ID HXK2_HUMAN Reviewed; 917 AA.
AC P52789; D6W5J2; Q8WU87; Q9UN82;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 07-DEC-2004, sequence version 2.
DT 27-MAR-2024, entry version 219.
DE RecName: Full=Hexokinase-2 {ECO:0000305};
DE EC=2.7.1.1 {ECO:0000269|PubMed:23185017, ECO:0000269|PubMed:26985301, ECO:0000269|PubMed:29298880};
DE AltName: Full=Hexokinase type II {ECO:0000303|PubMed:8250948, ECO:0000303|PubMed:8786021};
DE Short=HK II {ECO:0000303|PubMed:8250948, ECO:0000303|PubMed:8786021};
DE AltName: Full=Hexokinase-B {ECO:0000250|UniProtKB:P27881};
DE AltName: Full=Muscle form hexokinase {ECO:0000303|PubMed:8250948};
GN Name=HK2 {ECO:0000312|HGNC:HGNC:4923};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC TISSUE=Skeletal muscle;
RX PubMed=8250948; DOI=10.1006/bbrc.1993.2442;
RA Deeb S.S., Malkki M., Laakso M.;
RT "Human hexokinase II: sequence and homology to other hexokinases.";
RL Biochem. Biophys. Res. Commun. 197:68-74(1993).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT HIS-142.
RC TISSUE=Blood, Muscle, and Placenta;
RX PubMed=8786021; DOI=10.1007/bf00400608;
RA Lehto M., Huang X., Davis E.M., Le Beau M.M., Laurila E., Eriksson K.F.,
RA Bell G.I., Groop L.C.;
RT "Human hexokinase II gene: exon-intron organization, mutation screening in
RT NIDDM, and its relationship to muscle hexokinase activity.";
RL Diabetologia 38:1466-1474(1995).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Skeletal muscle;
RA Malkki M., Heikkinen S., Deeb S.S., Laakso M.;
RL Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases.
RN [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANTS HIS-142; CYS-274; PRO-314;
RP ILE-331; SER-387; GLN-801; LYS-844 AND ASN-881.
RG NIEHS SNPs program;
RL Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [7]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 614-739.
RX PubMed=7518342; DOI=10.1016/0304-3835(94)90142-2;
RA Shinohara Y., Yamamoto K., Kogure K., Ichihara J., Terada H.;
RT "Steady state transcript levels of the type II hexokinase and type 1
RT glucose transporter in human tumor cell lines.";
RL Cancer Lett. 82:27-32(1994).
RN [8]
RP FUNCTION, AND SUBCELLULAR LOCATION.
RX PubMed=18350175; DOI=10.1371/journal.pone.0001852;
RA Chiara F., Castellaro D., Marin O., Petronilli V., Brusilow W.S.,
RA Juhaszova M., Sollott S.J., Forte M., Bernardi P., Rasola A.;
RT "Hexokinase II detachment from mitochondria triggers apoptosis through the
RT permeability transition pore independent of voltage-dependent anion
RT channels.";
RL PLoS ONE 3:E1852-E1852(2008).
RN [9]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [10]
RP FUNCTION, CATALYTIC ACTIVITY, AND INTERACTION WITH TIGAR.
RX PubMed=23185017; DOI=10.1073/pnas.1206530109;
RA Cheung E.C., Ludwig R.L., Vousden K.H.;
RT "Mitochondrial localization of TIGAR under hypoxia stimulates HK2 and
RT lowers ROS and cell death.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:20491-20496(2012).
RN [11]
RP ACETYLATION [LARGE SCALE ANALYSIS] AT MET-1, AND IDENTIFICATION BY MASS
RP SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=25944712; DOI=10.1002/pmic.201400617;
RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D.,
RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.;
RT "N-terminome analysis of the human mitochondrial proteome.";
RL Proteomics 15:2519-2524(2015).
