Glucokinase is an ATP-dependent enzyme that converts D-glucose to glucose 6-phosphate. Its relatively low glucose affinity and cooperative response couple glucose availability to metabolic flux. In pancreatic beta cells, this activity helps set the threshold for glucose-stimulated insulin secretion; in hepatocytes it supports glucose utilization and glycogen accumulation. Cytosolic GCK can be sequestered in the nucleus through interaction with GCKR. Tissue-specific promoters and alternative splicing generate proteins with different amino termini. Reduced GCK activity causes hyperglycemia, whereas activating variants can cause hyperinsulinemic hypoglycemia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001678 intracellular glucose homeostasis | IBA GO_REF:0000033 | ACCEPT | Summary: The curated intracellular glucose-homeostasis inheritance is biologically coherent. Reason: The actual AN2/PTN000455350 assertion and descendant path were verified. Human GCK performs the conserved glucose-phosphorylation step; the multi-organism donor evidence is retained without equating donor count with strength or confusing intracellular control with every whole-organism phenotype. |
| GO:0001678 intracellular glucose homeostasis | IEA GO_REF:0000002 | ACCEPT | Summary: Glucose phosphorylation directly contributes to intracellular glucose homeostasis. Reason: The conserved hexokinase-domain assignment is consistent with GCK’s concentration-dependent conversion of free glucose to glucose 6-phosphate. This is direct metabolic work controlling intracellular glucose utilization, not merely an association with diabetes. |
| GO:0004340 glucokinase activity | EXP PMID:7742312 Sugar specificity of human beta-cell glucokinase: correlatio... | ACCEPT | Summary: Purified human beta-cell GCK catalyzes glucose phosphorylation. Reason: The authentic PMID:7742312 abstract directly reports human beta-cell GCK glucose phosphorylation. The separately inspected UniProt BIOPHYSICOCHEMICAL PROPERTIES block attributes a glucose Km of 6.03 mM and kcat of 66.4 s−1 at 30 °C and pH 7.5 to this paper. These curated numerical values are available even though the original tables were not accessed; the core glucose reaction is directly supported. |
| GO:0004340 glucokinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Conserved glucose phosphorylation is the principal GCK activity. Reason: Human enzyme assays independently establish ATP-dependent glucose phosphorylation. The actual PTHR19443 tree and MIA place the target below the glucokinase IBD at AN0/PTN004516717; there is no target-lineage loss. Human GCK appearing among the descendant evidence is legitimate target grounding, not circularity. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN004516717 SUPPORTS TRANSFER Actual AN0 IBD, target descent and literal donor set independently replayed; human biochemical grounding agrees. |
| GO:0004340 glucokinase activity | IDA PMID:12941786 Insights into the biochemical and genetic basis of glucokina... | ACCEPT | Summary: The hyperinsulinism study directly assays human glucokinase. Reason: The authentic PMID12941786 abstract describes purified human GCK variants and wild-type comparisons, including altered catalytic properties of activating substitutions. Those measurements establish the underlying normal glucose-phosphorylation activity. The modeled insulin-secretion threshold is a separate inference and is not needed to establish this molecular function. Supporting Evidence: |
| GO:0004340 glucokinase activity | IDA PMID:16173921 Effects of novel maturity-onset diabetes of the young (MODY)... | ACCEPT | Summary: Original human wild-type and variant assays directly support glucokinase activity. Reason: The inspected PMID16173921 Methods and Results measure glucose-dependent activity of purified human beta-cell GST-GCK alongside disease variants using a glucose-6-phosphate-dehydrogenase-coupled assay. This is direct catalytic support; the loss of activity in particular substitutions does not negate wild-type GCK activity. Supporting Evidence: |
| GO:0004340 glucokinase activity | IDA PMID:22611063 Insights into the pathogenicity of rare missense GCK variant... | ACCEPT | Summary: The compound-variant study measures human GCK glucose phosphorylation directly. Reason: The available original PMID22611063 Methods and Results use human pancreatic GCK sequence NM_000162.3, purified wild-type and mutant GST proteins, and coupled glucose/ATP kinetic assays. The study separates kinetic changes, instability and neutral variation. Its wild-type comparison supports the normal enzyme activity independently of clinical classification. Supporting Evidence: |
| GO:0004340 glucokinase activity | IDA PMID:8446612 Glucokinase mutations associated with non-insulin-dependent ... | ACCEPT | Summary: Direct human recombinant-enzyme mutagenesis supports the glucose reaction. Reason: PMID8446612 reports expression and kinetic characterization of human beta-cell glucokinase and disease-associated variants. The wild-type and mutant glucose-dependent measurements support glucokinase activity; structural modeling and the clinical interpretation are distinct from the experimentally measured reaction. Supporting Evidence: |
| GO:0004340 glucokinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The combined ortholog and reaction mapping identifies the correct glucose reaction. Reason: The mapped reaction is ATP-dependent conversion of D-glucose to glucose 6-phosphate, matching the official term definition and direct human GCK assays. The retained ortholog and RHEA source fields describe this valid conserved catalytic assignment; they do not imply that every natural human product was assayed. Supporting Evidence: |
| GO:0004340 glucokinase activity | IMP PMID:18322640 Biochemical characterization of novel glucokinase mutations ... | ACCEPT | Summary: Human MODY2 variant kinetics support the canonical catalytic function. Reason: The authentic PMID18322640 abstract reports functional characterization of six human GCK variants against wild type, with reduced or undetectable activity in particular mutants. It supports the normal glucose-phosphorylation function without treating each pathogenic substitution or every natural product as functionally equivalent. Supporting Evidence: |
