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.
| 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 |
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