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"; CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- 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 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. DR Genevisible; P52789; HS. 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 //