UniProtKB - P17712 (HXK4_RAT)
Protein
Hexokinase-4
Gene
Gck
Organism
Rattus norvegicus (Rat)
Status
Functioni
Catalyzes the phosphorylation of hexose, such as D-glucose, D-fructose and D-mannose, to hexose 6-phosphate (D-glucose 6-phosphate, D-fructose 6-phosphate and D-mannose 6-phosphate, respectively) (PubMed:6477520, PubMed:12513690, PubMed:24187134). Compared to other hexokinases, has a weak affinity for D-glucose, and is effective only when glucose is abundant (PubMed:6477520). Mainly expressed in pancreatic beta cells and the liver and constitutes a rate-limiting step in glucose metabolism in these tissues (By similarity). Since insulin secretion parallels glucose metabolism and the low glucose affinity of GCK ensures that it can change its enzymatic activity within the physiological range of glucose concentrations, GCK acts as a glucose sensor in the pancreatic beta cell (By similarity). In pancreas, plays an important role in modulating insulin secretion (By similarity). In liver, helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage (By similarity). Required to provide D-glucose 6-phosphate for the synthesis of glycogen (By similarity). Mediates the initial step of glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-phosphate (PubMed:6477520, PubMed:12513690).By similarity3 Publications
Catalytic activityi
- EC:2.7.1.12 PublicationsThis reaction proceeds in the forward2 Publications direction.
- EC:2.7.1.11 PublicationThis reaction proceeds in the forward1 Publication direction.
- EC:2.7.1.12 PublicationsThis reaction proceeds in the forward2 Publications direction.
- EC:2.7.1.1By similarityThis reaction proceeds in the forwardBy similarity direction.
Activity regulationi
Subject to allosteric regulation (By similarity). Low glucose and high fructose-6-phosphate triggers association with the inhibitor GCKR followed by sequestration in the nucleus (PubMed:10456334).By similarity1 Publication
: hexose metabolism Pathwayi
This protein is involved in the pathway hexose metabolism, which is part of Carbohydrate metabolism.2 PublicationsView all proteins of this organism that are known to be involved in the pathway hexose metabolism and in Carbohydrate metabolism.
Pathwayi: glycolysis
This protein is involved in step 1 of the subpathway that synthesizes D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose.2 PublicationsProteins known to be involved in the 4 steps of the subpathway in this organism are:
- Hexokinase (Hk3), Hexokinase, Hexokinase-4 (Gck), Hexokinase-2 (Hk2), Phosphotransferase (Gck), Hexokinase-3 (Hk3), Hexokinase (Hk1), Hexokinase (Hk3), Phosphotransferase (Gck), Hexokinase-1 (Hk1), Hexokinase
- Glucose-6-phosphate isomerase (Gpi)
- ATP-dependent 6-phosphofructokinase (Pfkm), ATP-dependent 6-phosphofructokinase (Pfkp), ATP-dependent 6-phosphofructokinase (Pfkl), ATP-dependent 6-phosphofructokinase, muscle type (Pfkm), ATP-dependent 6-phosphofructokinase, liver type (Pfkl), ATP-dependent 6-phosphofructokinase, platelet type (Pfkp), ATP-dependent 6-phosphofructokinase (Pfkm), ATP-dependent 6-phosphofructokinase (Pfkp)
- Fructose-bisphosphate aldolase (Aldoc), Fructose-bisphosphate aldolase, Fructose-bisphosphate aldolase (Aldoart2), Fructose-bisphosphate aldolase A (Aldoa), Fructose-bisphosphate aldolase B (Aldob), Fructose-bisphosphate aldolase (Aldoc), Fructose-bisphosphate aldolase C (Aldoc), Fructose-bisphosphate aldolase (Aldoc), Fructose-bisphosphate aldolase (Aldob)
View all proteins of this organism that are known to be involved in the subpathway that synthesizes D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose, the pathway glycolysis and in Carbohydrate degradation.