| GO:0004340 glucokinase activity | IMP PMID:19146401 Activating mutations in the human glucokinase gene revealed ... | ACCEPT | Summary: Human activating-variant assays retain the same glucokinase reaction. Reason: PMID19146401 reports human GCK mutagenesis and kinetic characterization of activating variants, including increased catalytic efficiency relative to wild type. Altered efficiency is evidence about an existing glucose-phosphorylation reaction, not a distinct molecular function or a general claim about all natural products. Supporting Evidence: |
| GO:0004340 glucokinase activity | TAS Reactome:R-HSA-5621918 | ACCEPT | Summary: Normal GCK glucokinase activity is supported separately from the defective Reactome event. Reason: The cited R-HSA-5621918 is explicitly a defective GCK-mutant reaction. Its linked normal event R-HSA-70420 resolves through catalyst set R-HSA-450097 to human P35557, chain 1–465, and glucose-to-glucose-6-phosphate chemistry. Retain the true molecular function on this original context using that normal target chain and independent human assays; do not portray the failed mutant event itself as a successful wild-type assay. |
| GO:0004340 glucokinase activity | TAS Reactome:R-HSA-70420 | ACCEPT | Summary: The normal Reactome catalyst chain explicitly includes human GCK. Reason: R-HSA-70420 represents ATP-dependent glucose phosphorylation. Its catalyst set R-HSA-450097 contains GCK entity R-HSA-450094, explicitly UniProt P35557 residues 1–465 in cytosol. This is a target-specific curated reaction chain, corroborated by human enzyme measurements, rather than an assignment from the pathway name alone. |
| GO:0004396 hexokinase activity | EXP PMID:11916951 The second activating glucokinase mutation (A456V): implicat... | TOO GENERAL | Summary: The A456V study supports a more specific glucose reaction already retained. Reason: The authentic PMID11916951 abstract compares purified human wild-type and A456V GCK kinetics, directly supporting glucose phosphorylation. That evidence is valid. The parent hexokinase term is less informative than accepted GO:0004340, its official is_a descendant; the action addresses term redundancy rather than rejecting this experiment. Supporting Evidence: |
| GO:0004396 hexokinase activity | EXP PMID:15277402 Severe persistent hyperinsulinemic hypoglycemia due to a de ... | TOO GENERAL | Summary: The activating Y214C study is valid support for the retained glucokinase activity. Reason: PMID15277402 links a human activating GCK variant to hyperinsulinism and reports recombinant-enzyme kinetic characterization. Its glucose reaction is already represented by accepted GO:0004340. GO:0004396 is the true but redundant enzyme-class parent; the variant phenotype is not evidence that the reference enzyme lacks this class of activity. Supporting Evidence: |
| GO:0004396 hexokinase activity | EXP PMID:17082186 Biochemical basis of glucokinase activation and the regulati... | TOO GENERAL | Summary: The kinetic-mechanism study supports the specific activity already asserted. Reason: The authentic PMID17082186 abstract examines human wild-type and activating GCK variants, glucose binding and kinetic transitions. The evidence supports the glucose reaction while distinguishing ligand binding from catalytic conformational steps. The broad hexokinase class is subsumed by accepted GO:0004340 through the verified is_a edge. Supporting Evidence: |
| GO:0004396 hexokinase activity | EXP PMID:18322640 Biochemical characterization of novel glucokinase mutations ... | TOO GENERAL | Summary: The broad term duplicates the specific activity supported by the same variant study. Reason: PMID18322640 genuinely measures human GCK variant function relative to wild type. Its glucose-phosphorylation evidence also supports the specific glucokinase annotation retained above. The enzyme-class parent GO:0004396 adds no further functional specificity; this judgment does not dispute the experimental measurements. Supporting Evidence: |
| GO:0004396 hexokinase activity | EXP PMID:19146401 Activating mutations in the human glucokinase gene revealed ... | TOO GENERAL | Summary: Human activating-variant kinetics are already represented at glucose-reaction specificity. Reason: PMID19146401 provides human GCK kinetic evidence, not merely a sequence-family prediction. The supported activity is captured by accepted GO:0004340, an actual is_a child of GO:0004396. Mark only the redundant broad term as too general while retaining this source as evidence for the enzyme. Supporting Evidence: |
| GO:0004396 hexokinase activity | EXP PMID:25015100 Phenotypic severity of homozygous GCK mutations causing neon... | TOO GENERAL | Summary: The original stability study includes direct glucose/ATP activity assays. Reason: The inspected PMID25015100 Results and Methods use wild-type and mutant human beta-cell GCK, coupled glucose-phosphorylation assays and thermostability measurements. Protein stability helps explain the clinical variation, but the catalytic measurements also support the specific glucokinase function. Its hexokinase parent is redundant with accepted GO:0004340, not biologically false. Supporting Evidence: |
| GO:0004396 hexokinase activity | EXP PMID:8325892 Structure/function studies of human beta-cell glucokinase. E... | TOO GENERAL | Summary: Human GCK mutagenesis supports the glucose activity already retained. Reason: The authentic PMID8325892 abstract describes direct functional characterization of human beta-cell glucokinase mutations. The broad ATP-dependent hexose-phosphorylation class is correct, but accepted GO:0004340 supplies its verified glucose-specific is_a descendant. Preserve the evidence while avoiding a redundant broad molecular-function assertion. Supporting Evidence: |
