Hexokinase-1 (HK1, EC 2.7.1.1) is the ubiquitously expressed hexokinase isozyme that catalyzes the first committed step of glucose metabolism, the ATP-dependent phosphorylation of D-glucose to D-glucose 6-phosphate (G6P). G6P is then partitioned between glycolysis, the pentose phosphate pathway, and glycogen synthesis. HK1 is a ~100 kDa enzyme that arose by duplication and fusion of an ancestral ~50 kDa hexokinase; its C-terminal half carries the catalytic site while the N-terminal half carries a regulatory glucose-6-phosphate binding site. It also phosphorylates other D-hexoses including D-mannose, D-fructose, and D-glucosamine. As an allosteric enzyme it is feedback-inhibited by its product G6P. HK1 is largely cytosolic but a pool associates with the mitochondrial outer membrane through the voltage-dependent anion channel (VDAC/porin) via an N-terminal mitochondrial-binding peptide; this association couples glycolysis to oxidative phosphorylation and confers an anti-apoptotic role. Loss of red-cell hexokinase activity causes non-spherocytic hemolytic anemia, and specific HK1 variants cause hereditary motor and sensory neuropathy and retinitis pigmentosa.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004340 glucokinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA transfer of glucose-phosphorylating (glucokinase) activity across the hexokinase family. In GOA practice this term is used for the glucose-to-G6P reaction catalyzed by hexokinases, which is HK1's core catalytic reaction, though captured most precisely by the broad hexokinase activity term. Reason: HK1 phosphorylates D-glucose to D-glucose 6-phosphate, the first committed step of glycolysis, consistent with the phylogenetic (IBA) inference and directly supported experimentally. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Catalyzes the phosphorylation of various hexoses, such as D- |
| GO:0008865 fructokinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA transfer of fructokinase activity. HK1 does phosphorylate D-fructose, but this is one facet of its broad hexose-kinase activity rather than a specialist fructokinase function. Reason: HK1 phosphorylates D-fructose to D-fructose 6-phosphate as one of several hexose substrates; the phylogenetic inference is consistent with the documented substrate range. Supporting Evidence: file:human/HK1/HK1-uniprot.txt hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, |
| GO:0032473 cytoplasmic side of mitochondrial outer membrane | IBA GO_REF:0000033 | ACCEPT | Summary: IBA localization to the cytoplasmic (outer) face of the mitochondrial outer membrane, where a pool of HK1 associates with VDAC. This is well supported experimentally and is the specific location of the mitochondrial HK1 pool. Reason: A fraction of HK1 associates with the mitochondrial outer membrane via an N-terminal mitochondrial-binding peptide interacting with VDAC/porin, exposed on the cytoplasmic side; this is the physiologically relevant mitochondrial localization. Supporting Evidence: PMID:1985912 acids are involved in the binding of hexokinase to mitochondrial porin these |
| GO:0006096 glycolytic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA involvement in the glycolytic process. HK1 catalyzes the first committed, irreversible step of glycolysis (glucose to G6P), a core biological process for this gene. Reason: Phosphorylation of glucose to G6P by HK1 is the entry step of glycolysis; strongly supported by phylogeny and by direct human data. Supporting Evidence: file:human/HK1/HK1-uniprot.txt its product D-glucose 6-phosphate (PubMed:1637300). Hexokinase activity |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: IBA localization to the cytosol. The bulk of HK1 is cytosolic and its catalytic activity acts in the cytosol; this is a core localization. Reason: HK1 is predominantly a cytosolic enzyme (with a mitochondrion-outer-membrane-associated subpool); the cytosol is where the committed glycolytic reaction takes place. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Cytoplasm, cytosol |
| GO:0006006 glucose metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA involvement in glucose metabolic process, reflecting HK1's role in phosphorylating glucose to G6P as the gateway to glucose catabolism and downstream pathways. Reason: HK1 initiates cellular glucose utilization by producing G6P; a core biological process well supported by phylogeny and direct evidence. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Catalyzes the phosphorylation of various hexoses, such as D- |
