HK1

UniProt ID: P19367
Organism: Homo sapiens
Review Status: INITIALIZED
šŸ“ Provide Detailed Feedback

Gene Description

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.

Existing Annotations Review

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
PKCĪµ 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

Core Functions

ATP-dependent phosphorylation of D-glucose to D-glucose 6-phosphate, the first committed and rate-limiting step of glycolysis, feeding glucose into glycolysis, the pentose phosphate pathway and glycogen synthesis; the enzyme is allosterically inhibited by its product glucose 6-phosphate.

Molecular Function:
hexokinase activity
Directly Involved In:
glycolytic process
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:1637300
    not only to catalyse glucose phosphorylation, but
  • file:human/HK1/HK1-uniprot.txt
    hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate,

Phosphorylation of glucose to glucose 6-phosphate as the gateway of cellular glucose metabolism, contributing to intracellular glucose utilization and homeostasis.

Molecular Function:
hexokinase activity
Directly Involved In:
glucose metabolic process
Cellular Locations:
cytosol
Supporting Evidence:
  • PMID:3207429
    retained the glucose binding site and glucose phosphorylating

Association of a subpool of hexokinase-1 with the cytoplasmic face of the mitochondrial outer membrane via VDAC/porin, mediated by an N-terminal mitochondrial-binding peptide, coupling glycolysis to oxidative phosphorylation.

Molecular Function:
hexokinase activity
Cellular Locations:
mitochondrial outer membrane
Supporting Evidence:
  • PMID:1985912
    acids are involved in the binding of hexokinase to mitochondrial porin these

References

GO_REF:0000002
Gene Ontology annotation through association of InterPro records with GO terms
GO_REF:0000024
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
GO_REF:0000033
Annotation inferences using phylogenetic trees
GO_REF:0000041
Gene Ontology annotation based on UniPathway vocabulary mapping
GO_REF:0000044
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
GO_REF:0000052
Gene Ontology annotation based on curation of immunofluorescence data
GO_REF:0000107
Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara
GO_REF:0000116
Automatic Gene Ontology annotation based on Rhea mapping
GO_REF:0000117
Electronic Gene Ontology annotations created by ARBA machine learning models
GO_REF:0000120
Combined Automated Annotation using Multiple IEA Methods
file:human/HK1/HK1-uniprot.txt
UniProtKB entry P19367 (HXK1_HUMAN), Hexokinase-1
PMID:13681085
Mannose metabolism and the demonstration of mannokinase and phosphomannoisomerase activities in the lactating rat mammary gland.
PMID:14191428
EFFECT OF DIETARY CARBOHYDRATE AND GLUCOKINASE AND MANNOKINASE ACTIVITIES OF VARIOUS RAT TISSUES.
PMID:1637300
A recombinant human 'mini'-hexokinase is catalytically active and regulated by hexose 6-phosphates.
PMID:1985912
Human hexokinase type I microheterogeneity is due to different amino-terminal sequences.
PMID:20833797
Phosphoproteome analysis of functional mitochondria isolated from resting human muscle reveals extensive phosphorylation of inner membrane protein complexes and enzymes.
PMID:22304920
PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria.
PMID:23962723
Hexokinase activity is required for recruitment of parkin to depolarized mitochondria.
PMID:27374331
Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan.
PMID:28054552
c-Src phosphorylation and activation of hexokinase promotes tumorigenesis and metastasis.
PMID:3207429
Human hexokinase: sequences of amino- and carboxyl-terminal halves are homologous.
PMID:34800366
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
PMID:35156780
CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput screening system.
PMID:35271311
OpenCell: Endogenous tagging for the cartography of human cellular organization.
PMID:36012204
Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment in Multiple SLC Transporters.
Reactome:R-HSA-446205
Synthesis of GDP-mannose
Reactome:R-HSA-5621888
Defective HK1 does not phosphorylate Glc to form G6P
Reactome:R-HSA-70171
Glycolysis
Reactome:R-HSA-70420
HK1,2,3,GCK,HKDC1 phosphorylate Glc to form G6P
Reactome:R-HSA-9909159
HK1 phosphorylates Mannose to Man6P

šŸ“š Additional Documentation

Notes

(HK1-notes.md)

HK1 (Hexokinase-1, P19367) ā€” review notes

Summary of gene function

HK1 is the ubiquitously-expressed hexokinase isozyme (EC 2.7.1.1) that catalyses the
first committed step of glucose catabolism: 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 protein arising from
duplication and fusion of an ancestral 50 kDa yeast-type hexokinase; the C-terminal half
carries the catalytic site while the N-terminal half carries a regulatory/allosteric
glucose-6-phosphate binding site (both halves fold as a hexokinase domain)
[PMID:1637300; PMID:3207429].

