by-similarity from HK1-type orthologs; mitochondrial
      outer-membrane binding is a property of HK1-3 that have an N-terminal membrane
      anchor absent from GCK, which is cytosolic and nuclear.
    action: MARK_AS_OVER_ANNOTATED
    reason: GCK lacks the N-terminal mitochondrial-binding anchor of HK1-3; the mitochondrial
      annotation is a family/by-similarity over-propagation rather than a GCK-specific
      location.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro-based electronic assignment of the broad carbohydrate metabolic
      process term. Accurate but general; more specific glucose metabolic/glycolytic
      terms are annotated.
    action: ACCEPT
    reason: Correct high-level process term; a valid parent of the more specific glucose
      metabolism annotations.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Carbohydrate metabolism; hexose metabolism
- term:
    id: GO:0006006
    label: glucose metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning electronic assignment of glucose metabolic process,
      redundant with the curated IBA annotation and accurate for GCK.
    action: ACCEPT
    reason: Correct; duplicate of the curated glucose metabolic process annotation.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: rate-limiting step in glucose metabolism in these tissues
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: Electronic assignment of glycolytic process via UniPathway mapping, redundant
      with the curated IBA annotation. GCK catalyzes the first step of glycolysis.
    action: ACCEPT
    reason: Correct; duplicate of the curated glycolytic process annotation.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Mediates the initial step of glycolysis by catalyzing
- term:
    id: GO:0006163
    label: purine nucleotide metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA electronic assignment of purine nucleotide metabolic process. This
      almost certainly derives from GCK using ATP (a purine nucleotide) as co-substrate;
      consuming ATP as a phosphate donor does not make GCK a participant in purine
      nucleotide metabolism.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-interpretation of ATP co-substrate usage. GCK does not metabolize
      purine nucleotides; ATP is a universal phosphoryl donor and this term misrepresents
      the gene's biological role.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: a D-hexose + ATP = a D-hexose 6-phosphate + ADP
- term:
    id: GO:0008865
    label: fructokinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: RHEA-based electronic assignment of fructokinase activity (D-fructose
      + ATP reaction). Same weak in-vitro promiscuous activity as the IBA/EXP fructokinase
      annotations (KM ~240 mM), not physiologically relevant.
    action: KEEP_AS_NON_CORE
    reason: Genuine in-vitro side-activity but physiologically negligible due to the
      very high KM for fructose.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Reaction=D-fructose + ATP = D-fructose 6-phosphate + ADP
- term:
    id: GO:0019158
    label: mannokinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: RHEA-based electronic assignment of mannokinase activity (D-mannose +
      ATP reaction). GCK phosphorylates mannose in vitro, but this is a minor physiological
      substrate.
    action: KEEP_AS_NON_CORE
    reason: Genuine in-vitro activity but not the physiologically dominant function
      of GCK.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Reaction=D-mannose + ATP = D-mannose 6-phosphate + ADP
- term:
    id: GO:0032024
    label: positive regulation of insulin secretion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA electronic assignment of positive regulation of insulin secretion,
      redundant with the human IMP annotations. Glucokinase drives glucose-stimulated
      insulin secretion in the beta cell.
    action: ACCEPT
    reason: Correct; duplicate of curated IMP annotations for positive regulation
      of insulin secretion.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: modulating insulin secretion
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA electronic assignment of glucose homeostasis, redundant with the
      human IMP annotations. GCK is a central determinant of whole-body glucose homeostasis.
    action: ACCEPT
    reason: Correct; duplicate of curated glucose homeostasis annotations.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: insulin-sensitive determinant of hepatic glucose usage
- term:
    id: GO:0046496
    label: nicotinamide nucleotide metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA electronic assignment of nicotinamide nucleotide (NAD/NADP) metabolic
      process. GCK has no role in NAD/NADP metabolism; its reaction consumes ATP and
      produces glucose 6-phosphate, and this term appears to be a spurious machine-learning
      mapping.
    action: REMOVE
    reason: Demonstrably wrong electronic inference. Glucokinase does not participate
      in nicotinamide nucleotide (NAD/NADP) metabolism; there is no biochemical basis
      for this ARBA mapping, which should be removed.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: a D-hexose + ATP = a D-hexose 6-phosphate + ADP
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:11522786
  qualifier: enables
  review:
    summary: IntAct binary-interaction annotation. PMID:11522786 identified PFKFB1
      (6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase) as a glucokinase interaction
      partner via phage-display and yeast two-hybrid. The interaction is real and
      biologically interesting, but the generic protein binding term is uninformative
      as a molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Per curation guidelines, bare protein binding (GO:0005515) is not an informative
      molecular function. The underlying PFKFB1 (and GCKR) interaction is captured
      in the gene description/notes; the IPI itself is retained but flagged as over-annotated.
    supported_by:
    - reference_id: PMID:11522786
      supporting_text: The second consensus motif, SLKVWT, showed a complete homology
        to the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: IntAct binary-interaction annotation from the HuRI human interactome
      map (PMID:32296183), a high-throughput yeast two-hybrid screen. The generic
      protein binding term does not convey a specific molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines;
      derived from a proteome-scale binary interactome screen. Retained but flagged
      as over-annotated.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: a human 'all-by-all' reference interactome map of human binary
        protein interactions, or 'HuRI'
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: Electronic (RHEA/UniProt combined) assignment of glucokinase activity,
      the specific EC 2.7.1.1 D-glucose + ATP reaction. Redundant with the many curated
      EXP/IDA/IMP/IBA glucokinase activity annotations.