RN [12] {ECO:0007744|PDB:5HEX, ECO:0007744|PDB:5HFU, ECO:0007744|PDB:5HG1}
RP X-RAY CRYSTALLOGRAPHY (2.73 ANGSTROMS) OF 17-917 IN COMPLEX WITH
RP GLUCOSE-6-PHOSPHATE, FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=26985301; DOI=10.1021/acsmedchemlett.5b00214;
RA Lin H., Zeng J., Xie R., Schulz M.J., Tedesco R., Qu J., Erhard K.F.,
RA Mack J.F., Raha K., Rendina A.R., Szewczuk L.M., Kratz P.M., Jurewicz A.J.,
RA Cecconie T., Martens S., McDevitt P.J., Martin J.D., Chen S.B., Jiang Y.,
RA Nickels L., Schwartz B.J., Smallwood A., Zhao B., Campobasso N., Qian Y.,
RA Briand J., Rominger C.M., Oleykowski C., Hardwicke M.A., Luengo J.I.;
RT "Discovery of a novel 2,6-disubstituted glucosamine series of potent and
RT selective hexokinase 2 inhibitors.";
RL ACS Med. Chem. Lett. 7:217-222(2016).
RN [13]
RP X-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS) OF 17-916 IN COMPLEX WITH GLUCOSE
RP AND GLUCOSE-6-PHOSPHATE, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL
RP PROPERTIES, SUBCELLULAR LOCATION, DOMAIN, AND MUTAGENESIS OF ASP-209;
RP ARG-468 AND ASP-657.
RX PubMed=29298880; DOI=10.1042/bsr20171666;
RA Nawaz M.H., Ferreira J.C., Nedyalkova L., Zhu H., Carrasco-Lopez C.,
RA Kirmizialtin S., Rabeh W.M.;
RT "The catalytic inactivation of the N-half of human hexokinase 2 and
RT structural and biochemical characterization of its mitochondrial
RT conformation.";
RL Biosci. Rep. 38:0-0(2018).
RN [14]
RP VARIANTS VAL-314; CYS-353 AND GLN-775.
RX PubMed=7883120; DOI=10.2337/diab.44.3.330;
RA Laakso M., Malkki M., Deeb S.S.;
RT "Amino acid substitutions in hexokinase II among patients with NIDDM.";
RL Diabetes 44:330-334(1995).
RN [15]
RP VARIANT HIS-142.
RX PubMed=7883122; DOI=10.2337/diab.44.3.340;
RA Vidal-Puig A., Printz R.L., Stratton I.M., Granner D.K., Moller D.E.;
RT "Analysis of the hexokinase II gene in subjects with insulin resistance and
RT NIDDM and detection of a Gln142-->His substitution.";
RL Diabetes 44:340-346(1995).
RN [16]
RP VARIANTS HIS-142; PHE-148; GLN-497 AND LYS-844.
RX PubMed=7883123; DOI=10.2337/diab.44.3.347;
RA Echwald S.M., Bjoerbaek C., Hansen T., Clausen J.O., Vestergaard H.,
RA Zierath J.R., Printz R.L., Granner D.K., Pedersen O.;
RT "Identification of four amino acid substitutions in hexokinase II and
RT studies of relationships to NIDDM, glucose effectiveness, and insulin
RT sensitivity.";
RL Diabetes 44:347-353(1995).