Key established facts:

  • Catalysis / substrate range. Phosphorylates several D-hexoses ā€” D-glucose,
    D-mannose, D-fructose, D-glucosamine, 2-deoxy-D-glucose ā€” to their 6-phosphates
    (UniProt FUNCTION; PubMed:1637300, 25316723, 27374331). Does NOT phosphorylate
    N-acetyl-D-glucosamine (PubMed:27374331). The GOA MF terms glucokinase activity
    (GO:0004340), fructokinase activity (GO:0008865), mannokinase activity (GO:0019158),
    and glucosamine kinase activity (GO:0047931) are all facets of this broad
    hexose-kinase (hexokinase, GO:0004396) activity ā€” HK1 is not a specialist for any of
    these individual sugars.
  • Product inhibition / allostery. Allosteric enzyme inhibited by its product
    D-glucose 6-phosphate (PubMed:1637300); the C-terminal "mini-hexokinase" retains both
    catalysis and G6P inhibition.
  • Subcellular localization. Cytosol, with a pool associated with the mitochondrial
    outer membrane via VDAC/porin; the N-terminal mitochondrial-binding peptide (residues
    1-10) mediates the association (PubMed:1985912). Erythrocyte and testis isoforms with
    altered N-termini cannot bind mitochondria. Dissociates from the OMM upon inhibition
    by N-acetyl-D-glucosamine, relocating to cytosol (PubMed:27374331). The mito-OMM
    association couples glycolysis to oxidative phosphorylation and is anti-apoptotic.
  • Moonlighting immune role. In macrophages HK1 acts as a cytosolic pattern-recognition
    receptor: bacterial peptidoglycan-derived N-acetyl-D-glucosamine (NAG) inhibits HK1,
    causing it to dissociate from the mitochondrial outer membrane, which is sufficient to
    activate the NLRP3 inflammasome and IL-1Ī²/IL-18 production (PubMed:27374331).
  • Regulation by c-Src. c-Src binds and phosphorylates HK1 at Tyr732, lowering Km and
    raising Vmax by disrupting HK1 homodimer, enhancing glycolysis and tumour growth
    (PubMed:28054552).
  • Mitophagy. Hexokinase activity (HK1/HK2) is required for recruitment of parkin to
    depolarized mitochondria (PubMed:23962723; abstract foregrounds HK2 but the study
    addresses hexokinases including HK1).

Disease

  • CNSHA5 (non-spherocytic hemolytic anemia, MIM 235700) ā€” recessive, decreased RBC
    hexokinase activity (PubMed:7655856, 12393545).
  • HMSNR / CMT (hereditary motor and sensory neuropathy, Russe type; MIM 605285)
    (PubMed:19536174, 34193129).
  • RP79 (retinitis pigmentosa 79, dominant; MIM 617460) (PubMed:25190649, 25316723).
  • NEDVIBA (neurodevelopmental disorder with visual defects and brain anomalies; MIM
    618547) (PubMed:30778173).

Curation decisions (rationale)

Core: hexokinase activity (GO:0004396) MF; glycolytic process (GO:0006096) and glucose
metabolic process (GO:0006006) BP; cytosol (GO:0005829) CC. Mitochondrial-outer-membrane
association is a real, well-supported localization (accept CC), but the enzymatic core
function acts in the cytosol.

  • The various single-sugar MF terms (glucokinase, fructokinase, mannokinase, glucosamine
    kinase) are ACCEPTed where experimental/Rhea/Reactome-backed, but flagged as facets of
    the broad hexokinase activity rather than substrate-specialist functions. Glucokinase
    activity (GO:0004340) as an IBA/ISS/Reactome term is the community convention for the
    glucoseā†’G6P reaction of hexokinases; accepted.
  • Bare protein binding (GO:0005515) IPIs (VDAC1, SRC, CFTR Ɨ2) ā†’ MARK_AS_OVER_ANNOTATED
    (uninformative; underlying interactions are real but the term conveys no function).
  • High-throughput mitochondrion localizations (HDA/HTP/IDA) accepted as non-core given
    the strong experimental OMM evidence.
  • peptidoglycan binding (GO:0042834) and immune/IL-1Ī² terms accepted (KEEP_AS_NON_CORE
    where non-core) ā€” supported by PMID:27374331 as a genuine moonlighting function.
  • GDP-mannose biosynthetic process (GO:0009298): HK1 does not synthesize GDP-mannose;
    it produces mannose-6-P which feeds upstream of that pathway ā†’ MARK_AS_OVER_ANNOTATED.

Deep research: falcon provider out of credits (HTTP 402); no -deep-research-falcon.md was
generated. Review grounded in UniProt P19367, seeded GOA, and cached publications.