| GO:0019158 mannokinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: IBA transfer of mannokinase activity. HK1 phosphorylates D-mannose to D-mannose 6-phosphate, one facet of its broad hexose-kinase activity. Reason: D-mannose is among the hexose substrates phosphorylated by HK1; consistent with phylogeny and with the documented substrate range. Supporting Evidence: file:human/HK1/HK1-uniprot.txt hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, |
| GO:0051156 glucose 6-phosphate metabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: IBA involvement in glucose 6-phosphate metabolic process. HK1 produces G6P, the metabolite that is central to this process. Reason: By generating G6P, HK1 participates in glucose 6-phosphate metabolism; supported by phylogeny and enzymology. Supporting Evidence: file:human/HK1/HK1-uniprot.txt its product D-glucose 6-phosphate (PubMed:1637300). Hexokinase activity |
| GO:0001678 intracellular glucose homeostasis | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: IBA involvement in intracellular glucose homeostasis. By committing glucose to phosphorylation (trapping it as G6P), HK1 helps maintain intracellular glucose levels. Reason: HK1 contributes to intracellular glucose homeostasis as a downstream consequence of its glucose-phosphorylating activity; a valid but higher-level process annotation, non-core relative to the direct enzymatic function. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Catalyzes the phosphorylation of various hexoses, such as D- |
| GO:0001678 intracellular glucose homeostasis | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO (IPR001312, Hexokinase) mapping to intracellular glucose homeostasis. Duplicates the IBA annotation to the same term. Reason: Consistent with the hexokinase family domain; a higher-level process annotation that is valid but non-core relative to the direct catalytic function. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Catalyzes the phosphorylation of various hexoses, such as D- |
| GO:0004396 hexokinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA (combined multiple methods, including ARBA, InterPro, Rhea and EC 2.7.1.1) assignment of hexokinase activity. This is the most precise molecular-function term for HK1's core catalytic activity. Reason: HK1 is a bona fide hexokinase (EC 2.7.1.1) phosphorylating D-hexoses to hexose 6-phosphate; this is the core molecular function, corroborated by direct experimental evidence. Supporting Evidence: file:human/HK1/HK1-uniprot.txt hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping of ATP binding from the hexokinase domain. HK1 uses ATP as the phosphate donor and has crystallographically defined ATP-binding sites. Reason: HK1 binds ATP (Mg-ATP) as the phosphoryl donor for hexose phosphorylation; supported by structure (ATP/AMP-PNP-bound crystal structures) and by the catalytic mechanism. Supporting Evidence: file:human/HK1/HK1-uniprot.txt IN COMPLEX WITH AMP-PNP AND |
| GO:0005536 D-glucose binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping of D-glucose binding. HK1 binds D-glucose in both the catalytic and regulatory domains, as defined by crystal structures. Reason: D-glucose binding is a defined molecular function of HK1, with dedicated binding residues characterized crystallographically (glucose/G6P-bound structures). Supporting Evidence: file:human/HK1/HK1-uniprot.txt IN COMPLEX WITH GLUCOSE AND |
| GO:0005741 mitochondrial outer membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt-SubCell mapping to mitochondrial outer membrane. A pool of HK1 associates with the mitochondrial outer membrane via VDAC; experimentally supported. Reason: The mitochondrial-outer-membrane-associated HK1 pool is well documented experimentally (see PMID:1985912, PMID:27374331); this localization is biologically important. Supporting Evidence: file:human/HK1/HK1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane |
| GO:0005829 cytosol | IEA GO_REF:0000120 | ACCEPT | Summary: IEA localization to cytosol. Duplicates the well-supported cytosolic localization of HK1. Reason: HK1 is predominantly cytosolic; consistent with experimental subcellular location data. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Cytoplasm, cytosol |
| GO:0005975 carbohydrate metabolic process | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping to carbohydrate metabolic process, a broad parent term consistent with HK1's role in hexose phosphorylation. Reason: Correct but very general; more specific glycolytic and glucose-metabolic terms capture HK1's role. Retained as a valid high-level annotation. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Catalyzes the phosphorylation of various hexoses, such as D- |