Sites
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Binding sitei | 228 | ATPBy similarity | 1 | |
Binding sitei | 231 | SubstrateBy similarity | 1 | |
Binding sitei | 256 | SubstrateBy similarity | 1 | |
Binding sitei | 290 | SubstrateBy similarity | 1 |
Regions
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Nucleotide bindingi | 78 – 83 | ATPBy similarity | 6 | |
Nucleotide bindingi | 295 – 296 | ATPBy similarity | 2 | |
Nucleotide bindingi | 332 – 336 | ATPBy similarity | 5 | |
Nucleotide bindingi | 411 – 415 | ATPBy similarity | 5 |
GO - Molecular functioni
- ADP binding Source: RGD
- ATP binding Source: RGD
- fructokinase activity Source: UniProtKB
- glucokinase activity Source: UniProtKB
- glucose binding Source: RGD
- hexokinase activity Source: RGD
- magnesium ion binding Source: RGD
- mannokinase activity Source: UniProtKB
- protein phosphatase binding Source: RGD
GO - Biological processi
- calcium ion import Source: RGD
- carbohydrate phosphorylation Source: RGD
- cellular glucose homeostasis Source: RGD
- cellular response to glucose starvation Source: RGD
- cellular response to insulin stimulus Source: BHF-UCL
- cellular response to leptin stimulus Source: BHF-UCL
- detection of glucose Source: BHF-UCL
- fructose 2,6-bisphosphate metabolic process Source: RGD
- fructose 6-phosphate metabolic process Source: UniProtKB
- glucose 6-phosphate metabolic process Source: UniProtKB
- glucose homeostasis Source: RGD
- glucose metabolic process Source: RGD
- glycogen biosynthetic process Source: RGD
- glycolytic process Source: RGD
- lipid homeostasis Source: RGD
- mannose metabolic process Source: UniProtKB
- NADP metabolic process Source: RGD
- negative regulation of epinephrine secretion Source: RGD
- negative regulation of gluconeogenesis Source: UniProtKB
- positive regulation of cytosolic calcium ion concentration Source: RGD
- positive regulation of glycogen biosynthetic process Source: UniProtKB
- positive regulation of glycolytic process Source: RGD
- positive regulation of insulin secretion Source: RGD
- positive regulation of phosphorylation Source: RGD
- regulation of insulin secretion Source: RGD
- regulation of potassium ion transport Source: RGD
- response to glucose Source: RGD
- second-messenger-mediated signaling Source: RGD
Keywordsi
Molecular function | Allosteric enzyme, Kinase, Transferase |
Biological process | Glycolysis |
Ligand | ATP-binding, Nucleotide-binding |
Enzyme and pathway databases
Reactomei | R-RNO-170822, Regulation of Glucokinase by Glucokinase Regulatory Protein R-RNO-70171, Glycolysis |
SABIO-RKi | P17712 |
UniPathwayi | UPA00109;UER00180 UPA00242 |
Names & Taxonomyi
Protein namesi | Recommended name: Hexokinase-4Curated (EC:2.7.1.12 Publications)Short name: HK4Curated Alternative name(s): Glucokinase1 Publication Hexokinase type IV1 Publication Short name: HK IV1 Publication Hexokinase-D1 Publication |
Gene namesi | Name:GckImported |
Organismi | Rattus norvegicus (Rat) |
Taxonomic identifieri | 10116 [NCBI] |
Taxonomic lineagei | Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Myomorpha › Muroidea › Muridae › Murinae › Rattus |
Proteomesi |
|
Organism-specific databases
RGDi | 2670, Gck |
Subcellular locationi
Mitochondrion
- Mitochondrion 1 Publication
Nucleus
- Nucleus 1 Publication
Other locations
- Cytoplasm 2 Publications
Note: Under low glucose concentrations, associates with GCKR and the inactive complex is recruited to the hepatocyte nucleus.1 Publication
Cytosol
- cytosol Source: RGD
Mitochondrion
- mitochondrion Source: RGD
Nucleus
- nucleoplasm Source: RGD
- nucleus Source: BHF-UCL
Other locations
- basal cortex Source: RGD
- cell cortex Source: RGD
- cytoplasm Source: BHF-UCL
- secretory granule Source: RGD
Keywords - Cellular componenti
Cytoplasm, Mitochondrion, NucleusPTM / Processingi
Molecule processing
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
ChainiPRO_0000197595 | 1 – 465 | Hexokinase-4Add BLAST | 465 |
Proteomic databases
PaxDbi | P17712 |
PRIDEi | P17712 |
Expressioni
Tissue specificityi
Expression is restricted to the liver and pancreatic islets (at protein level).1 Publication
Gene expression databases
Bgeei | ENSRNOG00000061527, Expressed in liver and 13 other tissues |
ExpressionAtlasi | P17712, baseline and differential |
Interactioni
Subunit structurei
GO - Molecular functioni
- protein phosphatase binding Source: RGD
Protein-protein interaction databases
IntActi | P17712, 2 interactors |
MINTi | P17712 |
STRINGi | 10116.ENSRNOP00000019625 |
Chemistry databases
BindingDBi | P17712 |
Family & Domainsi
Domains and Repeats
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Domaini | 10 – 454 | HexokinasePROSITE-ProRule annotationAdd BLAST | 445 |
Region
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Regioni | 67 – 203 | Hexokinase small subdomainPROSITE-ProRule annotationAdd BLAST | 137 | |
Regioni | 151 – 152 | Substrate bindingBy similarity | 2 | |
Regioni | 168 – 169 | Substrate bindingBy similarity | 2 | |
Regioni | 204 – 443 | Hexokinase large subdomainPROSITE-ProRule annotationAdd BLAST | 240 | |
Regioni | 204 – 205 | Substrate bindingBy similarity | 2 |
Sequence similaritiesi
Phylogenomic databases
eggNOGi | KOG1369, Eukaryota |
GeneTreei | ENSGT00950000182787 |
InParanoidi | P17712 |
PhylomeDBi | P17712 |
Family and domain databases
InterProi | View protein in InterPro IPR043129, ATPase_NBD IPR039073, GCK_chordate IPR001312, Hexokinase IPR019807, Hexokinase_BS IPR022673, Hexokinase_C IPR022672, Hexokinase_N |
PANTHERi | PTHR19443, PTHR19443, 1 hit PTHR19443:SF3, PTHR19443:SF3, 1 hit |
Pfami | View protein in Pfam PF00349, Hexokinase_1, 1 hit PF03727, Hexokinase_2, 1 hit |
SUPFAMi | SSF53067, SSF53067, 2 hits |
PROSITEi | View protein in PROSITE PS00378, HEXOKINASE_1, 1 hit PS51748, HEXOKINASE_2, 1 hit |
s (3+)i Sequence
Sequence statusi: Complete.