šŸ“„ View Raw YAML

 
id: P19367
gene_symbol: HK1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: 1 (Common)
  id: P19367-1
- name: 2 (Erythrocyte, R)
  id: P19367-2
  sequence_note: VSP_002071
- name: 3 (TA, TB)
  id: P19367-3
  sequence_note: VSP_002072
- name: 4 (TD)
  id: P19367-4
  sequence_note: VSP_002073
existing_annotations:
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Catalyzes the phosphorylation of various hexoses, such as D-"
- term:
    id: GO:0008865
    label: fructokinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate,"
- term:
    id: GO:0032473
    label: cytoplasmic side of mitochondrial outer membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:1985912
      supporting_text: acids are involved in the binding of hexokinase to mitochondrial
        porin these
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: Phosphorylation of glucose to G6P by HK1 is the entry step of glycolysis;
      strongly supported by phylogeny and by direct human data.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "its product D-glucose 6-phosphate (PubMed:1637300). Hexokinase activity"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    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.
    action: ACCEPT
    reason: HK1 is predominantly a cytosolic enzyme (with a mitochondrion-outer-membrane-associated
      subpool); the cytosol is where the committed glycolytic reaction takes place.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Cytoplasm, cytosol"
- term:
    id: GO:0006006
    label: glucose metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: HK1 initiates cellular glucose utilization by producing G6P; a core biological
      process well supported by phylogeny and direct evidence.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Catalyzes the phosphorylation of various hexoses, such as D-"
- term:
    id: GO:0019158
    label: mannokinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: IBA transfer of mannokinase activity. HK1 phosphorylates D-mannose to
      D-mannose 6-phosphate, one facet of its broad hexose-kinase activity.
    action: ACCEPT
    reason: D-mannose is among the hexose substrates phosphorylated by HK1; consistent
      with phylogeny and with the documented substrate range.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate,"
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: IBA involvement in glucose 6-phosphate metabolic process. HK1 produces
      G6P, the metabolite that is central to this process.
    action: ACCEPT
    reason: By generating G6P, HK1 participates in glucose 6-phosphate metabolism;
      supported by phylogeny and enzymology.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "its product D-glucose 6-phosphate (PubMed:1637300). Hexokinase activity"
- term:
    id: GO:0001678
    label: intracellular glucose homeostasis
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: IBA involvement in intracellular glucose homeostasis. By committing glucose
      to phosphorylation (trapping it as G6P), HK1 helps maintain intracellular glucose
      levels.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Catalyzes the phosphorylation of various hexoses, such as D-"
- term:
    id: GO:0001678
    label: intracellular glucose homeostasis
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO (IPR001312, Hexokinase) mapping to intracellular glucose
      homeostasis. Duplicates the IBA annotation to the same term.
    action: KEEP_AS_NON_CORE
    reason: Consistent with the hexokinase family domain; a higher-level process annotation
      that is valid but non-core relative to the direct catalytic function.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Catalyzes the phosphorylation of various hexoses, such as D-"
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate,"
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO mapping of ATP binding from the hexokinase domain. HK1 uses
      ATP as the phosphate donor and has crystallographically defined ATP-binding
      sites.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "IN COMPLEX WITH AMP-PNP AND"
- term:
    id: GO:0005536
    label: D-glucose binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: InterPro2GO mapping of D-glucose binding. HK1 binds D-glucose in both
      the catalytic and regulatory domains, as defined by crystal structures.
    action: ACCEPT
    reason: D-glucose binding is a defined molecular function of HK1, with dedicated
      binding residues characterized crystallographically (glucose/G6P-bound structures).
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "IN COMPLEX WITH GLUCOSE AND"
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: UniProt-SubCell mapping to mitochondrial outer membrane. A pool of HK1
      associates with the mitochondrial outer membrane via VDAC; experimentally supported.
    action: ACCEPT
    reason: The mitochondrial-outer-membrane-associated HK1 pool is well documented
      experimentally (see PMID:1985912, PMID:27374331); this localization is biologically
      important.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion outer membrane"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: IEA localization to cytosol. Duplicates the well-supported cytosolic
      localization of HK1.
    action: ACCEPT
    reason: HK1 is predominantly cytosolic; consistent with experimental subcellular
      location data.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Cytoplasm, cytosol"
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: InterPro2GO mapping to carbohydrate metabolic process, a broad parent
      term consistent with HK1's role in hexose phosphorylation.
    action: KEEP_AS_NON_CORE
    reason: Correct but very general; more specific glycolytic and glucose-metabolic
      terms capture HK1's role. Retained as a valid high-level annotation.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Catalyzes the phosphorylation of various hexoses, such as D-"