CC -!- FUNCTION: Catalyzes the phosphorylation of hexose, such as D-glucose
CC and D-fructose, to hexose 6-phosphate (D-glucose 6-phosphate and D-
CC fructose 6-phosphate, respectively) (PubMed:23185017, PubMed:26985301,
CC PubMed:29298880). Mediates the initial step of glycolysis by catalyzing
CC phosphorylation of D-glucose to D-glucose 6-phosphate
CC (PubMed:29298880). Plays a key role in maintaining the integrity of the
CC outer mitochondrial membrane by preventing the release of apoptogenic
CC molecules from the intermembrane space and subsequent apoptosis
CC (PubMed:18350175). {ECO:0000269|PubMed:18350175,
CC ECO:0000269|PubMed:23185017, ECO:0000269|PubMed:26985301,
CC ECO:0000269|PubMed:29298880}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + D-hexose = ADP + D-hexose 6-phosphate + H(+);
CC Xref=Rhea:RHEA:22740, ChEBI:CHEBI:4194, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61567, ChEBI:CHEBI:456216; EC=2.7.1.1;
CC Evidence={ECO:0000269|PubMed:23185017, ECO:0000269|PubMed:26985301,
CC ECO:0000269|PubMed:29298880};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22741;
CC Evidence={ECO:0000269|PubMed:23185017, ECO:0000269|PubMed:29298880};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + D-fructose = ADP + D-fructose 6-phosphate + H(+);
CC Xref=Rhea:RHEA:16125, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:37721, ChEBI:CHEBI:61527, ChEBI:CHEBI:456216; EC=2.7.1.1;
CC Evidence={ECO:0000250|UniProtKB:P27881};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16126;
CC Evidence={ECO:0000250|UniProtKB:P27881};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ATP + D-glucose = ADP + D-glucose 6-phosphate + H(+);
CC Xref=Rhea:RHEA:17825, ChEBI:CHEBI:4167, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:61548, ChEBI:CHEBI:456216; EC=2.7.1.1;
CC Evidence={ECO:0000269|PubMed:29298880};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17826;
CC Evidence={ECO:0000269|PubMed:29298880};
CC -!- ACTIVITY REGULATION: Hexokinase activity is specifically inhibited by
CC 2,6-disubstituted glucosamines. {ECO:0000269|PubMed:26985301}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=0.21 mM for D-glucose {ECO:0000269|PubMed:29298880};
CC KM=1.13 mM for ATP {ECO:0000269|PubMed:29298880};
CC -!- PATHWAY: Carbohydrate metabolism; hexose metabolism.
CC {ECO:0000305|PubMed:29298880}.
CC -!- PATHWAY: Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-
CC phosphate and glycerone phosphate from D-glucose: step 1/4.
CC {ECO:0000305|PubMed:29298880}.
CC -!- SUBUNIT: Monomer (By similarity). Interacts with TIGAR; the interaction
CC increases hexokinase activity in a hypoxia- and HIF1A-dependent manner
CC (PubMed:23185017). {ECO:0000250|UniProtKB:P19367,
CC ECO:0000269|PubMed:23185017}.
CC -!- INTERACTION:
CC P52789; P43365: MAGEA12; NbExp=3; IntAct=EBI-741469, EBI-749530;
CC P52789; Q9NQ88: TIGAR; NbExp=3; IntAct=EBI-741469, EBI-3920747;
CC P52789; Q9UMX0: UBQLN1; NbExp=4; IntAct=EBI-741469, EBI-741480;
CC P52789; Q9UMX0-2: UBQLN1; NbExp=3; IntAct=EBI-741469, EBI-10173939;
CC P52789; P05480: Src; Xeno; NbExp=4; IntAct=EBI-741469, EBI-298680;
CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane
CC {ECO:0000269|PubMed:18350175}; Peripheral membrane protein
CC {ECO:0000305}. Cytoplasm, cytosol {ECO:0000269|PubMed:18350175}.
CC Note=The mitochondrial-binding peptide (MBP) region promotes
CC association with the mitochondrial outer membrane (PubMed:29298880).
CC The interaction with the mitochondrial outer membrane via the
CC mitochondrial-binding peptide (MBP) region promotes higher stability of
CC the protein (PubMed:29298880). Release from the mitochondrial outer
CC membrane into the cytosol induces permeability transition pore (PTP)
CC opening and apoptosis (PubMed:18350175). {ECO:0000269|PubMed:18350175,
CC ECO:0000269|PubMed:29298880}.
CC -!- TISSUE SPECIFICITY: Predominant hexokinase isozyme expressed in
CC insulin-responsive tissues such as skeletal muscle.
CC {ECO:0000269|PubMed:8250948}.
CC -!- DOMAIN: The N- and C-terminal halves of the protein contain a
CC hexokinase domain (PubMed:29298880). In contrast to hexokinase-1 and -3
CC (HK1 and HK3, respectively), both hexokinase domains display catalytic
CC activity (PubMed:29298880). The region connecting the two hexokinase
CC domains is required for the catalytic activity of the N-terminal
CC hexokinase domain (PubMed:29298880). The N-terminal half regulates
CC stability of the whole enzyme (PubMed:29298880).
CC {ECO:0000269|PubMed:29298880}.