| GO:0006096 glycolytic process | IEA GO_REF:0000120 | ACCEPT | Summary: IEA (UniPathway/InterPro) involvement in glycolytic process. Duplicates the IBA and TAS glycolysis annotations. Reason: HK1 catalyzes the first step of glycolysis; core biological process, corroborated across evidence types. Supporting Evidence: file:human/HK1/HK1-uniprot.txt its product D-glucose 6-phosphate (PubMed:1637300). Hexokinase activity |
| GO:0008865 fructokinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based IEA (RHEA:16125, D-fructose + ATP) mapping of fructokinase activity, matching a UniProt catalytic-activity statement. Reason: HK1 phosphorylates D-fructose (RHEA:16125); one facet of its hexose-kinase activity. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Reaction=D-fructose + ATP = D-fructose 6-phosphate + ADP + H(+); |
| GO:0019158 mannokinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based IEA (RHEA:11028, D-mannose + ATP) mapping of mannokinase activity, matching a UniProt catalytic-activity statement. Reason: HK1 phosphorylates D-mannose (RHEA:11028); one facet of its hexose-kinase activity. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Reaction=D-mannose + ATP = D-mannose 6-phosphate + ADP + H(+); |
| GO:0019637 organophosphate metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning IEA to organophosphate metabolic process, a very broad parent capturing that HK1 produces phosphorylated sugars. Reason: Technically correct (hexose 6-phosphates are organophosphates) but far too general to be informative; retained as a valid high-level annotation rather than a core function. Supporting Evidence: file:human/HK1/HK1-uniprot.txt hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, |
| GO:0047931 glucosamine kinase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Rhea-based IEA (RHEA:10948, D-glucosamine + ATP) mapping of glucosamine kinase activity, matching a UniProt catalytic-activity statement and direct experimental data. Reason: HK1 phosphorylates D-glucosamine to D-glucosamine 6-phosphate; directly demonstrated in PMID:27374331 and captured by RHEA:10948. A facet of the broad hexose-kinase activity. Supporting Evidence: PMID:27374331 GAM, is phosphorylated by hexokinase |
| GO:1901135 carbohydrate derivative metabolic process | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA machine-learning IEA to carbohydrate derivative metabolic process, a broad parent term. Reason: Correct but overly general; retained as a valid high-level annotation rather than a core function. Supporting Evidence: file:human/HK1/HK1-uniprot.txt hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate, |
| GO:0005515 protein binding | IPI PMID:22304920 PKCΞ΅ promotes oncogenic functions of ATF2 in the nucleus whi... | MARK AS OVER ANNOTATED | Summary: IntAct IPI recording HK1 interaction with VDAC1 (P21796). The HK1-VDAC1 complex is physiologically real and mediates mitochondrial-outer-membrane association, but the GO term protein binding is uninformative about molecular function. Reason: The underlying HK1-VDAC1 interaction is genuine and biologically important, but bare protein binding conveys no specific molecular function. The functionally meaningful consequence (mitochondrial outer membrane association) is captured by the localization annotations. Supporting Evidence: PMID:22304920 perturbs the HK1-VDAC1 complex |
| GO:0005515 protein binding | IPI PMID:28054552 c-Src phosphorylation and activation of hexokinase promotes ... | MARK AS OVER ANNOTATED | Summary: IntAct IPI recording HK1 interaction with c-Src (P05480). c-Src binds and phosphorylates HK1 (Tyr732), activating it; the interaction is real but the protein binding term is uninformative. Reason: The HK1-c-Src interaction is experimentally established (PMID:28054552), but bare protein binding conveys no specific molecular function. The functional output is HK1 activation/regulation, not a distinct binding function to annotate here. Supporting Evidence: PMID:28054552 c-Src can interact with and phosphorylate hexokinases HK1 and HK2, the |
| GO:0005515 protein binding | IPI PMID:28054552 c-Src phosphorylation and activation of hexokinase promotes ... | MARK AS OVER ANNOTATED | Summary: IntAct IPI recording HK1 interaction with SRC (P12931), the human c-Src. Duplicate protein binding annotation to the c-Src interaction. Reason: Real interaction (PMID:28054552) but the term is uninformative; see the companion c-Src interaction annotation. Supporting Evidence: PMID:28054552 We also found strong co-localization between c-Src and HK1 in cytosol |