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: IEA (UniPathway/InterPro) involvement in glycolytic process. Duplicates
      the IBA and TAS glycolysis annotations.
    action: ACCEPT
    reason: HK1 catalyzes the first step of glycolysis; core biological process, corroborated
      across evidence types.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "its product D-glucose 6-phosphate (PubMed:1637300). Hexokinase activity"
- term:
    id: GO:0008865
    label: fructokinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: Rhea-based IEA (RHEA:16125, D-fructose + ATP) mapping of fructokinase
      activity, matching a UniProt catalytic-activity statement.
    action: ACCEPT
    reason: HK1 phosphorylates D-fructose (RHEA:16125); one facet of its hexose-kinase
      activity.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Reaction=D-fructose + ATP = D-fructose 6-phosphate + ADP + H(+);"
- term:
    id: GO:0019158
    label: mannokinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: Rhea-based IEA (RHEA:11028, D-mannose + ATP) mapping of mannokinase activity,
      matching a UniProt catalytic-activity statement.
    action: ACCEPT
    reason: HK1 phosphorylates D-mannose (RHEA:11028); one facet of its hexose-kinase
      activity.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Reaction=D-mannose + ATP = D-mannose 6-phosphate + ADP + H(+);"
- term:
    id: GO:0019637
    label: organophosphate metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning IEA to organophosphate metabolic process, a very
      broad parent capturing that HK1 produces phosphorylated sugars.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate,"
- term:
    id: GO:0047931
    label: glucosamine kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000116
  qualifier: enables
  review:
    summary: Rhea-based IEA (RHEA:10948, D-glucosamine + ATP) mapping of glucosamine
      kinase activity, matching a UniProt catalytic-activity statement and direct
      experimental data.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:27374331
      supporting_text: GAM, is phosphorylated by hexokinase
- term:
    id: GO:1901135
    label: carbohydrate derivative metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: ARBA machine-learning IEA to carbohydrate derivative metabolic process,
      a broad parent term.
    action: KEEP_AS_NON_CORE
    reason: Correct but overly general; retained as a valid high-level annotation
      rather than a core function.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate,"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22304920
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:22304920
      supporting_text: perturbs the HK1-VDAC1 complex
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28054552
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:28054552
      supporting_text: c-Src can interact with and phosphorylate hexokinases HK1 and
        HK2, the
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:28054552
  qualifier: enables
  review:
    summary: IntAct IPI recording HK1 interaction with SRC (P12931), the human c-Src.
      Duplicate protein binding annotation to the c-Src interaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: Real interaction (PMID:28054552) but the term is uninformative; see the
      companion c-Src interaction annotation.
    supported_by:
    - reference_id: PMID:28054552
      supporting_text: We also found strong co-localization between c-Src and HK1
        in cytosol
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35156780
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:35156780
      supporting_text: CFTR interactome mapping using the mammalian membrane two-hybrid
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:35271311
  qualifier: enables
  review:
    summary: IntAct IPI from the OpenCell endogenous-tagging and mass-spectrometry
      interactome resource (VDAC1, P21796). A large-scale interaction consistent with
      HK1-VDAC association.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput interaction data; bare protein binding is uninformative
      about molecular function, and HK1-VDAC association is already captured by localization
      annotations.
    supported_by:
    - reference_id: PMID:35271311
      supporting_text: Endogenous tagging for the cartography of human cellular
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:36012204
  qualifier: enables
  review:
    summary: IntAct IPI from a CFTR proximity-labeling interactome study (CFTR, P13569).
      HK1 appears among proximity-labeled proteins; bare protein binding is uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: High-throughput proximity-labeling interaction; the term conveys no specific
      molecular function and the biological significance for HK1 is unclear.
    supported_by:
    - reference_id: PMID:36012204
      supporting_text: Differential CFTR-Interactome Proximity Labeling Procedures
        Identify Enrichment
- term:
    id: GO:0002720
    label: positive regulation of cytokine production involved in immune response
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:27374331
      supporting_text: this study shows that a metabolic enzyme can act as a
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: HK1 phosphorylates D-glucose to D-glucose 6-phosphate (RHEA:17825); the
      core catalytic reaction, best captured overall by hexokinase activity.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Reaction=D-glucose + ATP = D-glucose 6-phosphate + ADP + H(+);"
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: IEA localization to mitochondrion (broad parent of mitochondrial outer
      membrane), consistent with the mitochondrion-associated HK1 pool.
    action: ACCEPT
    reason: The mitochondrion-associated HK1 pool is well supported; a correct but