    action: ACCEPT
    reason: Correct and specific core molecular function; duplicate of curated glucokinase
      activity annotations.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Reaction=D-glucose + ATP = D-glucose 6-phosphate + ADP
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: Ensembl-projected electronic assignment of cytosolic localization from
      the mouse ortholog. Consistent with the human IDA (HPA) and IBA cytosol annotations.
    action: ACCEPT
    reason: Cytosol is the principal location of active glucokinase; well supported
      across multiple evidence lines.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0070509
    label: calcium ion import
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-projected electronic annotation of calcium ion import from the
      mouse ortholog. Glucokinase is a cytosolic kinase with no transport activity;
      any link to calcium import would be an indirect downstream consequence of glucose-stimulated
      insulin secretion physiology, not a function of GCK itself.
    action: MARK_AS_OVER_ANNOTATED
    reason: Over-propagated electronic inference. GCK does not import calcium; this
      is at best an indirect, distal physiological association projected from the ortholog
      and does not represent a molecular activity or direct process role of GCK.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Catalyzes the phosphorylation of hexose, such as D-glucose,
- term:
    id: GO:0061621
    label: canonical glycolysis
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70171
  qualifier: involved_in
  review:
    summary: Reactome traceable-author-statement annotation placing GCK in canonical
      glycolysis (the Glycolysis pathway). GCK catalyzes the committed first step
      of glucose catabolism via glycolysis.
    action: ACCEPT
    reason: GCK performs the first step of glycolysis; canonical glycolysis is an
      accurate, curator-asserted process.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Mediates the initial step of glycolysis by catalyzing
- term:
    id: GO:0019318
    label: hexose metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-based electronic assignment of hexose metabolic process. GCK
      phosphorylates hexoses (glucose, mannose, fructose) as the entry step of hexose
      utilization; accurate but general.
    action: ACCEPT
    reason: Correct high-level process; a valid parent of the more specific glucose
      metabolic process annotations.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Carbohydrate metabolism; hexose metabolism
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5621918
  qualifier: enables
  review:
    summary: Reactome TAS annotation of glucokinase activity, from the reaction describing
      defective GCK failing to phosphorylate glucose to G6P. Correct core molecular
      function.
    action: ACCEPT
    reason: Curator-traceable assertion of the core glucokinase activity; consistent
      with all other evidence.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Reaction=D-glucose + ATP = D-glucose 6-phosphate + ADP
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70420
  qualifier: enables
  review:
    summary: Reactome TAS annotation of glucokinase activity, from the reaction in
      which HK1,2,3,GCK,HKDC1 phosphorylate glucose to form G6P. Correct core molecular
      function.
    action: ACCEPT
    reason: Curator-traceable assertion of the core glucokinase activity.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Reaction=D-glucose + ATP = D-glucose 6-phosphate + ADP
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: Human Protein Atlas immunofluorescence (IDA) localizing GCK to the cytosol.
      This is a direct human experimental localization consistent with the enzyme's
      soluble cytosolic nature.
    action: ACCEPT
    reason: Direct immunofluorescence evidence for cytosolic localization; the principal
      compartment of active glucokinase.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: EXP
  original_reference_id: PMID:7742312
  qualifier: enables
  review:
    summary: Steady-state kinetic characterization of purified human beta-cell glucokinase
      phosphorylating glucose (and other sugars), establishing its glucokinase activity
      and the diagnostic weak glucose affinity (KM ~6 mM) with cooperative kinetics.
    action: ACCEPT
    reason: Direct experimental demonstration of glucokinase activity on the human
      enzyme; a primary source for the core molecular function.
    supported_by:
    - reference_id: PMID:7742312
      supporting_text: glucokinase phosphorylated the sugars in the order glucose
        = mannose > deoxyglucose > fructose = glucosamine
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: EXP
  original_reference_id: PMID:11916951
  qualifier: enables
  review:
    summary: Functional characterization of an activating GCK mutant (A456V) using
      the purified recombinant enzyme, measuring glucose phosphorylation kinetics
      (glucose S0.5, kcat). Confirms hexokinase/glucokinase activity of human GCK.
    action: ACCEPT
    reason: Experimental measurement of GCK glucose-phosphorylating (hexokinase) activity
      on the purified human enzyme.
    supported_by:
    - reference_id: PMID:11916951
      supporting_text: The purified recombinant glutathionyl S-transferase fusion
        protein of the A456V glucokinase revealed a decreased glucose S(0.5)
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: EXP
  original_reference_id: PMID:15277402
  qualifier: enables
  review:
    summary: Functional study of the activating GCK-Y214C mutant, measuring glucose
      affinity, cooperativity and kcat of the purified enzyme, confirming GCK's glucose-phosphorylating
      (hexokinase) activity.
    action: ACCEPT
    reason: Experimental measurement of GCK enzymatic activity on the purified human
      enzyme; supports the hexokinase/glucokinase molecular function.
    supported_by:
    - reference_id: PMID:15277402
      supporting_text: Functional studies of purified recombinant glutathionyl S-transferase
        fusion protein of GK-Y214C showed a sixfold increase in its affinity for glucose
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: EXP
  original_reference_id: PMID:17082186
  qualifier: enables
  review:
    summary: Transient-kinetics analysis of glucose binding and turnover for wild-type
      and activating GCK mutants, characterizing the enzyme's glucose-phosphorylating
      activity and its GKRP regulation.
    action: ACCEPT
    reason: Direct kinetic characterization of GCK hexokinase activity on purified
      enzyme.
    supported_by:
    - reference_id: PMID:17082186
      supporting_text: the transient kinetics of glucose binding for activating mutations
        follows a general two-step mechanism
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: EXP
  original_reference_id: PMID:18322640
  qualifier: enables
  review:
    summary: Biochemical characterization of six MODY2 GCK mutants showing reduced
      enzymatic activity, based on assays of the recombinant enzyme; confirms GCK's
      glucose-phosphorylating (hexokinase) activity.