| GO:0004396 hexokinase activity | IEA GO_REF:0000120 | TOO GENERAL | Summary: The true hexokinase class adds no specificity beyond the retained substrate-defined activities. Reason: The RHEA, EC, ortholog and domain mapping correctly places GCK in ATP-dependent hexose phosphorylation. Official GO:0004340 glucokinase activity is an is_a child of GO:0004396 and is already accepted. The broad row is therefore redundant, not an erroneous transfer or a denial of the enzyme’s measured substrate range. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:11522786 Characterization of glucokinase-binding protein epitopes by ... | MODIFY | Summary: GCK binds the phosphatase domain of bifunctional PFKFB1. Reason: The original study maps the interaction to PFKFB1’s fructose-2,6-bisphosphatase domain, supporting phosphatase binding. Human beta-cell GCK was tested with rat liver PFKFB1; the incoming human WITH identifier remains unchanged. This is sugar-phosphatase binding, not protein-phosphatase binding, and does not establish that GCK activates PFKFB1. Proposed replacements: phosphatase binding Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:11522786 Characterization of glucokinase-binding protein epitopes by ... | REMOVE | Summary: The named GCKR interaction is supported but the generic binding term is uninformative. Reason: Human GCK binding to rat GCKR was demonstrated in the source study. Preserve that regulatory-complex evidence and the incoming human partner identifier. GCKR’s inhibition of GCK does not make GCK an enzyme inhibitor, and the fact that GCK is an enzyme does not establish enzyme binding when its partner is the regulator. Remove only the generic annotation under the protein-binding policy. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:16173921 Effects of novel maturity-onset diabetes of the young (MODY)... | REMOVE | Summary: Retain the GCK–GCKR evidence while removing generic protein binding. Reason: The selected original study includes GCK–GKRP interaction testing alongside purified human GCK kinetics; Q07071 is the rat GCKR record. The generic term adds no informative molecular role beyond the established regulated enzyme complex. Its removal does not reject binding or infer that the regulatory protein is a catalytic enzyme. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI supports the GCK–SPDYE4 pair without assigning a specific GCK binding function. Reason: The original dataset contains P35557-1/ORF3689 with A6NLX3/ORF70835 in array, pooling and validated two-hybrid records. These support the reported binary association in yeast. They do not establish a native GCK regulatory mechanism or physiological complex, so remove the uninformative generic term without denying the screen result. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: The GCKR-mapped HuRI interaction does not require a generic protein-binding annotation. Reason: The source clone uses A0A0C4DFN2/ORF54784; shared Ensembl gene and protein identifiers support its gene-level GCKR crosswalk to Q14397. Full clone-to-current-product sequence equivalence remains unverified. Preserve the positive two-hybrid result and incoming Q14397 field, while removing the generic term for lack of informative functional specificity. |
| GO:0005524 ATP binding | IDA PMID:12941786 Insights into the biochemical and genetic basis of glucokina... | ACCEPT | Summary: The human activating-variant study supports ATP-dependent catalysis. Reason: PMID12941786 provides direct kinetic characterization of human wild-type and activating GCK variants. The ATP-binding annotation is consistent with that substrate-dependent enzymology and with independent human GCK ATP kinetics; the clinical phenotype alone is not being used as a binding assay. |
| GO:0005524 ATP binding | IDA PMID:16173921 Effects of novel maturity-onset diabetes of the young (MODY)... | ACCEPT | Summary: Original human GCK kinetics directly vary the ATP co-substrate. Reason: The inspected PMID16173921 Methods and Results include ATP-dependent assays of purified human GCK and derive ATP affinity separately from glucose dependence. They support ATP engagement in catalysis without implying a separate physiological ATP-hydrolysis function. Supporting Evidence: |
| GO:0005524 ATP binding | IDA PMID:8446612 Glucokinase mutations associated with non-insulin-dependent ... | ACCEPT | Summary: The historical human GCK mutagenesis evidence is consistent with ATP binding. Reason: PMID8446612 directly characterizes human recombinant GCK and disease variants. Retain the curator’s ATP-binding assignment, independently corroborated by explicit human ATP kinetics in PMID16173921. The available abstract does not license an invented residue-level ATP contact or a claim of a newly inspected crystal structure. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ATP binding is a necessary molecular component of the central GCK reaction. Reason: The domain mapping agrees with human enzyme measurements using ATP as the phosphate donor. ATP binding is a distinct co-substrate-binding facet of the accepted glucokinase function, not evidence for a separate ATP-driven motor or ATPase role. Supporting Evidence: |
| GO:0005536 D-glucose binding | IDA PMID:12941786 Insights into the biochemical and genetic basis of glucokina... | ACCEPT | Summary: Human GCK variant kinetics support glucose recognition. Reason: PMID12941786 measures altered glucose-dependent catalytic properties of human activating variants against wild type. This supports the retained D-glucose-binding claim together with direct human enzyme kinetics; no modeled insulin-secretion threshold is substituted for the molecular measurement. Supporting Evidence: |
| GO:0005536 D-glucose binding | IDA PMID:16173921 Effects of novel maturity-onset diabetes of the young (MODY)... | ACCEPT | Summary: The original human enzyme study directly measures glucose-dependent kinetics. Reason: PMID16173921 tests purified human wild-type and mutant GCK across glucose concentrations. The resulting glucose-affinity and activity measurements support substrate binding as part of the central reaction. They do not establish identical binding properties for every natural product. Supporting Evidence: |