This entry describes 3 produced by isoformsialternative promoter usage and alternative splicing. AlignAdd to basketNote: A number of isoforms are produced by alternative promoter usage. The use of alternative promoters apparently enables the type IV hexokinase gene to be regulated by insulin in the liver and glucose in the beta cell. This may constitute an important feedback loop for maintaining glucose homeostasis.By similarity
This entry has 3 described isoforms and 1 potential isoform that is computationally mapped.Show allAlign All
Isoform 1 (identifier: P17712-1) [UniParc]FASTAAdd to basket
This isoform has been chosen as the sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry. canonicali
10 20 30 40 50
MLDDRARMEA TKKEKVEQIL AEFQLQEEDL KKVMSRMQKE MDRGLRLETH
60 70 80 90 100
EEASVKMLPT YVRSTPEGSE VGDFLSLDLG GTNFRVMLVK VGEGEAGQWS
110 120 130 140 150
VKTKHQMYSI PEDAMTGTAE MLFDYISECI SDFLDKHQMK HKKLPLGFTF
160 170 180 190 200
SFPVRHEDLD KGILLNWTKG FKASGAEGNN IVGLLRDAIK RRGDFEMDVV
210 220 230 240 250
AMVNDTVATM ISCYYEDRQC EVGMIVGTGC NACYMEEMQN VELVEGDEGR
260 270 280 290 300
MCVNTEWGAF GDSGELDEFL LEYDRMVDES SANPGQQLYE KIIGGKYMGE
310 320 330 340 350
LVRLVLLKLV DENLLFHGEA SEQLRTRGAF ETRFVSQVES DSGDRKQIHN
360 370 380 390 400
ILSTLGLRPS VTDCDIVRRA CESVSTRAAH MCSAGLAGVI NRMRESRSED
410 420 430 440 450
VMRITVGVDG SVYKLHPSFK ERFHASVRRL TPNCEITFIE SEEGSGRGAA
460
LVSAVACKKA CMLAQ
Computationally mapped potential isoform sequencesi
There is 1 potential isoform mapped to this entry.BLASTAlignShow allAdd to basketQ64596 | Q64596_RAT | Phosphotransferase | Gck rCG_35874 | 498 | Annotation score: |
Alternative sequence
Feature key | Position(s) | DescriptionActions | Graphical view | Length |
---|---|---|---|---|
Alternative sequenceiVSP_002077 | 1 – 15 | MLDDR…TKKEK → MAMDTTRCGAQLLTL in isoform 3. 1 PublicationAdd BLAST | 15 | |
Alternative sequenceiVSP_002078 | 122 – 138 | Missing in isoform 2. CuratedAdd BLAST | 17 |
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | J04218 mRNA Translation: AAA41229.1 M24952 , M24943, M24944, M24945, M24947, M24948, M24949, M24950, M24951 Genomic DNA Translation: AAA41230.1 M25806 Genomic DNA Translation: AAA41238.1 M25807 mRNA Translation: AAA41239.1 M58759 mRNA Translation: AAA41236.1 X53588 mRNA Translation: CAA37657.1 X53590 Genomic DNA Translation: CAA37660.1 M30770 Genomic DNA Translation: AAA41231.1 |
PIRi | A31810 I84740 |
RefSeqi | NP_001257779.1, NM_001270850.1 [P17712-2] NP_036697.1, NM_012565.2 [P17712-3] XP_006251241.1, XM_006251179.3 [P17712-1] |
Genome annotation databases
Ensembli | ENSRNOT00000086343; ENSRNOP00000071435; ENSRNOG00000061527 [P17712-3] ENSRNOT00000086474; ENSRNOP00000069954; ENSRNOG00000061527 [P17712-2] |
GeneIDi | 24385 |
KEGGi | rno:24385 |
UCSCi | RGD:2670, rat [P17712-1] |
Keywords - Coding sequence diversityi
Alternative promoter usage, Alternative splicingSimilar proteinsi
Cross-referencesi
Sequence databases