    action: ACCEPT
    reason: Experimental enzyme-activity assays of human GCK; supports the hexokinase/glucokinase
      molecular function.
    supported_by:
    - reference_id: PMID:18322640
      supporting_text: All these mutations produced enzymes that presented reduced
        enzymatic activity in various degrees
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: EXP
  original_reference_id: PMID:19146401
  qualifier: enables
  review:
    summary: Identification and kinetic characterization of 11 activating GCK mutations,
      reporting kcat/K0.5 for glucose on the recombinant enzyme; confirms GCK's glucose-phosphorylating
      (hexokinase) activity.
    action: ACCEPT
    reason: Experimental measurement of GCK glucose-phosphorylating activity on the
      human enzyme.
    supported_by:
    - reference_id: PMID:19146401
      supporting_text: I211F is the most active variant identified to date, with a
        k(cat)/K(0.5,glucose) value
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: EXP
  original_reference_id: PMID:25015100
  qualifier: enables
  review:
    summary: Kinetic and thermostability analysis of 16 homozygous GCK missense mutants
      (relative activity index), assaying the recombinant human enzyme's glucose-phosphorylating
      activity.
    action: ACCEPT
    reason: Experimental enzyme-activity measurement on purified human GCK; supports
      the hexokinase/glucokinase molecular function.
    supported_by:
    - reference_id: PMID:25015100
      supporting_text: Recombinant mutant GCK proteins were analyzed for kinetic and
        thermostability characteristics and assigned a relative activity index
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: EXP
  original_reference_id: PMID:8325892
  qualifier: enables
  review:
    summary: Structure/function study expressing native and mutant human beta-cell
      glucokinase and measuring Vmax and Km for glucose, directly characterizing GCK's
      glucose-phosphorylating (hexokinase) activity.
    action: ACCEPT
    reason: Direct experimental characterization of GCK enzymatic activity on the
      human enzyme.
    supported_by:
    - reference_id: PMID:8325892
      supporting_text: a Vmax that was 20-100% of normal but a Km for glucose that
        was 8-14-fold greater than the native enzyme
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:10456334
  qualifier: located_in
  review:
    summary: Experimental demonstration that liver glucokinase concentrates in the
      nucleus of hepatocytes at low glucose, in a GCKR-dependent manner. Establishes
      the regulated nuclear localization of hepatic GCK.
    action: ACCEPT
    reason: Direct experimental evidence for regulated nuclear localization of GCK
      via GCKR binding; genuine although condition-dependent.
    supported_by:
    - reference_id: PMID:10456334
      supporting_text: concentrated in the nucleus of cultured rat hepatocytes at
        low glucose and translocated to the cytoplasm at high glucose
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: EXP
  original_reference_id: PMID:24187134
  qualifier: located_in
  review:
    summary: Fluorescence-microscopy study of GCK and its interaction partner midnolin
      in pancreatic beta cells, consistent with a nuclear/cytoplasmic distribution
      of glucokinase.
    action: ACCEPT
    reason: Supports nuclear (and cytoplasmic) localization of GCK; consistent with
      its regulated subcellular distribution.
    supported_by:
    - reference_id: PMID:24187134
      supporting_text: revealed localization of midnolin in nucleus and cytoplasm
        and co-localization with glucokinase in pancreatic beta cells
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:10456334
  qualifier: located_in
  review:
    summary: Experimental demonstration that liver glucokinase translocates to the
      cytoplasm at high glucose, establishing cytoplasm as the compartment of active
      hepatic GCK.
    action: ACCEPT
    reason: Direct experimental evidence for cytoplasmic localization of active GCK.
    supported_by:
    - reference_id: PMID:10456334
      supporting_text: concentrated in the nucleus of cultured rat hepatocytes at
        low glucose and translocated to the cytoplasm at high glucose
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: EXP
  original_reference_id: PMID:24187134
  qualifier: located_in
  review:
    summary: Fluorescence-microscopy evidence for cytoplasmic (and nuclear) localization
      of glucokinase in pancreatic beta cells.
    action: ACCEPT
    reason: Supports cytoplasmic localization of GCK; consistent with the enzyme's
      soluble cytosolic nature.
    supported_by:
    - reference_id: PMID:24187134
      supporting_text: revealed localization of midnolin in nucleus and cytoplasm
        and co-localization with glucokinase in pancreatic beta cells
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: ISS transfer of mitochondrial localization from an ortholog (UniProtKB:P17712,
      rat hexokinase). Mitochondrial outer-membrane binding is a documented property
      of HK1-3 (which have an N-terminal membrane anchor) but not of GCK, which lacks
      this anchor and is cytosolic/nuclear.
    action: MARK_AS_OVER_ANNOTATED
    reason: The ISS source is a membrane-anchored hexokinase; GCK lacks the N-terminal
      mitochondrial-binding domain, so mitochondrial localization is a family-level
      over-transfer rather than a GCK-specific location.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0008865
    label: fructokinase activity
  evidence_type: EXP
  original_reference_id: PMID:7742312
  qualifier: enables
  review:
    summary: Kinetic measurements showing purified human beta-cell glucokinase phosphorylates
      D-fructose in vitro, but with very weak affinity (KM ~240 mM), far above any
      physiological fructose concentration.
    action: KEEP_AS_NON_CORE
    reason: A genuine, experimentally measured in-vitro activity, but physiologically
      negligible given the extremely high KM for fructose; kept as non-core.