| GO:0005536 D-glucose binding | IDA PMID:8446612 Glucokinase mutations associated with non-insulin-dependent ... | ACCEPT | Summary: Human recombinant GCK mutagenesis supports D-glucose binding. Reason: The authentic PMID8446612 abstract reports functional effects on human GCK glucose kinetics. Retain the established substrate-binding assignment; the available evidence supports glucose recognition without requiring a residue-specific structural claim from an unread full paper. Supporting Evidence: |
| GO:0005536 D-glucose binding | IEA GO_REF:0000002 | ACCEPT | Summary: D-glucose binding is intrinsic to GCK’s principal catalytic and sensing functions. Reason: The domain-based assignment agrees with direct human glucose-dependent enzyme measurements. Binding D-glucose is the substrate-recognition facet of the established glucose-phosphorylation activity; it does not imply transport across a membrane or binding every sugar equally. Supporting Evidence: |
| GO:0005634 nucleus | EXP PMID:10456334 Glucokinase regulatory protein is essential for the proper s... | MODIFY | Summary: Nuclear localization is supported, with a more precise nucleoplasmic assignment available. Reason: The cited work used rat and Xenopus constructs in several recipient cell systems; recipient species does not identify construct species. Preserve the incoming experimental context. The independently checked human GCK–GCKR nucleoplasmic model supports the refinement, not a claim that the original experiment directly tested every human natural product. Proposed replacements: nucleoplasm |
| GO:0005634 nucleus | EXP PMID:24187134 Identification of the ubiquitin-like domain of midnolin as a... | MODIFY | Summary: The reported nuclear pool is compatible with nucleoplasmic GCK. Reason: The selected original study distinguishes cellular systems and overexpression conditions; it does not establish universal nuclear residence. Retain that conditional pool and refine using the separately verified human nucleoplasmic participant chain. This does not turn the MIDN interaction into a nuclear enzyme reaction. Proposed replacements: nucleoplasm |
| GO:0005634 nucleus | IEA GO_REF:0000120 | MODIFY | Summary: The nuclear pool can be placed more precisely in the nucleoplasm. Reason: The ortholog/keyword synthesis is consistent with regulated nuclear sequestration. The human Reactome chain places P35557 in the nucleoplasmic GCK–GCKR pool. Refine to nucleoplasm through its verified part_of nuclear-lumen/nucleus path, without claiming the mouse inference itself resolved the subcompartment. Proposed replacements: nucleoplasm Supporting Evidence: Reactome:R-HSA-170810 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-170796 | ACCEPT | Summary: The import reaction explicitly places GCK in a nucleoplasmic complex. Reason: R-HSA-170796 outputs complex170804, whose GCK component450102 is human P35557, chain1–465, in nucleoplasm. This supports the regulated nuclear pool, not a GCK nuclear-pore structural or transport activity. Supporting Evidence: Reactome:R-HSA-170796 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-170810 | ACCEPT | Summary: Nucleoplasmic dissociation contains the exact human GCK participant. Reason: R-HSA-170810 links complex170804 to free GCK450102/P35557 in nucleoplasm. The location belongs to the enzyme’s regulated pool; GCK is not assigned GCKR’s inhibitory function or an exclusive nuclear localization. Supporting Evidence: Reactome:R-HSA-170810 |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-170825 | ACCEPT | Summary: The nuclear export reaction directly identifies nucleoplasmic GCK. Reason: R-HSA-170825 uses GCK450102/P35557 in nucleoplasm as input and GCK450094 in cytosol as output. Its role as transported cargo supports location without making GCK the nuclear-export machinery. Supporting Evidence: Reactome:R-HSA-170825 |
| GO:0005737 cytoplasm | EXP PMID:10456334 Glucokinase regulatory protein is essential for the proper s... | MODIFY | Summary: Refine the broad cytoplasmic localization to cytosol. Reason: Preserve the original mixed construct/recipient provenance and experimental evidence code. Human cytosolic GCK is independently represented in the reaction70420→set450097→P35557 entity450094 chain, supporting a more precise location without claiming the cited assay alone resolves every subcellular pool. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | EXP PMID:24187134 Identification of the ubiquitin-like domain of midnolin as a... | MODIFY | Summary: The cytoplasmic GCK pool is more precisely represented as cytosol. Reason: The selected original localization evidence is consistent with cytosolic GCK in the tested cell systems. Its separate nuclear observations are nonexclusive. Refine the broad term through the verified cytosol part_of cytoplasm edge, with independent human Reactome support. Proposed replacements: cytosol |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | MODIFY | Summary: Cytosol specifies the informative component of the broad cytoplasmic pool. Reason: The keyword assignment agrees with established soluble GCK activity. The verified cytosol part_of cytoplasm edge and exact human Reactome enzyme entity support refinement to cytosol; this does not exclude independently retained mitochondrial association. Proposed replacements: cytosol Supporting Evidence: Reactome:R-HSA-70420 |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: The mitochondrial synthesis is compatible with a secondary GCK pool. Reason: The mouse/keyword inference is consistent with the retained PAINT surface placement and rat mitochondrial observations. These do not establish that mitochondrial residence is GCK’s principal functional location or prove a specific topology in every product. Retain the organelle claim under the root-organelle policy. Supporting Evidence: |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain mitochondrial association as a secondary ortholog-supported location. Reason: The rat donor’s mitochondrial evidence is positive but leaves cytoskeletal association and the identity of all measured low-Km kinase activity unresolved. It supports a bounded organelle association, not human matrix import or a GCK-specific respiratory-coupling mechanism. Keep the root-organelle claim without replacing it with a finer compartment. Supporting Evidence: |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: Cytosol is the principal compartment of active GCK. Reason: The actual AN2/PTN000455350 IBD covers human GCK, with legitimate target experimental evidence among its descendants. Human GCK catalysis and the verified Reactome P35557 cytosolic entity independently support this central location; self-donor evidence is not circular. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: The human localization record supports the principal cytosolic pool. Reason: Retain the direct HPA cytosol assignment, independently consistent with the human GCK reaction entity450094/P35557. No antibody image reanalysis or natural-product exclusivity is claimed from the retained GOA record. Supporting Evidence: GO_REF:0000052 Reactome:R-HSA-70420 |
| GO:0005829 cytosol | IEA GO_REF:0000107 | ACCEPT | Summary: Cytosolic localization is conserved and central to GCK function. Reason: The mouse-to-human inference agrees with direct human localization and the exact P35557 cytosolic reaction entity. Retain the incoming ortholog identifiers; conservation does not imply that the nuclear or mitochondrial pools are absent. Supporting Evidence: Reactome:R-HSA-70420 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170796 | ACCEPT | Summary: The nuclear-import input complex contains cytosolic human GCK. Reason: R-HSA-170796 input170827 contains GCK450094/P35557 in cytosol before import. This is a location assertion for the cargo, not a GCK transport function. Supporting Evidence: Reactome:R-HSA-170796 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170799 | ACCEPT | Summary: Cytosolic GCK is an explicit participant of complex dissociation. Reason: R-HSA-170799 connects cytosolic complex170827 with GCK450094/P35557. Retain the location while distinguishing the enzyme from its inhibitory regulator. Supporting Evidence: Reactome:R-HSA-170799 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170824 | ACCEPT | Summary: Complex assembly explicitly includes cytosolic GCK. Reason: R-HSA-170824 uses GCK450094/P35557 in cytosol and produces complex170827. The inhibitor activity assigned in the event belongs to GCKR, not GCK. Supporting Evidence: Reactome:R-HSA-170824 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-170825 | ACCEPT | Summary: Cytosolic GCK is the verified output of nuclear export. Reason: R-HSA-170825 outputs entity450094/P35557 in cytosol. This supports the active cytosolic pool without treating a transported protein as the export machinery. Supporting Evidence: Reactome:R-HSA-170825 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5621918 | ACCEPT | Summary: The defective-variant record is compatible with the independently verified cytosolic location. Reason: R-HSA-5621918 represents defective GCK variants, not a wild-type catalytic success assay. Its normal reaction70420 contains the exact cytosolic P35557 entity450094, independently supporting the retained location. Supporting Evidence: Reactome:R-HSA-5621918 Reactome:R-HSA-70420 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5661474 | ACCEPT | Summary: The defective nuclear-pore event still contains cytosolic GCK cargo. Reason: R-HSA-5661474 input170827 contains GCK450094/P35557. The defect is assigned to the nuclear-pore complex, and normal transport is170796. Retain GCK’s location without attributing the pore defect or thyroid-carcinoma mechanism to GCK. Supporting Evidence: Reactome:R-HSA-5661474 Reactome:R-HSA-170796 |
| GO:0005829 cytosol | TAS Reactome:R-HSA-70420 | ACCEPT | Summary: The human glucose-phosphorylation event explicitly contains cytosolic GCK. Reason: R-HSA-70420 catalyst set450097 includes entity450094/P35557, chain1–465, in cytosol. This directly supports the location of the principal metabolic activity. Supporting Evidence: Reactome:R-HSA-70420 |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | TOO GENERAL | Summary: The broad carbohydrate-metabolism claim is already covered more informatively. Reason: The domain mapping is true, but accepted glucose catabolism is a strict is_a descendant of carbohydrate metabolism through the verified ontology paths. Retain the specific metabolic claims rather than a second uninformative family-level umbrella; the underlying enzymatic evidence is not disputed. |
| GO:0006006 glucose metabolic process | IBA GO_REF:0000033 | TOO GENERAL | Summary: Valid glucose-metabolism inheritance is superseded in specificity by retained glucose catabolism. Reason: The actual AN0/PTN004516717 placement is sound and human self-evidence is legitimate. GO:0006007 is_a GO:0006006, and the former is retained with direct human support. This is a granularity decision, not a failure of PAINT or a claim that glucose metabolism is false. Supporting Evidence: |
| GO:0006007 glucose catabolic process | IMP PMID:12941786 Insights into the biochemical and genetic basis of glucokina... | ACCEPT | Summary: Human GCK catalyses the entry reaction into glucose catabolism. Reason: The activating-variant study directly characterizes human glucose-dependent enzyme activity. Together with the exact human glucose-phosphorylation reaction, it supports participation in glucose catabolism by catalysis, rather than assigning the process merely from the hypoglycemia phenotype. |
| GO:0006096 glycolysis | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited glycolytic role agrees with GCK’s actual catalytic step. Reason: The verified AN2 assertion covers human GCK. Reactome independently places its P35557 enzyme entity in the glucose-to-glucose-6-phosphate reaction within glycolysis. The function is supported by direct pathway participation, not by the number or identities of family donors alone. Supporting Evidence: Reactome:R-HSA-70171 Reactome:R-HSA-70420 |