CC -!- POLYMORPHISM: Although found in NIDDM patients, genetic variations of
CC HK2 do not contribute to the disease (PubMed:7883122, PubMed:7883123).
CC {ECO:0000269|PubMed:7883122, ECO:0000269|PubMed:7883123}.
CC -!- SIMILARITY: Belongs to the hexokinase family. {ECO:0000255|PROSITE-
CC ProRule:PRU01084, ECO:0000305}.
CC -!- CAUTION: Hexokinase is known to act as a monomer in normal conditions
CC (By similarity). It however homodimerizes at elevated protein
CC concentrations used for crystallizations (PubMed:26985301,
CC PubMed:29298880). {ECO:0000250|UniProtKB:P19367,
CC ECO:0000269|PubMed:26985301, ECO:0000269|PubMed:29298880}.
CC -!- WEB RESOURCE: Name=NIEHS-SNPs;
CC URL="http://egp.gs.washington.edu/data/hk2/";
CC -!- WEB RESOURCE: Name=Wikipedia; Note=Hexokinase entry;
CC URL="https://en.wikipedia.org/wiki/Hexokinase";
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DR EMBL; Z46376; CAA86511.1; -; mRNA.
DR EMBL; Z46354; CAA86476.2; -; Genomic_DNA.
DR EMBL; Z46355; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46604; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46356; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46357; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46358; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46359; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46360; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46361; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46362; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46363; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46364; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46365; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46366; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46367; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46368; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; Z46369; CAA86476.2; JOINED; Genomic_DNA.
DR EMBL; AF148513; AAD30174.1; -; mRNA.
DR EMBL; AY623118; AAT38114.1; -; Genomic_DNA.
DR EMBL; CH471053; EAW99601.1; -; Genomic_DNA.
DR EMBL; CH471053; EAW99602.1; -; Genomic_DNA.
DR EMBL; BC021116; AAH21116.1; -; mRNA.
DR EMBL; BC064369; AAH64369.1; -; mRNA.
DR EMBL; D25412; BAA04999.1; -; Genomic_DNA.
DR CCDS; CCDS1956.1; -.
DR PIR; S48809; JC2025.
DR RefSeq; NP_000180.2; NM_000189.4.
DR PDB; 2NZT; X-ray; 2.45 A; A/B=17-916.
DR PDB; 5HEX; X-ray; 2.73 A; A/B=17-917.
DR PDB; 5HFU; X-ray; 2.92 A; A/B=17-917.
DR PDB; 5HG1; X-ray; 2.76 A; A=17-916.
DR PDBsum; 2NZT; -.
DR PDBsum; 5HEX; -.
DR PDBsum; 5HFU; -.
DR PDBsum; 5HG1; -.
DR AlphaFoldDB; P52789; -.
DR SMR; P52789; -.
DR BioGRID; 109346; 151.
DR DIP; DIP-50110N; -.
DR IntAct; P52789; 37.
DR MINT; P52789; -.
DR STRING; 9606.ENSP00000290573; -.
DR BindingDB; P52789; -.
DR ChEMBL; CHEMBL2640; -.
DR GlyGen; P52789; 2 sites, 1 O-linked glycan (2 sites).
DR iPTMnet; P52789; -.
DR MetOSite; P52789; -.
DR PhosphoSitePlus; P52789; -.
DR SwissPalm; P52789; -.
DR BioMuta; HK2; -.
DR DMDM; 56405344; -.
DR EPD; P52789; -.
DR jPOST; P52789; -.
DR MassIVE; P52789; -.
DR MaxQB; P52789; -.
DR PaxDb; 9606-ENSP00000290573; -.
DR PeptideAtlas; P52789; -.
DR ProteomicsDB; 56533; -.
DR Pumba; P52789; -.
DR Antibodypedia; 31617; 792 antibodies from 38 providers.
DR DNASU; 3099; -.
DR Ensembl; ENST00000290573.7; ENSP00000290573.2; ENSG00000159399.10.
DR GeneID; 3099; -.
DR KEGG; hsa:3099; -.
DR MANE-Select; ENST00000290573.7; ENSP00000290573.2; NM_000189.5; NP_000180.2.
DR UCSC; uc002snd.4; human.
DR AGR; HGNC:4923; -.