      less specific localization than mitochondrial outer membrane.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion outer membrane"
- term:
    id: GO:0009298
    label: GDP-mannose biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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).
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: Reactome:R-HSA-446205
      supporting_text: It is synthesized from fructose 6-phosphate and GTP in three
        steps
- term:
    id: GO:0032731
    label: positive regulation of interleukin-1 beta production
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:27374331
      supporting_text: resulting in its dissociation from the mitochondrial outer
        membrane
- term:
    id: GO:0042834
    label: peptidoglycan binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:27374331
      supporting_text: detected in the cytosol by the glycolytic enzyme
- term:
    id: GO:0045121
    label: membrane raft
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    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.
    action: UNDECIDED
    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.
- term:
    id: GO:0046835
    label: carbohydrate phosphorylation
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-Compara IEA to carbohydrate phosphorylation, directly describing
      HK1's catalytic process of phosphorylating hexoses to hexose 6-phosphates.
    action: ACCEPT
    reason: HK1 phosphorylates carbohydrates (hexoses) to their 6-phosphates; a correct
      process annotation directly reflecting the enzyme's activity.
    supported_by:
    - reference_id: PMID:27374331
      supporting_text: we confirmed that NAG is a dose-dependent inhibitor of hexokinase
        enzymatic activity
- term:
    id: GO:0061621
    label: canonical glycolysis
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: Ensembl-Compara IEA to canonical glycolysis, a specific child of glycolytic
      process. HK1 catalyzes its first committed step.
    action: ACCEPT
    reason: HK1 performs the entry step of canonical glycolysis (glucose to G6P); consistent
      with the TAS and Reactome annotations to the same term.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "its product D-glucose 6-phosphate (PubMed:1637300). Hexokinase activity"
- term:
    id: GO:0009298
    label: GDP-mannose biosynthetic process
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-446205
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: Reactome:R-HSA-446205
      supporting_text: It is synthesized from fructose 6-phosphate and GTP in three
        steps
- term:
    id: GO:0061621
    label: canonical glycolysis
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70171
  qualifier: involved_in
  review:
    summary: Reactome TAS (Glycolysis) placing HK1 in canonical glycolysis. HK1 catalyzes
      the committed entry step.
    action: ACCEPT
    reason: HK1 initiates the cytosolic glycolytic pathway that converts glucose (via
      G6P) to pyruvate; a core biological process.
    supported_by:
    - reference_id: Reactome:R-HSA-70171
      supporting_text: convert glucose 6-phosphate to pyruvate. The entire process
        is cytosolic
- term:
    id: GO:0019318
    label: hexose metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000041
  qualifier: involved_in
  review:
    summary: UniPathway-based IEA to hexose metabolic process, consistent with the
      UniProt PATHWAY statement (carbohydrate metabolism; hexose metabolism).
    action: KEEP_AS_NON_CORE
    reason: Correct but a broad parent capturing HK1's phosphorylation of multiple
      hexoses; retained as a valid high-level annotation.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Catalyzes the phosphorylation of various hexoses, such as D-"
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5621888
  qualifier: enables
  review:
    summary: Reactome TAS for glucose-phosphorylating (glucokinase) activity (from
      the defective-HK1 disease reaction). Reflects HK1's core glucose-to-G6P reaction.
    action: ACCEPT
    reason: HK1 catalyzes phosphorylation of glucose to G6P; a core catalytic reaction,
      best captured overall by hexokinase activity.
    supported_by:
    - reference_id: Reactome:R-HSA-70420
      supporting_text: catalyze the irreversible reaction of glucose and ATP to form
        glucose 6 phosphate and ADP
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70420
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: HK1 phosphorylates glucose to G6P in the irreversible committed reaction;
      core catalytic function.
    supported_by:
    - reference_id: Reactome:R-HSA-70420
      supporting_text: catalyze the irreversible reaction of glucose and ATP to form
        glucose 6 phosphate and ADP
- term:
    id: GO:0019158
    label: mannokinase activity
  evidence_type: EXP
  original_reference_id: PMID:13681085
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: Reactome:R-HSA-9909159
      supporting_text: The properties of the human enzyme are inferred from those
        of its better-studied rat ortholog
- term:
    id: GO:0019158
    label: mannokinase activity
  evidence_type: EXP
  original_reference_id: PMID:14191428
  qualifier: enables
  review:
    summary: Reactome-assigned experimental annotation for mannokinase activity from
      a second classic rat-tissue biochemistry study, supporting hexose (mannose)
      phosphorylation.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: Reactome:R-HSA-9909159
      supporting_text: Cytosolic hexokinase 1 (HK1) catalyzes the phosphorylation
        of mannose (Man) to form D-mannose 6-phosphate (Man6P)
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: HPA immunofluorescence IDA localizing HK1 to mitochondrion, consistent
      with the mitochondrion-associated HK1 pool.
    action: ACCEPT
    reason: Direct immunofluorescence supports mitochondrial localization of a HK1