| GO:0006096 glycolysis | IEA GO_REF:0000120 | ACCEPT | Summary: The electronic glycolysis mapping is appropriate for GCK. Reason: The mapped pathway and domain agree with glucose phosphorylation by human GCK and the verified reaction membership. GCK catalyses a pathway step; the annotation does not require it to catalyse every glycolytic reaction or establish an identical role for each alternative product. Supporting Evidence: Reactome:R-HSA-70171 Reactome:R-HSA-70420 |
| GO:0006110 regulation of glycolysis | NAS PMID:9570959 Organization of the human glucokinase regulator gene GCKR. | ACCEPT | Summary: GCK controls glycolytic entry through its regulated glucose-phosphorylation activity. Reason: The cited GCKR gene paper provides regulatory context rather than a new GCK catalytic assay. The physiological claim is independently grounded in the concentration-dependent enzyme and its regulated availability. GCK’s role in setting glucose utilization is retained without assigning GCKR’s kinase-inhibitor activity to GCK. |
| GO:0008865 fructokinase activity | EXP PMID:7742312 Sugar specificity of human beta-cell glucokinase: correlatio... | MARK AS OVER ANNOTATED | Summary: The human fructose assay is accepted; its physiological function is not established here. Reason: Human fructose-to-fructose-6-phosphate turnover is experimentally supported. UniProt attributes Km 240 mM and kcat 116.9 s−1 at 30 °C and pH 7.5 to PMID:7742312, giving an approximate kcat/Km of 0.49 mM−1 s−1 versus 11.0 for glucose under the reported conditions. This quantified activity does not establish a physiological GCK fructose role; retain the unknown-relevance tier without equating it to KHK fructose-1-phosphate chemistry or inventing an in-vivo substrate concentration. |
| GO:0008865 fructokinase activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Inherited fructose phosphorylation is real chemistry with unresolved GCK-specific physiological use. Reason: The actual AN0/PTN004516717 IBD and target descent are valid. Human turnover of fructose is reported in PMID7742312, but the selected evidence does not establish a physiological role for GCK in this reaction. Apply the unknown-relevance activity tier, without asserting a lineage error or loss. GO:0008865 denotes fructose-6-phosphate production, not KHK’s fructose-1-phosphate reaction. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN004516717 SUPPORTS TRANSFER Actual AN0 IBD, target descent and donor set match. No lineage or propagation failure is asserted; the action concerns uncertain physiological relevance of the verified activity. UniProtKB:P35557 SUPPORTS TRANSFER Human fructose phosphorylation in PMID7742312 is legitimate experimental self-donor support. It does not independently establish GCK-specific physiological fructose utilization. |
| GO:0008865 fructokinase activity | IEA GO_REF:0000116 | MARK AS OVER ANNOTATED | Summary: The mapped fructose reaction exceeds the established physiological scope. Reason: RHEA:16125 maps to genuine fructose-to-fructose-6-phosphate chemistry. The human substrate study supports turnover, while GCK-dependent physiological use remains unresolved in the selected evidence. Retain the measurement and literal mapping but mark its functional assignment as over-annotated; no quantitative comparison with another enzyme is asserted. |
| GO:0009749 response to glucose | ISS GO_REF:0000024 | ACCEPT | Summary: Glucose-dependent GCK activity is part of the physiological glucose response. Reason: Rat donor experiments connect GCK to glucose sensing through enzyme-activity changes and inhibitor-sensitive neuronal calcium oscillations, beyond expression alone. Independent human enzyme and insulin-response studies support the conserved glucose-responsive role. Preserve the ISS donor context without treating rat neural experiments as direct human assays. |
| GO:0019158 mannokinase activity | EXP PMID:7742312 Sugar specificity of human beta-cell glucokinase: correlatio... | MARK AS OVER ANNOTATED | Summary: Efficient human mannose phosphorylation is established; its physiological GCK contribution remains unresolved. Reason: UniProt attributes mannose Km 4.35 mM and kcat 56.4 s−1 to PMID:7742312, compared with glucose 6.03 mM and 66.4 s−1 at the same reported temperature and pH. The approximate kcat/Km values are 13.0 and 11.0 mM−1 s−1: mannose activity is substantial, not noise. The functional uncertainty is GCK-dependent physiological use, not missing numerical kinetics. Reaction-direction curation does not establish cellular flux; retain MARK_AS_OVER_ANNOTATED under the unknown-relevance tier. |
| GO:0019158 mannokinase activity | IBA GO_REF:0000033 | MARK AS OVER ANNOTATED | Summary: Valid mannokinase inheritance does not by itself establish physiological mannose use by GCK. Reason: Actual AN108/PTN002714980 descent and the human experimental self-donor support mannokinase inheritance. The curated numerical kinetics confirm substantial mannose activity, but do not resolve its contribution in cells where substrate concentrations and competing hexokinases matter. This is the unknown-physiological-relevance tier, not a false reaction, absent kinetic data or defective PAINT placement. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002714980 SUPPORTS TRANSFER Actual AN108 IBD, target descent and donor set match. No lineage or propagation failure is asserted; the action concerns uncertain physiological relevance of the verified activity. UniProtKB:P35557 SUPPORTS TRANSFER Human mannose phosphorylation in PMID7742312 is legitimate experimental self-donor support. It does not independently establish GCK-specific physiological mannose utilization. |