DR CTD; 3099; -.
DR DisGeNET; 3099; -.
DR GeneCards; HK2; -.
DR HGNC; HGNC:4923; HK2.
DR HPA; ENSG00000159399; Tissue enhanced (retina).
DR MIM; 601125; gene.
DR neXtProt; NX_P52789; -.
DR OpenTargets; ENSG00000159399; -.
DR PharmGKB; PA29301; -.
DR VEuPathDB; HostDB:ENSG00000159399; -.
DR eggNOG; KOG1369; Eukaryota.
DR GeneTree; ENSGT00950000182787; -.
DR InParanoid; P52789; -.
DR OMA; SYLVSWT; -.
DR OrthoDB; 5481886at2759; -.
DR PhylomeDB; P52789; -.
DR TreeFam; TF314238; -.
DR BioCyc; MetaCyc:HS08399-MONOMER; -.
DR BRENDA; 2.7.1.1; 2681.
DR PathwayCommons; P52789; -.
DR Reactome; R-HSA-70171; Glycolysis.
DR SABIO-RK; P52789; -.
DR SignaLink; P52789; -.
DR SIGNOR; P52789; -.
DR UniPathway; UPA00109; UER00180.
DR UniPathway; UPA00242; -.
DR BioGRID-ORCS; 3099; 92 hits in 1170 CRISPR screens.
DR ChiTaRS; HK2; human.
DR EvolutionaryTrace; P52789; -.
DR GeneWiki; HK2; -.
DR GenomeRNAi; 3099; -.
DR Pharos; P52789; Tchem.
DR PRO; PR:P52789; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; P52789; Protein.
DR Bgee; ENSG00000159399; Expressed in corpus epididymis and 200 other cell types or tissues.
DR ExpressionAtlas; P52789; baseline and differential.
DR Genevisible; P52789; HS.
DR GO; GO:0005813; C:centrosome; IDA:HPA.
DR GO; GO:0005829; C:cytosol; IDA:HPA.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0016020; C:membrane; HDA:UniProtKB.
DR GO; GO:0005741; C:mitochondrial outer membrane; IDA:MGI.
DR GO; GO:0005739; C:mitochondrion; IDA:HPA.
DR GO; GO:0016529; C:sarcoplasmic reticulum; IEA:Ensembl.
DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW.
DR GO; GO:0008865; F:fructokinase activity; ISS:UniProtKB.
DR GO; GO:0004340; F:glucokinase activity; IDA:UniProtKB.
DR GO; GO:0005536; F:glucose binding; IEA:Ensembl.
DR GO; GO:0004396; F:hexokinase activity; IDA:UniProtKB.
DR GO; GO:0008637; P:apoptotic mitochondrial changes; IDA:MGI.
DR GO; GO:0061621; P:canonical glycolysis; TAS:Reactome.
DR GO; GO:0046835; P:carbohydrate phosphorylation; IBA:GO_Central.
DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; IEA:Ensembl.
DR GO; GO:0072655; P:establishment of protein localization to mitochondrion; IMP:ParkinsonsUK-UCL.
DR GO; GO:0006002; P:fructose 6-phosphate metabolic process; ISS:UniProtKB.
DR GO; GO:0051156; P:glucose 6-phosphate metabolic process; IDA:UniProtKB.
DR GO; GO:0006006; P:glucose metabolic process; IBA:GO_Central.
DR GO; GO:0006096; P:glycolytic process; IBA:GO_Central.
DR GO; GO:0001678; P:intracellular glucose homeostasis; IBA:GO_Central.
DR GO; GO:0007595; P:lactation; IEA:Ensembl.
DR GO; GO:0072656; P:maintenance of protein location in mitochondrion; IMP:ParkinsonsUK-UCL.
DR GO; GO:0035795; P:negative regulation of mitochondrial membrane permeability; IEA:Ensembl.
DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; IEA:Ensembl.
DR GO; GO:0045766; P:positive regulation of angiogenesis; IMP:BHF-UCL.
DR GO; GO:1904925; P:positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization; IMP:ParkinsonsUK-UCL.
DR GO; GO:0046324; P:regulation of glucose import; IEA:Ensembl.