| GO:0005515 protein binding | IPI PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hy... | MARK AS OVER ANNOTATED | Summary: IntAct IPI from a high-throughput CFTR (P13569) mammalian-membrane-two-hybrid interactome screen. HK1 appears as a CFTR interactor; bare protein binding is uninformative. Reason: A high-throughput interaction from an interactome screen; the term protein binding conveys no specific molecular function and the biological significance of an HK1-CFTR interaction is unclear. Supporting Evidence: PMID:35156780 CFTR interactome mapping using the mammalian membrane two-hybrid |
| GO:0005515 protein binding | IPI PMID:35271311 OpenCell: Endogenous tagging for the cartography of human ce... | MARK AS OVER ANNOTATED | Summary: IntAct IPI from the OpenCell endogenous-tagging and mass-spectrometry interactome resource (VDAC1, P21796). A large-scale interaction consistent with HK1-VDAC association. Reason: High-throughput interaction data; bare protein binding is uninformative about molecular function, and HK1-VDAC association is already captured by localization annotations. Supporting Evidence: PMID:35271311 Endogenous tagging for the cartography of human cellular |
| GO:0005515 protein binding | IPI PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures ... | MARK AS OVER ANNOTATED | Summary: IntAct IPI from a CFTR proximity-labeling interactome study (CFTR, P13569). HK1 appears among proximity-labeled proteins; bare protein binding is uninformative. Reason: High-throughput proximity-labeling interaction; the term conveys no specific molecular function and the biological significance for HK1 is unclear. Supporting Evidence: PMID:36012204 Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment |
| GO:0002720 positive regulation of cytokine production involved in immune response | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara IEA transferred from mouse ortholog, reflecting the moonlighting role of hexokinase in innate immunity, whereby HK1 dissociation from mitochondria promotes inflammasome-driven cytokine production. Reason: HK1 acts as a cytosolic sensor of bacterial peptidoglycan whose inhibition and dissociation activates the NLRP3 inflammasome and IL-1beta/IL-18 production (PMID:27374331); a genuine but non-core (moonlighting) process. Supporting Evidence: PMID:27374331 this study shows that a metabolic enzyme can act as a |
| GO:0004340 glucokinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: IEA (combined methods including RHEA:17825, D-glucose + ATP) assignment of glucose-phosphorylating (glucokinase) activity, matching a UniProt catalytic-activity statement. This is HK1's core glucose reaction. Reason: HK1 phosphorylates D-glucose to D-glucose 6-phosphate (RHEA:17825); the core catalytic reaction, best captured overall by hexokinase activity. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Reaction=D-glucose + ATP = D-glucose 6-phosphate + ADP + H(+); |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | Summary: IEA localization to mitochondrion (broad parent of mitochondrial outer membrane), consistent with the mitochondrion-associated HK1 pool. Reason: The mitochondrion-associated HK1 pool is well supported; a correct but less specific localization than mitochondrial outer membrane. Supporting Evidence: file:human/HK1/HK1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane |
| GO:0009298 GDP-mannose biosynthetic process | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Ensembl-Compara IEA transferred from mouse ortholog to GDP-mannose biosynthetic process. HK1 produces mannose 6-phosphate, which is upstream of, but not part of, the GDP-mannose biosynthetic pathway (which starts from fructose 6-phosphate). Reason: HK1 does not synthesize GDP-mannose; the GDP-mannose pathway proper is synthesized from fructose 6-phosphate and GTP in three steps by other enzymes. Attributing the whole biosynthetic process to HK1 over-extends its role from producing an upstream hexose 6-phosphate. Supporting Evidence: Reactome:R-HSA-446205 It is synthesized from fructose 6-phosphate and GTP in three steps |
| GO:0032731 positive regulation of interleukin-1 beta production | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara IEA transferred from mouse ortholog, reflecting the innate-immune moonlighting role in which HK1 dissociation from mitochondria activates the NLRP3 inflammasome and IL-1beta secretion. Reason: Supported experimentally in macrophages (PMID:27374331); NAG-induced hexokinase dissociation from mitochondria triggers NLRP3 inflammasome activation and IL-1beta production. A genuine non-core (moonlighting) process. Supporting Evidence: PMID:27374331 resulting in its dissociation from the mitochondrial outer membrane |