      pool; consistent with the well-documented mitochondrial-outer-membrane association.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion outer membrane"
- term:
    id: GO:0004340
    label: glucokinase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: ISS transfer (from rat P05708) of glucose-phosphorylating (glucokinase)
      activity. HK1's core glucose-to-G6P reaction.
    action: ACCEPT
    reason: HK1 phosphorylates glucose to G6P; core catalytic reaction, best captured
      overall by hexokinase activity.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Reaction=D-glucose + ATP = D-glucose 6-phosphate + ADP + H(+);"
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: EXP
  original_reference_id: PMID:1637300
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: The recombinant human enzyme catalyzes glucose phosphorylation and shows
      product (G6P) inhibition, directly demonstrating hexokinase activity and its
      allosteric regulation.
    supported_by:
    - reference_id: PMID:1637300
      supporting_text: not only to catalyse glucose phosphorylation, but
    - reference_id: PMID:1637300
      supporting_text: also to be inhibited by glucose 6-phosphate and other mono-
        and bis-phosphate
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: EXP
  original_reference_id: PMID:1985912
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: PMID:1985912
      supporting_text: acids are involved in the binding of hexokinase to mitochondrial
        porin these
- term:
    id: GO:0005741
    label: mitochondrial outer membrane
  evidence_type: EXP
  original_reference_id: PMID:27374331
  qualifier: located_in
  review:
    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.
    action: ACCEPT
    reason: Hexokinase associates with the mitochondrial outer membrane via VDAC and
      dissociates into the cytosol upon inhibition; directly demonstrated.
    supported_by:
    - reference_id: PMID:27374331
      supporting_text: resulting in its dissociation from the mitochondrial outer
        membrane
- term:
    id: GO:0008865
    label: fructokinase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: ISS transfer (from rat P05708) of fructokinase activity; HK1 phosphorylates
      D-fructose as part of its broad hexose-kinase activity.
    action: ACCEPT
    reason: HK1 phosphorylates D-fructose to D-fructose 6-phosphate; consistent with
      the documented substrate range.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Reaction=D-fructose + ATP = D-fructose 6-phosphate + ADP + H(+);"
- term:
    id: GO:0019158
    label: mannokinase activity
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: enables
  review:
    summary: ISS transfer (from rat P05708) of mannokinase activity; HK1 phosphorylates
      D-mannose as part of its broad hexose-kinase activity.
    action: ACCEPT
    reason: HK1 phosphorylates D-mannose to D-mannose 6-phosphate; consistent with
      the documented substrate range.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Reaction=D-mannose + ATP = D-mannose 6-phosphate + ADP + H(+);"
- term:
    id: GO:0047931
    label: glucosamine kinase activity
  evidence_type: EXP
  original_reference_id: PMID:27374331
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: HK1 phosphorylates D-glucosamine to D-glucosamine 6-phosphate, directly
      shown in PMID:27374331; a facet of the broad hexose-kinase activity.
    supported_by:
    - reference_id: PMID:27374331
      supporting_text: GAM, is phosphorylated by hexokinase
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: High-throughput mitochondrial proteome study localizing HK1 to mitochondrion,
      consistent with the mitochondrion-associated HK1 pool.
    action: ACCEPT
    reason: High-throughput proteomic detection in mitochondria corroborates the well-documented
      mitochondrial-outer-membrane-associated HK1 pool.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion outer membrane"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-5621888
  qualifier: located_in
  review:
    summary: Reactome TAS localizing HK1 to cytosol, consistent with its predominantly
      cytosolic distribution.
    action: ACCEPT
    reason: HK1 is predominantly cytosolic where the committed glycolytic reaction
      occurs; a core localization.
    supported_by:
    - reference_id: Reactome:R-HSA-70171
      supporting_text: convert glucose 6-phosphate to pyruvate. The entire process
        is cytosolic
- term:
    id: GO:0006002
    label: fructose 6-phosphate metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS transfer (from rat P05708) to fructose 6-phosphate metabolic process,
      reflecting that HK1 produces fructose 6-phosphate when phosphorylating fructose.
    action: KEEP_AS_NON_CORE
    reason: A valid downstream process annotation arising from HK1's fructose phosphorylation;
      non-core relative to the primary glucose reaction.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "Reaction=D-fructose + ATP = D-fructose 6-phosphate + ADP + H(+);"
- term:
    id: GO:0006013
    label: mannose metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS transfer (from rat P05708) to mannose metabolic process, reflecting
      HK1's phosphorylation of mannose to mannose 6-phosphate.
    action: KEEP_AS_NON_CORE
    reason: A valid downstream process annotation arising from HK1's mannose phosphorylation;
      non-core relative to the primary glucose reaction.
    supported_by:
    - reference_id: Reactome:R-HSA-9909159
      supporting_text: Cytosolic hexokinase 1 (HK1) catalyzes the phosphorylation
        of mannose (Man) to form D-mannose 6-phosphate (Man6P)
- term:
    id: GO:0051156
    label: glucose 6-phosphate metabolic process
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: ISS transfer (from rat P05708) to glucose 6-phosphate metabolic process.
      HK1 produces G6P, the metabolite central to this process.
    action: ACCEPT
    reason: By generating G6P, HK1 participates in glucose 6-phosphate metabolism;