DR GO; GO:0001666; P:response to hypoxia; IEA:Ensembl.
DR GO; GO:0002931; P:response to ischemia; IEA:Ensembl.
DR CDD; cd00012; NBD_sugar-kinase_HSP70_actin; 2.
DR Gene3D; 3.30.420.40; -; 2.
DR Gene3D; 3.40.367.20; -; 2.
DR InterPro; IPR043129; ATPase_NBD.
DR InterPro; IPR001312; Hexokinase.
DR InterPro; IPR019807; Hexokinase_BS.
DR InterPro; IPR022673; Hexokinase_C.
DR InterPro; IPR022672; Hexokinase_N.
DR PANTHER; PTHR19443; HEXOKINASE; 1.
DR PANTHER; PTHR19443:SF4; HEXOKINASE-2; 1.
DR Pfam; PF00349; Hexokinase_1; 2.
DR Pfam; PF03727; Hexokinase_2; 2.
DR PRINTS; PR00475; HEXOKINASE.
DR SUPFAM; SSF53067; Actin-like ATPase domain; 4.
DR PROSITE; PS00378; HEXOKINASE_1; 2.
DR PROSITE; PS51748; HEXOKINASE_2; 2.
PE 1: Evidence at protein level;
KW 3D-structure; Acetylation; Allosteric enzyme; ATP-binding; Cytoplasm;
KW Glycolysis; Kinase; Membrane; Mitochondrion; Mitochondrion outer membrane;
KW Nucleotide-binding; Reference proteome; Repeat; Transferase.
FT CHAIN 1..917
FT /note="Hexokinase-2"
FT /id="PRO_0000197587"
FT DOMAIN 16..458
FT /note="Hexokinase 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01084"
FT DOMAIN 464..906
FT /note="Hexokinase 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01084"
FT REGION 1..16
FT /note="Mitochondrial-binding peptide (MBP)"
FT /evidence="ECO:0000303|PubMed:29298880"
FT REGION 73..207
FT /note="Hexokinase small subdomain 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01084"
FT REGION 208..447
FT /note="Hexokinase large subdomain 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01084"
FT REGION 521..655
FT /note="Hexokinase small subdomain 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01084"
FT REGION 656..895
FT /note="Hexokinase large subdomain 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU01084"
FT BINDING 30
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P19367"
FT BINDING 84..89
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P19367"
FT BINDING 84..88
FT /ligand="D-glucose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:61548"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 155..156
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 172..173
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 208..209
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 209
FT /ligand="D-glucose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:61548"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 232
FT /ligand="D-glucose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:61548"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 235
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 260
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 291..294
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 413..415
FT /ligand="D-glucose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:61548"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 425..426
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="1"
FT /evidence="ECO:0000250|UniProtKB:P19367"
FT BINDING 449
FT /ligand="D-glucose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:61548"
FT /ligand_label="1"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 532..537
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P19367"
FT BINDING 532..536
FT /ligand="D-glucose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:61548"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:26985301,
FT ECO:0000269|PubMed:29298880, ECO:0007744|PDB:2NZT,
FT ECO:0007744|PDB:5HG1"
FT BINDING 603..604
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 620..621
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 656..657