    supported_by:
    - reference_id: PMID:7742312
      supporting_text: glucokinase phosphorylated the sugars in the order glucose
        = mannose > deoxyglucose > fructose = glucosamine
- term:
    id: GO:0019158
    label: mannokinase activity
  evidence_type: EXP
  original_reference_id: PMID:7742312
  qualifier: enables
  review:
    summary: Kinetic measurements showing purified human beta-cell glucokinase phosphorylates
      D-mannose in vitro with an affinity comparable to glucose (KM ~4.35 mM), a genuine
      but quantitatively minor physiological substrate.
    action: KEEP_AS_NON_CORE
    reason: An experimentally measured in-vitro activity of GCK; kept as non-core
      because glucose is the physiologically dominant substrate.
    supported_by:
    - reference_id: PMID:7742312
      supporting_text: glucokinase phosphorylated the sugars in the order glucose
        = mannose > deoxyglucose > fructose = glucosamine
- term:
    id: GO:0009749
    label: response to glucose
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS transfer of response to glucose from an ortholog. GCK function and
      protein level are modulated by glucose (glucose promotes the active cytosolic
      state and stabilizes the enzyme), so involvement in the cellular response to
      glucose is biologically reasonable.
    action: ACCEPT
    reason: Consistent with GCK's role as a glucose sensor whose activity, localization
      and stability respond to glucose; a reasonable orthology-based transfer.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: is effective only when glucose is abundant
- term:
    id: GO:0141089
    label: glucose sensor activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: ISS transfer of the specific molecular-function term glucose sensor activity.
      This precisely captures GCK's defining physiological role, its weak glucose
      affinity and cooperative kinetics allow it to function as the cellular glucose
      sensor setting the threshold for insulin secretion and hepatic glucose uptake.
    action: ACCEPT
    reason: Glucose sensor activity is the most specific and biologically apt molecular-function
      term for GCK; strongly supported by its kinetic properties and physiology.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: GCK acts as a glucose sensor in the pancreatic beta
- term:
    id: GO:0006007
    label: glucose catabolic process
  evidence_type: IMP
  original_reference_id: PMID:12941786
  qualifier: involved_in
  review:
    summary: IMP annotation from characterization of an activating hypoglycemia mutation
      (T65I) showing GCK catalyzes the rate-limiting step of beta-cell glucose metabolism/catabolism.
      GCK initiates glucose catabolism via glycolysis.
    action: ACCEPT
    reason: GCK performs the committed, rate-limiting first step of glucose catabolism;
      supported by mutation phenotype analysis.
    supported_by:
    - reference_id: PMID:12941786
      supporting_text: catalyzes the rate-limiting step for beta-cell glucose metabolism
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: IMP
  original_reference_id: PMID:19146401
  qualifier: enables
  review:
    summary: IMP annotation of glucokinase activity based on activating GCK mutations
      that alter the enzyme's glucose-phosphorylating kinetics (measured as kcat/K0.5,glucose).
    action: ACCEPT
    reason: Mutation-based evidence directly tying sequence changes to altered glucokinase
      activity; core molecular function.
    supported_by:
    - reference_id: PMID:19146401
      supporting_text: I211F is the most active variant identified to date, with a
        k(cat)/K(0.5,glucose) value
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IMP
  original_reference_id: PMID:19146401
  qualifier: involved_in
  review:
    summary: IMP annotation linking GCK to glucose 6-phosphate metabolic process,
      based on activating mutations altering the glucose-phosphorylating (G6P-producing)
      activity of the enzyme.
    action: ACCEPT
    reason: GCK produces glucose 6-phosphate; mutation effects on its activity directly
      support participation in G6P metabolism.
    supported_by:
    - reference_id: PMID:19146401
      supporting_text: activating mutations in the human glk gene
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: IMP
  original_reference_id: PMID:18322640
  qualifier: enables
  review:
    summary: IMP annotation of glucokinase activity from biochemical characterization
      of MODY2 mutants that reduce the enzyme's activity to varying degrees.
    action: ACCEPT
    reason: Mutation-phenotype evidence directly linking GCK sequence to glucokinase
      activity; core molecular function.
    supported_by:
    - reference_id: PMID:18322640
      supporting_text: All these mutations produced enzymes that presented reduced
        enzymatic activity in various degrees
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IMP
  original_reference_id: PMID:18322640
  qualifier: involved_in
  review:
    summary: IMP annotation linking GCK to glucose 6-phosphate metabolic process based
      on MODY2 mutations reducing its G6P-producing enzymatic activity.
    action: ACCEPT
    reason: The GCK product is glucose 6-phosphate; mutation effects on activity support
      participation in G6P metabolism.
    supported_by:
    - reference_id: PMID:18322640
      supporting_text: mutations in the glucokinase (GCK) gene that result in impaired
        glucokinase activity
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: IDA
  original_reference_id: PMID:22611063
  qualifier: enables
  review:
    summary: IDA of glucokinase activity from spectrophotometric G6P-dehydrogenase-coupled
      assays of GST-tagged wild-type and mutant human GCK proteins.
    action: ACCEPT
    reason: Direct in-vitro assay of GCK glucose-phosphorylating activity on the purified
      human enzyme; core molecular function.
    supported_by:
    - reference_id: PMID:22611063
      supporting_text: GCK activity was measured spectrophotometrically using glucose
        6-phosphate dehydrogenase-coupled assays
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5621918
  qualifier: located_in
  review:
    summary: Reactome TAS annotation of cytosolic localization, consistent with the
      cytosolic location of active glucokinase.
    action: ACCEPT
    reason: Cytosol is the principal compartment of active GCK; curator-traceable
      assertion consistent with all other evidence.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-170796
  qualifier: located_in
  review:
    summary: Reactome TAS annotation of nucleoplasmic localization, from the reaction
      transporting the GCK1:GCKR complex from cytosol to nucleoplasm. Reflects the
      regulated nuclear sequestration of hepatic GCK bound to GCKR at low glucose.