      duplicates the IBA annotation to the same term.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "its product D-glucose 6-phosphate (PubMed:1637300). Hexokinase activity"
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: IMP
  original_reference_id: PMID:27374331
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: The study directly assays hexokinase enzymatic activity (dose-dependent
      inhibition by NAG); supports the core hexokinase activity.
    supported_by:
    - reference_id: PMID:27374331
      supporting_text: we confirmed that NAG is a dose-dependent inhibitor of hexokinase
        enzymatic activity
- term:
    id: GO:0042834
    label: peptidoglycan binding
  evidence_type: IDA
  original_reference_id: PMID:27374331
  qualifier: enables
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:27374331
      supporting_text: detected in the cytosol by the glycolytic enzyme
- term:
    id: GO:0046835
    label: carbohydrate phosphorylation
  evidence_type: IMP
  original_reference_id: PMID:27374331
  qualifier: involved_in
  review:
    summary: CAFA IMP for carbohydrate phosphorylation based on PMID:27374331, directly
      describing HK1's catalytic process of phosphorylating hexoses.
    action: ACCEPT
    reason: HK1 phosphorylates hexoses to hexose 6-phosphates; a correct process annotation
      reflecting the enzyme's activity.
    supported_by:
    - reference_id: PMID:27374331
      supporting_text: GAM, is phosphorylated by hexokinase
- term:
    id: GO:0070585
    label: protein localization to mitochondrion
  evidence_type: IMP
  original_reference_id: PMID:23962723
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:23962723
      supporting_text: the brain-expressed hexokinase 1 (HK1)
- term:
    id: GO:0072656
    label: maintenance of protein location in mitochondrion
  evidence_type: IMP
  original_reference_id: PMID:23962723
  qualifier: involved_in
  review:
    summary: IMP annotation based on PMID:23962723 relating hexokinase activity to
      parkin localization at depolarized mitochondria.
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:23962723
      supporting_text: suggesting the effects are
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HDA
  original_reference_id: PMID:20833797
  qualifier: located_in
  review:
    summary: High-throughput phosphoproteome study of functional mitochondria detecting
      HK1, consistent with the mitochondrion-associated HK1 pool.
    action: ACCEPT
    reason: High-throughput proteomic detection in mitochondria corroborates the mitochondrial-outer-membrane-associated
      HK1 pool.
    supported_by:
    - reference_id: file:human/HK1/HK1-uniprot.txt
      supporting_text: "SUBCELLULAR LOCATION: Mitochondrion outer membrane"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70420
  qualifier: located_in
  review:
    summary: Reactome TAS localizing HK1 to cytosol (glucose-phosphorylation reaction),
      consistent with its predominantly cytosolic distribution.
    action: ACCEPT
    reason: HK1's committed glycolytic reaction occurs in the cytosol; a core localization.
    supported_by:
    - reference_id: Reactome:R-HSA-70171
      supporting_text: convert glucose 6-phosphate to pyruvate. The entire process
        is cytosolic
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9909159
  qualifier: located_in
  review:
    summary: Reactome TAS localizing HK1 to cytosol (mannose-phosphorylation reaction).
      Consistent with its predominantly cytosolic distribution.
    action: ACCEPT
    reason: HK1 is a cytosolic enzyme; Reactome explicitly describes cytosolic HK1
      catalyzing mannose phosphorylation.
    supported_by:
    - reference_id: Reactome:R-HSA-9909159
      supporting_text: Cytosolic hexokinase 1 (HK1) catalyzes the phosphorylation
        of mannose (Man) to form D-mannose 6-phosphate (Man6P)
- term:
    id: GO:0004396
    label: hexokinase activity
  evidence_type: TAS
  original_reference_id: PMID:3207429
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: The human hexokinase sequence encodes a catalytic domain retaining glucose-binding
      and glucose-phosphorylating activity; supports the core hexokinase activity.
    supported_by:
    - reference_id: PMID:3207429
      supporting_text: retained the glucose binding site and glucose phosphorylating
- term:
    id: GO:0006096
    label: glycolytic process
  evidence_type: TAS
  original_reference_id: PMID:3207429
  qualifier: involved_in
  review:
    summary: TAS involvement in glycolytic process from the human hexokinase cDNA-cloning
      paper. HK1 catalyzes the committed entry step of glycolysis.
    action: ACCEPT
    reason: HK1 initiates glycolysis by producing G6P; a core biological process,
      corroborated across evidence types.
    supported_by:
    - reference_id: PMID:3207429
      supporting_text: retained the glucose binding site and glucose phosphorylating
core_functions:
- description: ATP-dependent phosphorylation of D-glucose to D-glucose 6-phosphate,
    the first committed and rate-limiting step of glycolysis, feeding glucose into
    glycolysis, the pentose phosphate pathway and glycogen synthesis; the enzyme is
    allosterically inhibited by its product glucose 6-phosphate.
  molecular_function:
    id: GO:0004396
    label: hexokinase activity
  directly_involved_in:
  - id: GO:0006096
    label: glycolytic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:1637300
    supporting_text: not only to catalyse glucose phosphorylation, but
  - reference_id: file:human/HK1/HK1-uniprot.txt
    supporting_text: "hexose 6-phosphate (D-glucose 6-phosphate, D-glucosamine 6-phosphate,"
- description: Phosphorylation of glucose to glucose 6-phosphate as the gateway of
    cellular glucose metabolism, contributing to intracellular glucose utilization
    and homeostasis.
  molecular_function:
    id: GO:0004396