| GO:0019158 mannokinase activity | IEA GO_REF:0000116 | MARK AS OVER ANNOTATED | Summary: The mannose reaction mapping is chemically supported but physiologically unresolved. Reason: RHEA:11028 and GO:0019158 correctly specify mannose-to-mannose-6-phosphate conversion, and the curated human kinetics show substantial activity. PhysiologicalDirection=left-to-right records the reaction direction; it does not measure GCK-dependent cellular mannose flux. Keep the genuine reaction mapping and the unknown-relevance functional judgment distinct. |
| GO:0019318 hexose metabolic process | IEA GO_REF:0000041 | TOO GENERAL | Summary: Hexose metabolism is broader than the retained glucose-specific catabolic role. Reason: The current ontology places accepted glucose catabolism below hexose metabolism through is_a paths. The mapping remains true; the more specific existing claim supplies the informative scope. This does not promote the unresolved physiological mannose/fructose activities into central functions. |
| GO:0032024 positive regulation of insulin secretion | IMP PMID:8132752 Insulin secretory abnormalities in subjects with hyperglycem... | ACCEPT | Summary: Human GCK is a central positive regulator of glucose-stimulated insulin secretion. Reason: The original patient study measures a shifted glucose/insulin-secretion response using individualized C-peptide kinetics. Preserved first-phase or aggregate daily secretion does not negate the conditional defect. GCK performs the glucose-responsive catalytic step; it is not being labelled as exocytotic machinery. Supporting Evidence: |
| GO:0032024 positive regulation of insulin secretion | IMP PMID:8878425 Impaired hepatic glycogen synthesis in glucokinase-deficient... | ACCEPT | Summary: The source supports a conditional insulin-secretory effect of GCK deficiency. Reason: The original Results report reduced breakfast insulin peak and integrated response, with later meal responses preserved. Independent glucose-infusion experiments establish the GCK-dependent secretion mechanism. Retain the positive regulatory claim without treating the hepatic glycogen assay as an insulin-vesicle assay. |
| GO:0032473 cytoplasmic side of mitochondrial outer membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain the ancestral peripheral mitochondrial-surface placement with explicit topology limits. Reason: The actual AN2/PTN000455350 assertion includes the human target and donors HK2 and the single-domain plant hexokinase M4FD55. GO:0032473 includes peripheral association; it does not require the HK1/HK2 mitochondrial-binding peptide or VDAC interaction. GCK’s distinct amino terminus warrants caution about mechanism, but does not prove loss of all such association. The mouse BAD-containing GCK complex in the PMID:12931191 abstract and rat fractionation in PMID:16542652 provide bounded ortholog support, without resolving human sidedness or direct GCK–VDAC binding. Retain the genuine IBA as non-core. |
| GO:0032869 cellular response to insulin stimulus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Retain a contextual cellular response of GCK activity to insulin. Reason: The donor-source abstract reports insulin-dependent changes in hypothalamic GCK activity and prevention of a glucose-dependent activity decrease. This supports the bounded metabolic response, not insulin-receptor or signaling-transducer activity of GCK. The original human ISS from rat P17712 remains intact. Supporting Evidence: |
| GO:0042593 glucose homeostasis | IMP PMID:20668700 Effects of GCK, GCKR, G6PC2 and MTNR1B variants on glucose m... | ACCEPT | Summary: GCK’s role in glucose homeostasis has independent causal and physiological support. Reason: The cited cohort associates GCK variation with glucose and secretion-related traits; it is not a purified-protein perturbation experiment. Retain the incoming IMP context unchanged and assess the whole claim using independent human GCK mutation studies. Whole-organism glucose control is central, beyond intracellular substrate handling alone. |
| GO:0042593 glucose homeostasis | IMP PMID:8132752 Insulin secretory abnormalities in subjects with hyperglycem... | ACCEPT | Summary: Human glucose homeostasis depends on GCK’s glucose-sensing set point. Reason: The original glucose-infusion study links GCK mutations to altered beta-cell responsiveness and elevated glucose. This supports central systemic glucose control through GCK’s own concentration-responsive catalytic work; it is not a claim that all associated diabetic complications are direct GCK functions. Supporting Evidence: |
| GO:0044320 cellular response to leptin stimulus | ISS GO_REF:0000024 | UNDECIDED | Summary: The source-specific leptin response remains unresolved. Reason: The authentic abstract reports peptide effects in GT1-7 cells and rat hypothalamic slices, but only NPY significantly reduces activity in the specified rat-slice comparison. The inaccessible complete GT1-7 experiment prevents a confident leptin-specific judgment. That limitation does not establish no leptin effect throughout the paper or justify rejecting the donor curator. Supporting Evidence: |
| GO:0045721 negative regulation of gluconeogenesis | IMP PMID:8878425 Impaired hepatic glycogen synthesis in glucokinase-deficient... | KEEP AS NON CORE | Summary: Retain a bounded physiological effect on gluconeogenic contribution. Reason: The original study finds a higher relative indirect/gluconeogenic contribution to hepatic glycogen synthesis in GCK-deficient subjects. Mechanism remains unresolved, including altered hormone balance. Retain this contextual regulation without claiming direct inhibition of a gluconeogenic enzyme or deriving absolute flux from relative fractions. Supporting Evidence: |
| GO:0045725 positive regulation of glycogen biosynthetic process | IMP PMID:8878425 Impaired hepatic glycogen synthesis in glucokinase-deficient... | KEEP AS NON CORE | Summary: GCK activity promotes hepatic glycogen accumulation in the tested physiological setting. Reason: Lower post-meal hepatic glycogen accumulation persists when later-meal insulin/glucagon are similar, supporting a hepatic contribution of GCK. This is a tissue-specific outcome of glucose phosphorylation, not glycogen-polymer synthesis by GCK itself. Supporting Evidence: |