    action: ACCEPT
    reason: Consistent with documented GCKR-dependent nuclear sequestration of hepatic
      glucokinase; genuine although condition-dependent.
    supported_by:
    - reference_id: PMID:10456334
      supporting_text: concentrated in the nucleus of cultured rat hepatocytes at
        low glucose and translocated to the cytoplasm at high glucose
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-170810
  qualifier: located_in
  review:
    summary: Reactome TAS annotation of nucleoplasmic localization, from the reaction
      dissociating the nucleoplasmic GCK1:GCKR complex. Reflects regulated nuclear
      sequestration of hepatic GCK.
    action: ACCEPT
    reason: Consistent with GCKR-dependent nuclear sequestration of hepatic glucokinase.
    supported_by:
    - reference_id: PMID:10456334
      supporting_text: concentrated in the nucleus of cultured rat hepatocytes at
        low glucose and translocated to the cytoplasm at high glucose
- term:
    id: GO:0005654
    label: nucleoplasm
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-170825
  qualifier: located_in
  review:
    summary: Reactome TAS annotation of nucleoplasmic localization, from the reaction
      exporting GCK1 from the nucleus. Reflects the regulated nuclear/cytosolic shuttling
      of hepatic GCK.
    action: ACCEPT
    reason: Consistent with the documented regulated nuclear localization/export of
      hepatic glucokinase via GCKR.
    supported_by:
    - reference_id: PMID:10456334
      supporting_text: concentrated in the nucleus of cultured rat hepatocytes at
        low glucose and translocated to the cytoplasm at high glucose
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-170796
  qualifier: located_in
  review:
    summary: Reactome TAS annotation of cytosolic localization, from the reaction
      transporting GCK1:GCKR from cytosol to nucleoplasm; the cytosol is the origin
      compartment for active glucokinase.
    action: ACCEPT
    reason: Cytosol is the principal compartment of active GCK; consistent with all
      other localization evidence.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-170799
  qualifier: located_in
  review:
    summary: Reactome TAS annotation of cytosolic localization, from the reaction
      describing the cytosolic GCK1:GKRP complex equilibrium.
    action: ACCEPT
    reason: Cytosolic location of GCK; curator-traceable and consistent with other
      evidence.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-170824
  qualifier: located_in
  review:
    summary: Reactome TAS annotation of cytosolic localization, from the reaction
      forming the GCK1:GKRP complex from cytosolic glucokinase and GKRP.
    action: ACCEPT
    reason: Cytosolic location of GCK; consistent with other localization evidence.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-170825
  qualifier: located_in
  review:
    summary: Reactome TAS annotation of cytosolic localization, from the reaction
      exporting GCK1 from the nucleus back to the cytosol.
    action: ACCEPT
    reason: Cytosolic location of active GCK; consistent with the regulated nuclear/cytosolic
      shuttling of hepatic glucokinase.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5661474
  qualifier: located_in
  review:
    summary: Reactome TAS annotation of cytosolic localization, from the (disease)
      reaction of defective nuclear pore transport of GCK1:GKRP; cytosol is the origin
      compartment.
    action: ACCEPT
    reason: Cytosolic location of GCK; consistent with other localization evidence.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70420
  qualifier: located_in
  review:
    summary: Reactome TAS annotation of cytosolic localization, from the reaction
      in which HK1,2,3,GCK,HKDC1 phosphorylate glucose to G6P in the cytosol.
    action: ACCEPT
    reason: Cytosol is the site where GCK phosphorylates glucose; consistent with
      all other evidence.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: 'SUBCELLULAR LOCATION: Cytoplasm'
- term:
    id: GO:0006110
    label: regulation of glycolytic process
  evidence_type: NAS
  original_reference_id: PMID:9570959
  qualifier: involved_in
  review:
    summary: NAS annotation citing a paper on the GCKR gene structure, asserting that
      glucokinase regulates insulin secretion in response to blood glucose. As the
      rate-limiting, flux-controlling enzyme of glucose entry into glycolysis in liver
      and beta cells, GCK regulates glycolytic flux.
    action: ACCEPT
    reason: GCK is the flux-controlling first enzyme of glycolysis in its tissues,
      so regulation of glycolytic process is a reasonable, non-experimental (NAS)
      assertion of its role.
    supported_by:
    - reference_id: PMID:9570959
      supporting_text: Glucokinase plays an important role in regulating insulin secretion
        in response to changes in blood glucose levels
- term:
    id: GO:0032869
    label: cellular response to insulin stimulus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS transfer of cellular response to insulin stimulus from an ortholog.
      In the liver, GCK expression is induced by insulin (insulin-dependent regulation
      via the alternative liver promoter), so its expression/activity responds to
      insulin.
    action: ACCEPT
    reason: Hepatic GCK is insulin-regulated (insulin induces liver GCK); a reasonable
      orthology-based transfer consistent with UniProt.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: hexokinase gene to be regulated by insulin in the liver
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: IMP
  original_reference_id: PMID:20668700
  qualifier: involved_in
  review:
    summary: IMP annotation from a genetic-association study showing common GCK variants
      (rs1799884) modulate fasting glucose and insulin secretion, supporting GCK's
      role in glucose homeostasis.
    action: ACCEPT
    reason: Human genetic variation in GCK affects fasting glucose levels, consistent
      with GCK being a determinant of glucose homeostasis.