    label: hexokinase activity
  directly_involved_in:
  - id: GO:0006006
    label: glucose metabolic process
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:3207429
    supporting_text: retained the glucose binding site and glucose phosphorylating
- description: Association of a subpool of hexokinase-1 with the cytoplasmic face of
    the mitochondrial outer membrane via VDAC/porin, mediated by an N-terminal mitochondrial-binding
    peptide, coupling glycolysis to oxidative phosphorylation.
  molecular_function:
    id: GO:0004396
    label: hexokinase activity
  locations:
  - id: GO:0005741
    label: mitochondrial outer membrane
  supported_by:
  - reference_id: PMID:1985912
    supporting_text: acids are involved in the binding of hexokinase to mitochondrial
      porin these
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000041
  title: Gene Ontology annotation based on UniPathway vocabulary mapping
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000116
  title: Automatic Gene Ontology annotation based on Rhea mapping
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/HK1/HK1-uniprot.txt
  title: UniProtKB entry P19367 (HXK1_HUMAN), Hexokinase-1
  findings: []
- id: PMID:13681085
  title: Mannose metabolism and the demonstration of mannokinase and phosphomannoisomerase
    activities in the lactating rat mammary gland.
  findings: []
- id: PMID:14191428
  title: EFFECT OF DIETARY CARBOHYDRATE AND GLUCOKINASE AND MANNOKINASE ACTIVITIES
    OF VARIOUS RAT TISSUES.
  findings: []
- id: PMID:1637300
  title: A recombinant human 'mini'-hexokinase is catalytically active and regulated
    by hexose 6-phosphates.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; abstract directly supports human hexokinase catalytic
      activity (glucose phosphorylation) and allosteric product inhibition by glucose
      6-phosphate.
- id: PMID:1985912
  title: Human hexokinase type I microheterogeneity is due to different amino-terminal
    sequences.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; supports that the N-terminal 10 residues mediate
      binding to mitochondrial porin (VDAC) and hence the mitochondrial-outer-membrane
      association.
- id: PMID:20833797
  title: Phosphoproteome analysis of functional mitochondria isolated from resting
    human muscle reveals extensive phosphorylation of inner membrane protein complexes
    and enzymes.
  findings: []
- id: PMID:22304920
  title: PKCĪµ promotes oncogenic functions of ATF2 in the nucleus while blocking its
    apoptotic function at mitochondria.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: PubMed-verified; abstract explicitly references the HK1-VDAC1 complex
      at mitochondria. Supports the HK1-VDAC1 interaction but the GO term (protein
      binding) is uninformative.
- id: PMID:23962723
  title: Hexokinase activity is required for recruitment of parkin to depolarized
    mitochondria.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Abstract-only cache; foregrounds HK2 but explicitly states the effect
      is shared among hexokinases including the brain-expressed HK1. Supports the
      parkin-recruitment (protein localization to mitochondrion) role of hexokinases.
- id: PMID:27374331
  title: Hexokinase Is an Innate Immune Receptor for the Detection of Bacterial Peptidoglycan.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Full text available; directly supports hexokinase enzymatic activity
      and its inhibition by N-acetylglucosamine, glucosamine phosphorylation, mitochondrial-outer-membrane
      association and dissociation, and the innate-immune (peptidoglycan/NAG-sensing,
      NLRP3/IL-1beta) moonlighting role.
- id: PMID:28054552
  title: c-Src phosphorylation and activation of hexokinase promotes tumorigenesis
    and metastasis.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Full text available; establishes HK1-c-Src interaction and Tyr732
      phosphorylation that activates HK1 and enhances glycolysis. Underlying interaction
      real; GO term (protein binding) uninformative.
- id: PMID:3207429
  title: 'Human hexokinase: sequences of amino- and carboxyl-terminal halves are homologous.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: PubMed-verified; the human hexokinase cDNA-cloning paper establishing
      the 917-aa two-domain structure with C-terminal catalytic (glucose-binding and
      glucose-phosphorylating) and N-terminal regulatory halves.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
- id: PMID:35156780
  title: CFTR interactome mapping using the mammalian membrane two-hybrid high-throughput
    screening system.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput CFTR interactome screen; HK1 appears as an interactor
      in the underlying dataset. Supports only a bare protein-binding annotation of
      unclear significance.
- id: PMID:35271311
  title: 'OpenCell: Endogenous tagging for the cartography of human cellular organization.'
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Large-scale endogenous-tagging and interactome resource; HK1-VDAC1
      interaction in the dataset. Supports only a bare protein-binding annotation.
- id: PMID:36012204
  title: Differential CFTR-Interactome Proximity Labeling Procedures Identify Enrichment
    in Multiple SLC Transporters.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: High-throughput CFTR proximity-labeling study; HK1 appears among
      proximity-labeled proteins. Supports only a bare protein-binding annotation
      of unclear significance.
- id: Reactome:R-HSA-446205
  title: Synthesis of GDP-mannose
  findings: []
- id: Reactome:R-HSA-5621888
  title: Defective HK1 does not phosphorylate Glc to form G6P
  findings: []
- id: Reactome:R-HSA-70171
  title: Glycolysis
  findings: []
- id: Reactome:R-HSA-70420
  title: HK1,2,3,GCK,HKDC1 phosphorylate Glc to form G6P
  findings: []
- id: Reactome:R-HSA-9909159
  title: HK1 phosphorylates Mannose to Man6P
  findings: []