| GO:0042834 peptidoglycan binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Ensembl-Compara IEA transferred from mouse ortholog. HK1 acts as a cytosolic sensor of bacterial peptidoglycan-derived N-acetyl-D-glucosamine (NAG); the functional readout is NAG binding at the active site rather than binding of intact peptidoglycan polymer. Reason: Experimentally, HK1 detects the NAG subunit of peptidoglycan via its glucose-binding active site (competitive inhibition), acting as a pattern-recognition receptor (PMID:27374331). Retained as a non-core moonlighting function; the precise molecular readout is NAG binding at the catalytic site. Supporting Evidence: PMID:27374331 detected in the cytosol by the glycolytic enzyme |
| GO:0045121 membrane raft | IEA GO_REF:0000107 | UNDECIDED | Summary: Ensembl-Compara IEA transferred from mouse ortholog placing HK1 in membrane rafts. This is not among the well-supported HK1 localizations (cytosol, mitochondrial outer membrane) in the human literature. Reason: Electronic transfer from ortholog; no direct human evidence for membrane-raft localization is available in the cached literature, and it does not fit the established cytosolic and mitochondrial-outer-membrane distribution. Cannot confirm or refute from available evidence. |
| GO:0046835 carbohydrate phosphorylation | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara IEA to carbohydrate phosphorylation, directly describing HK1's catalytic process of phosphorylating hexoses to hexose 6-phosphates. Reason: HK1 phosphorylates carbohydrates (hexoses) to their 6-phosphates; a correct process annotation directly reflecting the enzyme's activity. Supporting Evidence: PMID:27374331 we confirmed that NAG is a dose-dependent inhibitor of hexokinase enzymatic activity |
| GO:0061621 canonical glycolysis | IEA GO_REF:0000107 | ACCEPT | Summary: Ensembl-Compara IEA to canonical glycolysis, a specific child of glycolytic process. HK1 catalyzes its first committed step. Reason: HK1 performs the entry step of canonical glycolysis (glucose to G6P); consistent with the TAS and Reactome annotations to the same term. Supporting Evidence: file:human/HK1/HK1-uniprot.txt its product D-glucose 6-phosphate (PubMed:1637300). Hexokinase activity |
| GO:0009298 GDP-mannose biosynthetic process | TAS Reactome:R-HSA-446205 | MARK AS OVER ANNOTATED | Summary: Reactome TAS placing HK1 in GDP-mannose biosynthesis. HK1 produces mannose 6-phosphate (upstream), but the GDP-mannose pathway proper is synthesized from fructose 6-phosphate and GTP by other enzymes. Reason: HK1's contribution (mannose 6-phosphate production) is upstream of the GDP-mannose biosynthetic pathway rather than part of it; attributing the whole biosynthetic process to HK1 over-extends its role. Supporting Evidence: Reactome:R-HSA-446205 It is synthesized from fructose 6-phosphate and GTP in three steps |
| GO:0061621 canonical glycolysis | TAS Reactome:R-HSA-70171 | ACCEPT | Summary: Reactome TAS (Glycolysis) placing HK1 in canonical glycolysis. HK1 catalyzes the committed entry step. Reason: HK1 initiates the cytosolic glycolytic pathway that converts glucose (via G6P) to pyruvate; a core biological process. Supporting Evidence: Reactome:R-HSA-70171 convert glucose 6-phosphate to pyruvate. The entire process is cytosolic |
| GO:0019318 hexose metabolic process | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: UniPathway-based IEA to hexose metabolic process, consistent with the UniProt PATHWAY statement (carbohydrate metabolism; hexose metabolism). Reason: Correct but a broad parent capturing HK1's phosphorylation of multiple hexoses; retained as a valid high-level annotation. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Catalyzes the phosphorylation of various hexoses, such as D- |
| GO:0004340 glucokinase activity | TAS Reactome:R-HSA-5621888 | ACCEPT | Summary: Reactome TAS for glucose-phosphorylating (glucokinase) activity (from the defective-HK1 disease reaction). Reflects HK1's core glucose-to-G6P reaction. Reason: HK1 catalyzes phosphorylation of glucose to G6P; a core catalytic reaction, best captured overall by hexokinase activity. Supporting Evidence: Reactome:R-HSA-70420 catalyze the irreversible reaction of glucose and ATP to form glucose 6 phosphate and ADP |