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 657
FT /ligand="D-glucose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:61548"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:26985301,
FT ECO:0000269|PubMed:29298880, ECO:0007744|PDB:2NZT,
FT ECO:0007744|PDB:5HG1"
FT BINDING 680
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P19367"
FT BINDING 680
FT /ligand="D-glucose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:61548"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:26985301,
FT ECO:0000269|PubMed:29298880, ECO:0007744|PDB:2NZT,
FT ECO:0007744|PDB:5HG1"
FT BINDING 682..683
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 708
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 739..742
FT /ligand="D-glucose"
FT /ligand_id="ChEBI:CHEBI:4167"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:29298880,
FT ECO:0007744|PDB:2NZT"
FT BINDING 747..748
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P19367"
FT BINDING 784..788
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P19367"
FT BINDING 861..863
FT /ligand="D-glucose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:61548"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:26985301,
FT ECO:0000269|PubMed:29298880, ECO:0007744|PDB:2NZT,
FT ECO:0007744|PDB:5HG1"
FT BINDING 863..867
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /ligand_label="2"
FT /evidence="ECO:0000250|UniProtKB:P19367"
FT BINDING 897
FT /ligand="D-glucose 6-phosphate"
FT /ligand_id="ChEBI:CHEBI:61548"
FT /ligand_label="2"
FT /evidence="ECO:0000269|PubMed:26985301,
FT ECO:0000269|PubMed:29298880, ECO:0007744|PDB:2NZT,
FT ECO:0007744|PDB:5HG1"
FT MOD_RES 1
FT /note="N-acetylmethionine"
FT /evidence="ECO:0007744|PubMed:25944712"
FT VARIANT 142
FT /note="Q -> H (does not affect activity; dbSNP:rs2229621)"
FT /evidence="ECO:0000269|PubMed:7883122,
FT ECO:0000269|PubMed:7883123, ECO:0000269|PubMed:8786021,
FT ECO:0000269|Ref.4"
FT /id="VAR_003691"
FT VARIANT 148
FT /note="L -> F"
FT /evidence="ECO:0000269|PubMed:7883123"
FT /id="VAR_010577"
FT VARIANT 274
FT /note="R -> C (in dbSNP:rs28363006)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_020504"
FT VARIANT 314
FT /note="A -> P (in dbSNP:rs28363015)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_020505"
FT VARIANT 314
FT /note="A -> V"
FT /evidence="ECO:0000269|PubMed:7883120"
FT /id="VAR_010578"
FT VARIANT 331
FT /note="T -> I (in dbSNP:rs28363016)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_020506"
FT VARIANT 353
FT /note="R -> C (in dbSNP:rs61748096)"
FT /evidence="ECO:0000269|PubMed:7883120"
FT /id="VAR_010579"
FT VARIANT 387
FT /note="A -> S (in dbSNP:rs28363029)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_020507"
FT VARIANT 497
FT /note="R -> Q (in dbSNP:rs145124653)"
FT /evidence="ECO:0000269|PubMed:7883123"
FT /id="VAR_010580"
FT VARIANT 775
FT /note="R -> Q (in dbSNP:rs185927605)"
FT /evidence="ECO:0000269|PubMed:7883120"
FT /id="VAR_010581"
FT VARIANT 801
FT /note="R -> Q (in dbSNP:rs28363057)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_020508"
FT VARIANT 844
FT /note="R -> K (in dbSNP:rs2229629)"
FT /evidence="ECO:0000269|PubMed:7883123, ECO:0000269|Ref.4"
FT /id="VAR_010582"
FT VARIANT 881
FT /note="D -> N (in dbSNP:rs28363065)"
FT /evidence="ECO:0000269|Ref.4"
FT /id="VAR_020509"
FT MUTAGEN 209
FT /note="D->A: Decreased hexokinase activity."
FT /evidence="ECO:0000269|PubMed:29298880"
FT MUTAGEN 468
FT /note="R->A: Induces a rapid dissociation of D-glucose."
FT /evidence="ECO:0000269|PubMed:29298880"
FT MUTAGEN 657
FT /note="D->A: Decreased hexokinase activity."