Select the link destinations: EMBLi GenBanki DDBJi Links Updated | J04218 mRNA Translation: AAA41229.1 M24952 , M24943, M24944, M24945, M24947, M24948, M24949, M24950, M24951 Genomic DNA Translation: AAA41230.1 M25806 Genomic DNA Translation: AAA41238.1 M25807 mRNA Translation: AAA41239.1 M58759 mRNA Translation: AAA41236.1 X53588 mRNA Translation: CAA37657.1 X53590 Genomic DNA Translation: CAA37660.1 M30770 Genomic DNA Translation: AAA41231.1 |
PIRi | A31810 I84740 |
RefSeqi | NP_001257779.1, NM_001270850.1 [P17712-2] NP_036697.1, NM_012565.2 [P17712-3] XP_006251241.1, XM_006251179.3 [P17712-1] |
3D structure databases
SMRi | P17712 |
ModBasei | Search... |
Protein-protein interaction databases
IntActi | P17712, 2 interactors |
MINTi | P17712 |
STRINGi | 10116.ENSRNOP00000019625 |
Chemistry databases
BindingDBi | P17712 |
ChEMBLi | CHEMBL3882 |
Proteomic databases
PaxDbi | P17712 |
PRIDEi | P17712 |
Genome annotation databases
Ensembli | ENSRNOT00000086343; ENSRNOP00000071435; ENSRNOG00000061527 [P17712-3] ENSRNOT00000086474; ENSRNOP00000069954; ENSRNOG00000061527 [P17712-2] |
GeneIDi | 24385 |
KEGGi | rno:24385 |
UCSCi | RGD:2670, rat [P17712-1] |
Organism-specific databases
CTDi | 2645 |
RGDi | 2670, Gck |
Phylogenomic databases
eggNOGi | KOG1369, Eukaryota |
GeneTreei | ENSGT00950000182787 |
InParanoidi | P17712 |
PhylomeDBi | P17712 |
Enzyme and pathway databases
UniPathwayi | UPA00109;UER00180 UPA00242 |
Reactomei | R-RNO-170822, Regulation of Glucokinase by Glucokinase Regulatory Protein R-RNO-70171, Glycolysis |
SABIO-RKi | P17712 |
Miscellaneous databases
PROi | PR:P17712 |
Gene expression databases
Bgeei | ENSRNOG00000061527, Expressed in liver and 13 other tissues |
ExpressionAtlasi | P17712, baseline and differential |
Family and domain databases
InterProi | View protein in InterPro IPR043129, ATPase_NBD IPR039073, GCK_chordate IPR001312, Hexokinase IPR019807, Hexokinase_BS IPR022673, Hexokinase_C IPR022672, Hexokinase_N |
PANTHERi | PTHR19443, PTHR19443, 1 hit PTHR19443:SF3, PTHR19443:SF3, 1 hit |
Pfami | View protein in Pfam PF00349, Hexokinase_1, 1 hit PF03727, Hexokinase_2, 1 hit |
SUPFAMi | SSF53067, SSF53067, 2 hits |
PROSITEi | View protein in PROSITE PS00378, HEXOKINASE_1, 1 hit PS51748, HEXOKINASE_2, 1 hit |
ProtoNeti | Search... |
MobiDBi | Search... |
Entry informationi
Entry namei | HXK4_RAT | |
Accessioni | P17712Primary (citable) accession number: P17712 Secondary accession number(s): P17711 | |
Entry historyi | Integrated into UniProtKB/Swiss-Prot: | August 1, 1990 |
Last sequence update: | November 1, 1990 | |
Last modified: | December 2, 2020 | |
This is version 169 of the entry and version 2 of the sequence. See complete history. | ||
Entry statusi | Reviewed (UniProtKB/Swiss-Prot) | |
Annotation program | Chordata Protein Annotation Program |
Miscellaneousi
Keywords - Technical termi
Direct protein sequencing, Reference proteomeDocuments
- PATHWAY comments
Index of metabolic and biosynthesis pathways - SIMILARITY comments
Index of protein domains and families