| GO:0004340 glucokinase activity | TAS Reactome:R-HSA-70420 | ACCEPT | Summary: Reactome TAS (HK1,2,3,GCK,HKDC1 phosphorylate Glc to form G6P) for glucose-phosphorylating activity. HK1 is an annotated member of the enzyme set catalyzing glucose to G6P. Reason: HK1 phosphorylates glucose to G6P in the irreversible committed reaction; core catalytic function. Supporting Evidence: Reactome:R-HSA-70420 catalyze the irreversible reaction of glucose and ATP to form glucose 6 phosphate and ADP |
| GO:0019158 mannokinase activity | EXP PMID:13681085 Mannose metabolism and the demonstration of mannokinase and ... | ACCEPT | Summary: Reactome-assigned experimental annotation for mannokinase activity, based on classic biochemical demonstration of mannokinase activity (mannose to mannose 6-phosphate). HK1 phosphorylates D-mannose as part of its broad hexose-kinase activity. Reason: HK1 phosphorylates D-mannose to D-mannose 6-phosphate; the human enzyme's mannokinase activity is inferred from the well-studied rat ortholog in this classic study. A facet of the broad hexose-kinase activity. Supporting Evidence: Reactome:R-HSA-9909159 The properties of the human enzyme are inferred from those of its better-studied rat ortholog |
| GO:0019158 mannokinase activity | EXP PMID:14191428 EFFECT OF DIETARY CARBOHYDRATE AND GLUCOKINASE AND MANNOKINA... | ACCEPT | Summary: Reactome-assigned experimental annotation for mannokinase activity from a second classic rat-tissue biochemistry study, supporting hexose (mannose) phosphorylation. Reason: HK1 phosphorylates D-mannose to D-mannose 6-phosphate; supported by classic biochemistry (inferred to the human enzyme by Reactome). A facet of the broad hexose-kinase activity. Supporting Evidence: Reactome:R-HSA-9909159 Cytosolic hexokinase 1 (HK1) catalyzes the phosphorylation of mannose (Man) to form D-mannose 6-phosphate (Man6P) |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence IDA localizing HK1 to mitochondrion, consistent with the mitochondrion-associated HK1 pool. Reason: Direct immunofluorescence supports mitochondrial localization of a HK1 pool; consistent with the well-documented mitochondrial-outer-membrane association. Supporting Evidence: file:human/HK1/HK1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane |
| GO:0004340 glucokinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer (from rat P05708) of glucose-phosphorylating (glucokinase) activity. HK1's core glucose-to-G6P reaction. Reason: HK1 phosphorylates glucose to G6P; core catalytic reaction, best captured overall by hexokinase activity. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Reaction=D-glucose + ATP = D-glucose 6-phosphate + ADP + H(+); |
| GO:0004396 hexokinase activity | EXP PMID:1637300 A recombinant human 'mini'-hexokinase is catalytically activ... | ACCEPT | Summary: Direct experimental demonstration that recombinant human hexokinase catalyzes glucose phosphorylation and is inhibited by glucose 6-phosphate. This is the core molecular function of HK1. Reason: The recombinant human enzyme catalyzes glucose phosphorylation and shows product (G6P) inhibition, directly demonstrating hexokinase activity and its allosteric regulation. Supporting Evidence: PMID:1637300 not only to catalyse glucose phosphorylation, but PMID:1637300 also to be inhibited by glucose 6-phosphate and other mono- and bis-phosphate |
| GO:0005741 mitochondrial outer membrane | EXP PMID:1985912 Human hexokinase type I microheterogeneity is due to differe... | ACCEPT | Summary: Experimental protein-sequencing study showing that the N-terminal 10 residues mediate hexokinase binding to mitochondrial porin, directly supporting mitochondrial-outer-membrane localization of full-length HK1. Reason: The first 10 amino acids of HK1 mediate binding to mitochondrial porin (VDAC); N-terminally truncated forms cannot bind mitochondria. Direct support for the mitochondrial-outer-membrane-associated pool. Supporting Evidence: PMID:1985912 acids are involved in the binding of hexokinase to mitochondrial porin these |
| GO:0005741 mitochondrial outer membrane | EXP PMID:27374331 Hexokinase Is an Innate Immune Receptor for the Detection of... | ACCEPT | Summary: Experimental study (macrophages) showing HK1/hexokinase localizes to the mitochondrial outer membrane and dissociates upon N-acetylglucosamine-induced inhibition, directly supporting mitochondrial-outer-membrane localization. Reason: Hexokinase associates with the mitochondrial outer membrane via VDAC and dissociates into the cytosol upon inhibition; directly demonstrated. Supporting Evidence: PMID:27374331 resulting in its dissociation from the mitochondrial outer membrane |