    supported_by:
    - reference_id: PMID:20668700
      supporting_text: GCK, G6PC2 and MTNR1B variants modulated fasting glucose levels
- term:
    id: GO:0044320
    label: cellular response to leptin stimulus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS transfer of cellular response to leptin stimulus from an ortholog
      (UniProtKB:P17712). There is no direct human evidence that GCK participates
      in leptin signaling; this is a distal orthology-based association rather than
      a direct molecular role of glucokinase.
    action: MARK_AS_OVER_ANNOTATED
    reason: Weakly supported ISS transfer. No direct evidence for a GCK role in leptin
      response in the cited human record; treated as an over-annotation pending experimental
      support.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: Catalyzes the phosphorylation of hexose, such as D-glucose,
- term:
    id: GO:0050796
    label: regulation of insulin secretion
  evidence_type: IMP
  original_reference_id: PMID:20668700
  qualifier: involved_in
  review:
    summary: IMP annotation from a genetic-association study showing GCK variants
      affect first- and second-phase insulin secretion, supporting GCK's role in
      regulating insulin secretion.
    action: ACCEPT
    reason: Human GCK genetic variation affects insulin secretion phases, consistent
      with beta-cell GCK regulating insulin secretion.
    supported_by:
    - reference_id: PMID:20668700
      supporting_text: GCK and G6PC2 genetic variants were associated to both first-
        and second-phases insulin secretion
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: IDA
  original_reference_id: PMID:16173921
  qualifier: enables
  review:
    summary: IDA of glucokinase activity from enzymatic assays of affinity-purified
      recombinant human islet GCK (wild-type and MODY2 mutants), directly measuring
      the glucose-phosphorylating activity.
    action: ACCEPT
    reason: Direct in-vitro enzyme assays of purified human GCK; core molecular function.
    supported_by:
    - reference_id: PMID:16173921
      supporting_text: Enzymatic assays on the recombinant proteins revealed that
        mutations Thr206-->Met and Leu165-->Phe strongly affect the kinetic parameters
        of glucokinase
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:16173921
  qualifier: enables
  review:
    summary: IPI annotation. This paper tested the interaction of GCK MODY2 mutants
      with the glucokinase regulatory protein (GKRP/GCKR) in a yeast two-hybrid system.
      The generic protein binding term is uninformative as a molecular function.
    action: MARK_AS_OVER_ANNOTATED
    reason: Bare protein binding (GO:0005515) is uninformative per curation guidelines.
      The specific GCK-GCKR interaction is a well-established, biologically important
      relationship captured in the description/notes; the IPI is retained but flagged.
    supported_by:
    - reference_id: PMID:16173921
      supporting_text: none of the mutations tested appears to affect the interaction
        of gluco-kinase with the glucokinase regulatory protein in the yeast two-hybrid
        system
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IDA
  original_reference_id: PMID:16173921
  qualifier: enables
  review:
    summary: IDA of ATP binding, inferred from enzymatic assays of the purified recombinant
      GCK using ATP as the phosphoryl-donor co-substrate. ATP binding is also documented
      structurally.
    action: ACCEPT
    reason: GCK binds ATP as its co-substrate; supported by kinetic assays and structural
      studies.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: KM=4.5 mM for ATP (at pH 7)
- term:
    id: GO:0005536
    label: D-glucose binding
  evidence_type: IDA
  original_reference_id: PMID:16173921
  qualifier: enables
  review:
    summary: IDA of D-glucose binding from kinetic assays of purified recombinant
      GCK measuring glucose-dependent activity; glucose binding is the substrate-recognition
      function of glucokinase.
    action: ACCEPT
    reason: Glucose binding is a core molecular activity of GCK, directly supported
      by enzyme kinetics and glucose-bound structures.
    supported_by:
    - reference_id: PMID:16173921
      supporting_text: mutations Thr206-->Met and Leu165-->Phe strongly affect the
        kinetic parameters of glucokinase, in agreement with the localization of both
        residues close to the active site
- term:
    id: GO:0032024
    label: positive regulation of insulin secretion
  evidence_type: IMP
  original_reference_id: PMID:8878425
  qualifier: involved_in
  review:
    summary: IMP annotation from a study of glucokinase-deficient (MODY2) subjects.
      Impaired GCK reduces insulin secretion, indicating GCK positively regulates
      glucose-stimulated insulin secretion.
    action: ACCEPT
    reason: Loss of GCK function impairs insulin secretion in human subjects; GCK
      positively regulates insulin secretion.
    supported_by:
    - reference_id: PMID:8878425
      supporting_text: impaired insulin secretion has been observed in glucokinase-deficient
        subjects
- term:
    id: GO:0045721
    label: negative regulation of gluconeogenesis
  evidence_type: IMP
  original_reference_id: PMID:8878425
  qualifier: involved_in
  review:
    summary: IMP annotation. In glucokinase-deficient (MODY2) subjects, hepatic gluconeogenesis
      after meals was relatively augmented, implying that normal hepatic GCK activity
      suppresses gluconeogenic flux.
    action: ACCEPT
    reason: MODY2 subjects show augmented hepatic gluconeogenesis, so functional GCK
      normally restrains gluconeogenesis; a documented hepatic role.
    supported_by:
    - reference_id: PMID:8878425
      supporting_text: glucokinase-deficient subjects have decreased net accumulation
        of hepatic glycogen and relatively augmented hepatic gluconeogenesis after
        meals
- term:
    id: GO:0045725
    label: positive regulation of glycogen biosynthetic process
  evidence_type: IMP
  original_reference_id: PMID:8878425
  qualifier: involved_in
  review:
    summary: IMP annotation. Glucokinase-deficient (MODY2) subjects have decreased
      net hepatic glycogen accumulation after meals, showing that hepatic GCK is required
      to provide G6P for and to promote glycogen synthesis.