| GO:0050796 regulation of insulin secretion | IBA GO_REF:0000033 | TOO GENERAL | Summary: The valid general insulin-secretion regulation claim has a retained directional refinement. Reason: The AN108/PTN002714980 assertion and human self-donor grounding are sound. Accepted positive regulation of insulin secretion is a verified is_a child of this term and describes the supported direction. Use the more informative existing claim without calling the inherited one biologically false. Supporting Evidence: |
| GO:0050796 regulation of insulin secretion | IMP PMID:20668700 Effects of GCK, GCKR, G6PC2 and MTNR1B variants on glucose m... | TOO GENERAL | Summary: Retained positive regulation is more informative than undirected secretion regulation. Reason: The GCK association study supports secretion-related physiology but does not alone demonstrate a direct intervention. Independent human mutation studies establish the positive direction already retained under GO:0032024, a verified is_a child of this term. Preserve the original evidence fields and omit only the redundant general claim. |
| GO:0051156 glucose 6-phosphate metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: GCK directly produces glucose 6-phosphate. Reason: The actual AN2 assertion includes legitimate human experimental grounding. The accepted glucokinase reaction forms glucose 6-phosphate, and the current ontology explicitly places that molecular activity part_of glucose-6-phosphate metabolism. This is direct chemistry rather than an inferred downstream phenotype. |
| GO:0051156 glucose 6-phosphate metabolic process | IMP PMID:18322640 Biochemical characterization of novel glucokinase mutations ... | ACCEPT | Summary: Human GCK variant enzymology supports glucose-6-phosphate formation. Reason: The source directly compares mutant and wild-type glucose-dependent catalytic properties. Retain the product-metabolism claim through the established GCK reaction, while recognizing that an activating phenotype does not confer every downstream pathway role. Supporting Evidence: |
| GO:0051156 glucose 6-phosphate metabolic process | IMP PMID:19146401 Activating mutations in the human glucokinase gene revealed ... | ACCEPT | Summary: The GCK reaction directly participates in glucose-6-phosphate metabolism. Reason: The human activating-variant study measures altered glucose affinity and enzyme regulation. The retained reaction produces glucose 6-phosphate; the process assignment follows from that chemistry, not simply from clinical insulin excess. Supporting Evidence: |
| GO:0061621 obsolete canonical glycolysis | TAS Reactome:R-HSA-70171 | MODIFY | Summary: Replace the obsolete pathway label with the current glycolysis term. Reason: GO:0061621 is obsolete because it represents a GO-CAM model. The actual Reactome70171 pathway contains reaction70420 and its verified P35557 GCK catalyst member, so the biological pathway claim remains sound. Propose active GO:0006096 without rewriting the incoming machine-sourced identifier. Proposed replacements: glycolytic process Supporting Evidence: Reactome:R-HSA-70171 Reactome:R-HSA-70420 |
| GO:0070509 calcium ion import | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: The calcium-import assignment overextends a real upstream metabolic-coupling phenotype. Reason: The original Gck-siRNA control abolishes glucose-evoked calcium elevation in rat INS1 cells while preserving the tolbutamide insulin response. This is positive evidence for upstream metabolic coupling, which explains why the import annotation is biologically related rather than wholly baseless. It does not demonstrate that GCK performs the directed calcium movement defined by GO:0070509. MARK_AS_OVER_ANNOTATED records that unsupported extension; it does not deny the experiment, turn a BP into transporter activity, or assert a proven universal absence of involvement. Supporting Evidence: |
| GO:0141089 glucose sensor activity | ISS GO_REF:0000024 | ACCEPT | Summary: GCK directly couples glucose recognition and catalysis to glucose sensing. Reason: The official sensor definition includes binding and responding to cellular glucose concentration. Human GCK’s glucose-dependent kinetics and activating-variant effects support this mechanistic role, consistent with the rat ortholog assignment. Preserve the literal part_of glucose-response extension. GCK performs the concentration-responsive molecular step; this is not merely a protein required downstream of an unrelated sensor. |
Loading supporting content…
Download this section (compressed HTML)Q: What physiological mannose or fructose flux is specifically attributable to GCK at tissue-relevant sugar concentrations, distinct from other hexokinases and ketohexokinase?
Q: Do the 466- and 464-residue liver products differ in catalytic regulation, GCKR interaction or localization when compared at equal protein abundance?
Q: Which mitochondrial GCK pool and membrane topology are established in human cells, and how do these relate to the conserved PAINT localization and rat fractionation evidence?
Q: Which leptin-specific GT1-7 assay underlies the rat donor annotation, and does the response transfer to human GCK-containing cells?
Experiment: Measure isotope-labelled mannose and fructose phosphorylation with GCK-selective perturbation and rescue in human beta cells or hepatocytes while maintaining physiological competing glucose concentrations.
Hypothesis: Purified-enzyme substrate activity may differ from the GCK-dependent contribution to cellular alternative-sugar flux.
Experiment: Compare the three sequence-verified natural products at matched abundance for glucose kinetics, GCKR association and intracellular distribution.
Hypothesis: Amino-terminal and transcript differences may alter abundance or regulation without abolishing the shared catalytic activity.
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)