| GO:0008865 fructokinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer (from rat P05708) of fructokinase activity; HK1 phosphorylates D-fructose as part of its broad hexose-kinase activity. Reason: HK1 phosphorylates D-fructose to D-fructose 6-phosphate; consistent with the documented substrate range. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Reaction=D-fructose + ATP = D-fructose 6-phosphate + ADP + H(+); |
| GO:0019158 mannokinase activity | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer (from rat P05708) of mannokinase activity; HK1 phosphorylates D-mannose as part of its broad hexose-kinase activity. Reason: HK1 phosphorylates D-mannose to D-mannose 6-phosphate; consistent with the documented substrate range. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Reaction=D-mannose + ATP = D-mannose 6-phosphate + ADP + H(+); |
| GO:0047931 glucosamine kinase activity | EXP PMID:27374331 Hexokinase Is an Innate Immune Receptor for the Detection of... | ACCEPT | Summary: Direct experimental demonstration that hexokinase phosphorylates glucosamine (GAM) to glucosamine 6-phosphate (while it cannot phosphorylate N-acetyl-glucosamine). A facet of HK1's broad hexose-kinase activity. Reason: HK1 phosphorylates D-glucosamine to D-glucosamine 6-phosphate, directly shown in PMID:27374331; a facet of the broad hexose-kinase activity. Supporting Evidence: PMID:27374331 GAM, is phosphorylated by hexokinase |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput mitochondrial proteome study localizing HK1 to mitochondrion, consistent with the mitochondrion-associated HK1 pool. Reason: High-throughput proteomic detection in mitochondria corroborates the well-documented mitochondrial-outer-membrane-associated HK1 pool. Supporting Evidence: file:human/HK1/HK1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5621888 | ACCEPT | Summary: Reactome TAS localizing HK1 to cytosol, consistent with its predominantly cytosolic distribution. Reason: HK1 is predominantly cytosolic where the committed glycolytic reaction occurs; a core localization. Supporting Evidence: Reactome:R-HSA-70171 convert glucose 6-phosphate to pyruvate. The entire process is cytosolic |
| GO:0006002 fructose 6-phosphate metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer (from rat P05708) to fructose 6-phosphate metabolic process, reflecting that HK1 produces fructose 6-phosphate when phosphorylating fructose. Reason: A valid downstream process annotation arising from HK1's fructose phosphorylation; non-core relative to the primary glucose reaction. Supporting Evidence: file:human/HK1/HK1-uniprot.txt Reaction=D-fructose + ATP = D-fructose 6-phosphate + ADP + H(+); |
| GO:0006013 mannose metabolic process | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ISS transfer (from rat P05708) to mannose metabolic process, reflecting HK1's phosphorylation of mannose to mannose 6-phosphate. Reason: A valid downstream process annotation arising from HK1's mannose phosphorylation; non-core relative to the primary glucose reaction. Supporting Evidence: Reactome:R-HSA-9909159 Cytosolic hexokinase 1 (HK1) catalyzes the phosphorylation of mannose (Man) to form D-mannose 6-phosphate (Man6P) |
| GO:0051156 glucose 6-phosphate metabolic process | ISS GO_REF:0000024 | ACCEPT | Summary: ISS transfer (from rat P05708) to glucose 6-phosphate metabolic process. HK1 produces G6P, the metabolite central to this process. Reason: By generating G6P, HK1 participates in glucose 6-phosphate metabolism; duplicates the IBA annotation to the same term. Supporting Evidence: file:human/HK1/HK1-uniprot.txt its product D-glucose 6-phosphate (PubMed:1637300). Hexokinase activity |
| GO:0004396 hexokinase activity | IMP PMID:27374331 Hexokinase Is an Innate Immune Receptor for the Detection of... | ACCEPT | Summary: CAFA IMP for hexokinase activity based on PMID:27374331, which measures hexokinase enzymatic activity and its inhibition by N-acetylglucosamine. The core molecular function of HK1. Reason: The study directly assays hexokinase enzymatic activity (dose-dependent inhibition by NAG); supports the core hexokinase activity. Supporting Evidence: PMID:27374331 we confirmed that NAG is a dose-dependent inhibitor of hexokinase enzymatic activity |