    action: ACCEPT
    reason: Loss of GCK reduces hepatic glycogen synthesis; GCK positively regulates
      glycogen biosynthesis by providing glucose 6-phosphate.
    supported_by:
    - reference_id: PMID:8878425
      supporting_text: the net increment in hepatic glycogen content after each meal
        was 30-60% lower in glucokinase-deficient than in the control subjects
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: IDA
  original_reference_id: PMID:12941786
  qualifier: enables
  review:
    summary: IDA of glucokinase activity from functional analysis of purified recombinant
      GST-GCK fusion proteins (wild-type and activating T65I/W99R mutants), measuring
      the phosphorylating potential (activity index).
    action: ACCEPT
    reason: Direct in-vitro enzyme assays of purified human GCK; core molecular function.
    supported_by:
    - reference_id: PMID:12941786
      supporting_text: Functional analysis of the purified recombinant glutathionyl
        S-transferase fusion proteins of T65I and W99R GCK revealed that the kinetic
        changes result in a relative increased activity index
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: IDA
  original_reference_id: PMID:8446612
  qualifier: enables
  review:
    summary: IDA of glucokinase activity from expression of native and mutant human
      beta-cell glucokinase in E. coli and measurement of enzyme activity (Vmax, Km
      for glucose).
    action: ACCEPT
    reason: Direct in-vitro enzyme assays of the human enzyme; core molecular function.
    supported_by:
    - reference_id: PMID:8446612
      supporting_text: we have expressed
        native and mutant forms of this protein in Escherichia coli. All of the missense
        mutations show changes in enzyme activity
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IDA
  original_reference_id: PMID:12941786
  qualifier: enables
  review:
    summary: IDA of ATP binding, from functional assays of purified recombinant GCK
      that require ATP as the phosphoryl-donor co-substrate; ATP binding is also documented
      structurally.
    action: ACCEPT
    reason: GCK binds ATP as its co-substrate; supported by enzyme kinetics and structure.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: KM=4.5 mM for ATP (at pH 7)
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IDA
  original_reference_id: PMID:8446612
  qualifier: enables
  review:
    summary: IDA of ATP binding from enzyme-activity assays of purified human GCK
      that use ATP as substrate; consistent with structural evidence for ATP binding.
    action: ACCEPT
    reason: GCK binds ATP as its phosphoryl-donor substrate; well supported.
    supported_by:
    - reference_id: file:human/GCK/GCK-uniprot.txt
      supporting_text: KM=4.5 mM for ATP (at pH 7)
- term:
    id: GO:0005536
    label: D-glucose binding
  evidence_type: IDA
  original_reference_id: PMID:12941786
  qualifier: enables
  review:
    summary: IDA of D-glucose binding from kinetic characterization of purified GCK
      (activating mutations accelerate glucose binding to the apoenzyme); glucose
      binding is the substrate-recognition function of GCK.
    action: ACCEPT
    reason: Glucose binding is a core molecular activity of GCK; directly characterized
      kinetically.
    supported_by:
    - reference_id: PMID:12941786
      supporting_text: These mutations are within the recently
        identified heterotropic allosteric activator site
- term:
    id: GO:0005536
    label: D-glucose binding
  evidence_type: IDA
  original_reference_id: PMID:8446612
  qualifier: enables
  review:
    summary: IDA of D-glucose binding from enzyme assays of purified human GCK measuring
      Km for glucose across wild-type and mutant enzymes.
    action: ACCEPT
    reason: Glucose binding is a core molecular activity of GCK; directly measured
      as Km for glucose.
    supported_by:
    - reference_id: PMID:8446612
      supporting_text: increase in Km for glucose
- term:
    id: GO:0032024
    label: positive regulation of insulin secretion
  evidence_type: IMP
  original_reference_id: PMID:8132752
  qualifier: involved_in
  review:
    summary: IMP annotation from beta-cell function studies of human GCK-mutation
      carriers, showing a right-shifted glucose/insulin-secretion dose-response curve,
      demonstrating GCK's positive control of glucose-stimulated insulin secretion.
    action: ACCEPT
    reason: GCK mutation carriers show reduced/shifted insulin secretion, establishing
      GCK's positive regulation of glucose-stimulated insulin secretion.
    supported_by:
    - reference_id: PMID:8132752
      supporting_text: the dose-response curve relating
        glucose and ISR obtained during graded intravenous glucose infusions was shifted
        to the right in the subjects with GCK mutations
- term:
    id: GO:0042593
    label: glucose homeostasis
  evidence_type: IMP
  original_reference_id: PMID:8132752
  qualifier: involved_in
  review:
    summary: IMP annotation from studies of GCK-mutation carriers demonstrating that
      GCK sets the in-vivo glucose/insulin-secretion relationship, a central mechanism
      of glucose homeostasis.
    action: ACCEPT
    reason: GCK is a key determinant of the in-vivo glucose/insulin dose-response,
      i.e. of glucose homeostasis; supported by human mutation studies.
    supported_by:
    - reference_id: PMID:8132752
      supporting_text: support a key role for the enzyme GCK in determining the in
        vivo glucose/ISR dose-response relationships
references:
- id: file:human/GCK/GCK-uniprot.txt
  title: UniProtKB entry P35557 (HXK4_HUMAN), glucokinase / hexokinase-4
  findings: []
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10456334
  title: Glucokinase regulatory protein is essential for the proper subcellular localisation
    of liver glucokinase.
  findings: []
- id: PMID:11522786
  title: Characterization of glucokinase-binding protein epitopes by a phage-displayed
    peptide library. Identification of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase
    as a novel interaction partner.