FT /evidence="ECO:0000269|PubMed:29298880"
FT CONFLICT 803
FT /note="I -> T (in Ref. 1; CAA86511)"
FT /evidence="ECO:0000305"
FT CONFLICT 870
FT /note="Missing (in Ref. 2; CAA86476)"
FT /evidence="ECO:0000305"
FT HELIX 19..25
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 27..29
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 33..51
FT /evidence="ECO:0007829|PDB:2NZT"
FT TURN 53..55
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 56..58
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 78..97
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 100..102
FT /evidence="ECO:0007829|PDB:5HEX"
FT STRAND 106..112
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 116..119
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 123..141
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 143..145
FT /evidence="ECO:0007829|PDB:5HG1"
FT STRAND 148..154
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 161..164
FT /evidence="ECO:0007829|PDB:5HEX"
FT STRAND 165..168
FT /evidence="ECO:0007829|PDB:5HFU"
FT HELIX 185..194
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 201..207
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 209..218
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 224..241
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 242..244
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 252..258
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 261..263
FT /evidence="ECO:0007829|PDB:2NZT"
FT TURN 264..267
FT /evidence="ECO:0007829|PDB:2NZT"
FT TURN 269..273
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 276..283
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 285..287
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 292..295
FT /evidence="ECO:0007829|PDB:2NZT"
FT TURN 299..301
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 302..315
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 320..322
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 326..329
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 336..344
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 345..347
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 348..358
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 365..401
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 404..413
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 415..419
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 420..422
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 423..434
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 438..444
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 449..474
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 475..477
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 481..499
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 501..504
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 527..536
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 539..545
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 548..550
FT /evidence="ECO:0007829|PDB:5HEX"
FT STRAND 553..559
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 564..568
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 571..588
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 597..602
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 606..610
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 613..616
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 633..642
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 650..655
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 657..666
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 672..689
FT /evidence="ECO:0007829|PDB:2NZT"
FT TURN 690..692
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 699..706
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 709..711
FT /evidence="ECO:0007829|PDB:2NZT"
FT TURN 712..715
FT /evidence="ECO:0007829|PDB:2NZT"
FT TURN 717..721
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 724..731
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 733..735
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 742..744
FT /evidence="ECO:0007829|PDB:2NZT"
FT TURN 747..749
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 750..763
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 768..770
FT /evidence="ECO:0007829|PDB:2NZT"
FT TURN 774..776
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 785..788
FT /evidence="ECO:0007829|PDB:2NZT"
FT TURN 789..791
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 797..806
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 813..848
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 852..861
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 863..867
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 868..870
FT /evidence="ECO:0007829|PDB:5HG1"
FT HELIX 871..882
FT /evidence="ECO:0007829|PDB:2NZT"
FT STRAND 886..892
FT /evidence="ECO:0007829|PDB:2NZT"
FT HELIX 897..911
FT /evidence="ECO:0007829|PDB:2NZT"
SQ SEQUENCE 917 AA; 102380 MW; F17CE1938CF13880 CRC64;
MIASHLLAYF FTELNHDQVQ KVDQYLYHMR LSDETLLEIS KRFRKEMEKG LGATTHPTAA
VKMLPTFVRS TPDGTEHGEF LALDLGGTNF RVLWVKVTDN GLQKVEMENQ IYAIPEDIMR
GSGTQLFDHI AECLANFMDK LQIKDKKLPL GFTFSFPCHQ TKLDESFLVS WTKGFKSSGV
EGRDVVALIR KAIQRRGDFD IDIVAVVNDT VGTMMTCGYD DHNCEIGLIV GTGSNACYME
EMRHIDMVEG DEGRMCINME WGAFGDDGSL NDIRTEFDQE IDMGSLNPGK QLFEKMISGM
YMGELVRLIL VKMAKEELLF GGKLSPELLN TGRFETKDIS DIEGEKDGIR KAREVLMRLG
LDPTQEDCVA THRICQIVST RSASLCAATL AAVLQRIKEN KGEERLRSTI GVDGSVYKKH
PHFAKRLHKT VRRLVPGCDV RFLRSEDGSG KGAAMVTAVA YRLADQHRAR QKTLEHLQLS
HDQLLEVKRR MKVEMERGLS KETHASAPVK MLPTYVCATP DGTEKGDFLA LDLGGTNFRV
LLVRVRNGKW GGVEMHNKIY AIPQEVMHGT GDELFDHIVQ CIADFLEYMG MKGVSLPLGF
TFSFPCQQNS LDESILLKWT KGFKASGCEG EDVVTLLKEA IHRREEFDLD VVAVVNDTVG
TMMTCGFEDP HCEVGLIVGT GSNACYMEEM RNVELVEGEE GRMCVNMEWG AFGDNGCLDD
FRTEFDVAVD ELSLNPGKQR FEKMISGMYL GEIVRNILID FTKRGLLFRG RISERLKTRG
IFETKFLSQI ESDCLALLQV RAILQHLGLE STCDDSIIVK EVCTVVARRA AQLCGAGMAA
VVDRIRENRG LDALKVTVGV DGTLYKLHPH FAKVMHETVK DLAPKCDVSF LQSEDGSGKG
AALITAVACR IREAGQR
//