| GO:0042834 peptidoglycan binding | IDA PMID:27374331 Hexokinase Is an Innate Immune Receptor for the Detection of... | KEEP AS NON CORE | Summary: CAFA IDA for peptidoglycan binding based on PMID:27374331, in which hexokinase senses peptidoglycan-derived N-acetylglucosamine at its active site, acting as a cytosolic pattern-recognition receptor. Reason: HK1 detects the NAG subunit of bacterial peptidoglycan via its glucose-binding active site (competitive inhibition), functioning as an innate-immune sensor (PMID:27374331); a genuine non-core (moonlighting) function. Supporting Evidence: PMID:27374331 detected in the cytosol by the glycolytic enzyme |
| GO:0046835 carbohydrate phosphorylation | IMP PMID:27374331 Hexokinase Is an Innate Immune Receptor for the Detection of... | ACCEPT | Summary: CAFA IMP for carbohydrate phosphorylation based on PMID:27374331, directly describing HK1's catalytic process of phosphorylating hexoses. Reason: HK1 phosphorylates hexoses to hexose 6-phosphates; a correct process annotation reflecting the enzyme's activity. Supporting Evidence: PMID:27374331 GAM, is phosphorylated by hexokinase |
| GO:0070585 protein localization to mitochondrion | IMP PMID:23962723 Hexokinase activity is required for recruitment of parkin to... | KEEP AS NON CORE | Summary: IMP annotation based on PMID:23962723 showing hexokinase activity (HK1/HK2) is required for recruitment of parkin to depolarized mitochondria, i.e. HK1 participates in localizing another protein (parkin) to mitochondria. Reason: Hexokinase activity is required for parkin recruitment to depolarized mitochondria; the effect is shared among hexokinases including HK1 (PMID:23962723). A genuine but non-core process downstream of HK1's catalytic role. Supporting Evidence: PMID:23962723 the brain-expressed hexokinase 1 (HK1) |
| GO:0072656 maintenance of protein location in mitochondrion | IMP PMID:23962723 Hexokinase activity is required for recruitment of parkin to... | KEEP AS NON CORE | Summary: IMP annotation based on PMID:23962723 relating hexokinase activity to parkin localization at depolarized mitochondria. Reason: Related to the parkin-recruitment role of hexokinases including HK1 (PMID:23962723); a genuine but non-core process downstream of HK1's catalytic role. Supporting Evidence: PMID:23962723 suggesting the effects are |
| GO:0005739 mitochondrion | HDA PMID:20833797 Phosphoproteome analysis of functional mitochondria isolated... | ACCEPT | Summary: High-throughput phosphoproteome study of functional mitochondria detecting HK1, consistent with the mitochondrion-associated HK1 pool. Reason: High-throughput proteomic detection in mitochondria corroborates the mitochondrial-outer-membrane-associated HK1 pool. Supporting Evidence: file:human/HK1/HK1-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion outer membrane |
| GO:0005829 cytosol | TAS Reactome:R-HSA-70420 | ACCEPT | Summary: Reactome TAS localizing HK1 to cytosol (glucose-phosphorylation reaction), consistent with its predominantly cytosolic distribution. Reason: HK1's committed glycolytic reaction occurs in the cytosol; a core localization. Supporting Evidence: Reactome:R-HSA-70171 convert glucose 6-phosphate to pyruvate. The entire process is cytosolic |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9909159 | ACCEPT | Summary: Reactome TAS localizing HK1 to cytosol (mannose-phosphorylation reaction). Consistent with its predominantly cytosolic distribution. Reason: HK1 is a cytosolic enzyme; Reactome explicitly describes cytosolic HK1 catalyzing mannose phosphorylation. Supporting Evidence: Reactome:R-HSA-9909159 Cytosolic hexokinase 1 (HK1) catalyzes the phosphorylation of mannose (Man) to form D-mannose 6-phosphate (Man6P) |
| GO:0004396 hexokinase activity | TAS PMID:3207429 Human hexokinase: sequences of amino- and carboxyl-terminal ... | ACCEPT | Summary: TAS for hexokinase activity from the human hexokinase cDNA-cloning paper, which characterizes the 917-aa enzyme with catalytic (C-terminal) and regulatory (N-terminal) domains. Core molecular function. Reason: The human hexokinase sequence encodes a catalytic domain retaining glucose-binding and glucose-phosphorylating activity; supports the core hexokinase activity. Supporting Evidence: PMID:3207429 retained the glucose binding site and glucose phosphorylating |
| GO:0006096 glycolytic process | TAS PMID:3207429 Human hexokinase: sequences of amino- and carboxyl-terminal ... | ACCEPT | Summary: TAS involvement in glycolytic process from the human hexokinase cDNA-cloning paper. HK1 catalyzes the committed entry step of glycolysis. Reason: HK1 initiates glycolysis by producing G6P; a core biological process, corroborated across evidence types. Supporting Evidence: PMID:3207429 retained the glucose binding site and glucose phosphorylating |
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