  findings: []
- id: PMID:11916951
  title: 'The second activating glucokinase mutation (A456V): implications for glucose
    homeostasis and diabetes therapy.'
  findings: []
- id: PMID:12941786
  title: Insights into the biochemical and genetic basis of glucokinase activation
    from naturally occurring hypoglycemia mutations.
  findings: []
- id: PMID:15277402
  title: Severe persistent hyperinsulinemic hypoglycemia due to a de novo glucokinase
    mutation.
  findings: []
- id: PMID:16173921
  title: Effects of novel maturity-onset diabetes of the young (MODY)-associated mutations
    on glucokinase activity and protein stability.
  findings: []
- id: PMID:17082186
  title: Biochemical basis of glucokinase activation and the regulation by glucokinase
    regulatory protein in naturally occurring mutations.
  findings: []
- id: PMID:18322640
  title: Biochemical characterization of novel glucokinase mutations isolated from
    Spanish maturity-onset diabetes of the young (MODY2) patients.
  findings: []
- id: PMID:19146401
  title: Activating mutations in the human glucokinase gene revealed by genetic selection.
  findings: []
- id: PMID:20668700
  title: Effects of GCK, GCKR, G6PC2 and MTNR1B variants on glucose metabolism and
    insulin secretion.
  findings: []
- id: PMID:22611063
  title: Insights into the pathogenicity of rare missense GCK variants from the identification
    and functional characterization of compound heterozygous and double mutations
    inherited in cis.
  findings: []
- id: PMID:24187134
  title: Identification of the ubiquitin-like domain of midnolin as a new glucokinase
    interaction partner.
  findings: []
- id: PMID:25015100
  title: Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset
    diabetes is primarily mediated through effects on protein stability.
  findings: []
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
- id: PMID:7742312
  title: 'Sugar specificity of human beta-cell glucokinase: correlation of molecular
    models with kinetic measurements.'
  findings: []
- id: PMID:8132752
  title: Insulin secretory abnormalities in subjects with hyperglycemia due to glucokinase
    mutations.
  findings: []
- id: PMID:8325892
  title: Structure/function studies of human beta-cell glucokinase. Enzymatic properties
    of a sequence polymorphism, mutations associated with diabetes, and other site-directed
    mutants.
  findings: []
- id: PMID:8446612
  title: 'Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes
    mellitus have decreased enzymatic activity: implications for structure/function
    relationships.'
  findings: []
- id: PMID:8878425
  title: Impaired hepatic glycogen synthesis in glucokinase-deficient (MODY-2) subjects.
  findings: []
- id: PMID:9570959
  title: Organization of the human glucokinase regulator gene GCKR.
  findings: []
- id: Reactome:R-HSA-170796
  title: NPC transports GCK1:GCKR from cytosol to nucleoplasm
  findings: []
- id: Reactome:R-HSA-170799
  title: cytosolic GCK1:GKRP complex <=> glucokinase (GCK1) + glucokinase regulatory
    protein (GKRP)
  findings: []
- id: Reactome:R-HSA-170810
  title: nucleoplasmic GCK1:GCKR complex => glucokinase (GCK1) + glucokinase regulatory
    protein (GCKR)
  findings: []
- id: Reactome:R-HSA-170824
  title: glucokinase (GCK1) + glucokinase regulatory protein (GKRP) <=> GCK1:GKRP
    complex
  findings: []
- id: Reactome:R-HSA-170825
  title: NPC exports GCK1 from nucleus
  findings: []
- id: Reactome:R-HSA-5621918
  title: Defective GCK does not phosphorylate Glc to form G6P
  findings: []
- id: Reactome:R-HSA-5661474
  title: Defective NPC does not transport GCK1:GKRP from cytosol to nucleoplasm
  findings: []
- id: Reactome:R-HSA-70171
  title: Glycolysis
  findings: []
- id: Reactome:R-HSA-70420
  title: HK1,2,3,GCK,HKDC1 phosphorylate Glc to form G6P
  findings: []
core_functions:
- description: ATP-dependent phosphorylation of D-glucose to D-glucose 6-phosphate,
    the committed first step of glucose utilization, catalyzed by a low-affinity (high-KM),
    cooperative, product-inhibition-resistant enzyme that thereby functions as the
    cellular glucose sensor.
  molecular_function:
    id: GO:0004340
    label: glucokinase activity
  directly_involved_in:
  - id: GO:0006006
    label: glucose metabolic process
  supported_by:
  - reference_id: file:human/GCK/GCK-uniprot.txt
    supporting_text: Mediates the initial step of glycolysis by catalyzing
- description: In the pancreatic beta cell, glucokinase acts as the glucose sensor
    that sets the threshold for glucose-stimulated insulin secretion; the low glucose
    affinity ensures its activity tracks glucose across the physiological range, so
    it is the flux-controlling determinant coupling glycolytic glucose metabolism
    to insulin release.
  molecular_function:
    id: GO:0004340
    label: glucokinase activity
  directly_involved_in:
  - id: GO:0006096
    label: glycolytic process
  supported_by:
  - reference_id: file:human/GCK/GCK-uniprot.txt
    supporting_text: GCK acts as a glucose sensor in the pancreatic beta
- description: Glucokinase is a central determinant of whole-body glucose homeostasis;
    in the liver it drives glucose uptake and glycogen synthesis and restrains gluconeogenesis,
    and its loss (MODY2/PNDM) or gain (hyperinsulinism) of function shifts the glucose
    set-point.
  molecular_function:
    id: GO:0004340
    label: glucokinase activity
  directly_involved_in:
  - id: GO:0042593
    label: glucose homeostasis
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: file:human/GCK/GCK-uniprot.txt
    supporting_text: insulin-sensitive determinant of hepatic glucose usage