ID HXK2_RAT Reviewed; 917 AA. AC P27881; Q9QWR1; DT 01-AUG-1992, integrated into UniProtKB/Swiss-Prot. DT 01-AUG-1992, sequence version 1. DT 24-JAN-2024, entry version 172. DE RecName: Full=Hexokinase-2 {ECO:0000305}; DE EC=2.7.1.1 {ECO:0000269|PubMed:5871820}; DE AltName: Full=Hexokinase type II {ECO:0000303|PubMed:1897984}; DE Short=HK II {ECO:0000303|PubMed:1897984}; DE AltName: Full=Hexokinase-B {ECO:0000303|PubMed:5871820}; GN Name=Hk2 {ECO:0000312|RGD:2797}; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 11-18. RC TISSUE=Skeletal muscle; RX PubMed=1897984; DOI=10.1016/0003-9861(91)90094-y; RA Thelen A.P., Wilson J.E.; RT "Complete amino acid sequence of the type II isozyme of rat hexokinase, RT deduced from the cloned cDNA: comparison with a hexokinase from novikoff RT ascites tumor."; RL Arch. Biochem. Biophys. 286:645-651(1991). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-21. RC STRAIN=Wistar; RX PubMed=7873617; DOI=10.1016/0167-4781(94)00226-s; RA Shinohara Y., Ichihara J., Kogure K., Terada H.; RT "Nucleotide sequence of the 5'-flanking region of the rat type II RT hexokinase gene."; RL Biochim. Biophys. Acta 1260:365-368(1995). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-21. RC STRAIN=Sprague-Dawley; TISSUE=Hepatoma; RX PubMed=7622509; DOI=10.1074/jbc.270.28.16918; RA Mathupala S.P., Rempel A., Pedersen P.L.; RT "Glucose catabolism in cancer cells. Isolation, sequence, and activity of RT the promoter for type II hexokinase."; RL J. Biol. Chem. 270:16918-16925(1995). RN [4] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-21. RC STRAIN=Sprague-Dawley; RA Rempel A.; RT "Normal type II hexokinase promoter, first exon, and first intron from RT hepatocytes."; RL Submitted (MAR-2002) to the EMBL/GenBank/DDBJ databases. RN [5] RP FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES. RX PubMed=5871820; DOI=10.1016/0006-291x(64)90038-5; RA Gonzalez C., Ureta T., Sanchez R., Niemeyer H.; RT "Multiple molecular forms of ATP:hexose 6-phosphotransferase from rat RT liver."; RL Biochem. Biophys. Res. Commun. 16:347-352(1964). RN [6] RP REVIEW. RX PubMed=7044667; DOI=10.1016/0305-0491(82)90461-8; RA Ureta T.; RT "The comparative isozymology of vertebrate hexokinases."; RL Comp. Biochem. Physiol. 71:549-555(1982). 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:5871820). Mediates the CC initial step of glycolysis by catalyzing phosphorylation of D-glucose CC to D-glucose 6-phosphate (PubMed:5871820). Plays a key role in CC maintaining the integrity of the outer mitochondrial membrane by CC preventing the release of apoptogenic molecules from the intermembrane CC space and subsequent apoptosis (By similarity). CC {ECO:0000250|UniProtKB:P52789, ECO:0000269|PubMed:5871820}. 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:5871820}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22741; CC Evidence={ECO:0000269|PubMed:5871820}; 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:0000269|PubMed:5871820}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:16126; CC Evidence={ECO:0000269|PubMed:5871820}; 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:5871820}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17826; CC Evidence={ECO:0000269|PubMed:5871820}; CC -!- ACTIVITY REGULATION: Hexokinase activity is specifically inhibited by CC 2,6-disubstituted glucosamines. {ECO:0000250|UniProtKB:P52789}. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.13 mM for D-glucose {ECO:0000269|PubMed:5871820}; CC KM=3 mM for D-fructose {ECO:0000269|PubMed:5871820}; CC KM=0.7 mM for ATP {ECO:0000269|PubMed:5871820}; CC -!- PATHWAY: Carbohydrate metabolism; hexose metabolism. CC {ECO:0000305|PubMed:5871820}. CC -!- PATHWAY: Carbohydrate degradation; glycolysis; D-glyceraldehyde 3- CC phosphate and glycerone phosphate from D-glucose: step 1/4. CC {ECO:0000305|PubMed:5871820}. CC -!- SUBUNIT: Monomer (By similarity). Interacts with TIGAR; the interaction CC increases hexokinase activity in a hypoxia- and HIF1A-dependent manner CC (By similarity). {ECO:0000250|UniProtKB:P19367, CC ECO:0000250|UniProtKB:P52789}. CC -!- SUBCELLULAR LOCATION: Mitochondrion outer membrane CC {ECO:0000250|UniProtKB:P52789}; Peripheral membrane protein CC {ECO:0000250|UniProtKB:P52789}. Cytoplasm, cytosol CC {ECO:0000250|UniProtKB:P52789}. Note=The mitochondrial-binding peptide CC (MBP) region promotes association with the mitochondrial outer CC membrane. The interaction with the mitochondrial outer membrane via the CC mitochondrial-binding peptide (MBP) region promotes higher stability of CC the protein. Release from the mitochondrial outer membrane into the CC cytosol induces permeability transition pore (PTP) opening and CC apoptosis. {ECO:0000250|UniProtKB:P52789}. CC -!- DOMAIN: The N- and C-terminal halves of the protein contain a CC hexokinase domain. In contrast to hexokinase-1 and -3 (HK1 and HK3, CC respectively), both hexokinase domains display catalytic activity. The CC region connecting the two hexokinase domains is required for the CC catalytic activity of the N-terminal hexokinase domain. The N-terminal CC half regulates stability of the whole enzyme. CC {ECO:0000250|UniProtKB:P52789}. CC -!- SIMILARITY: Belongs to the hexokinase family. {ECO:0000255|PROSITE- CC ProRule:PRU01084, ECO:0000305}. 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; M68971; AAA41333.1; -; mRNA. DR EMBL; M68972; AAA41334.1; -; mRNA. DR EMBL; D26393; BAA05409.1; -; Genomic_DNA. DR EMBL; U19605; AAB09025.1; -; Genomic_DNA. DR EMBL; AY082375; AAL92551.1; -; Genomic_DNA. DR PIR; S15885; S15885. DR RefSeq; NP_036867.1; NM_012735.2. DR AlphaFoldDB; P27881; -. DR SMR; P27881; -. DR BioGRID; 247136; 4. DR DIP; DIP-37314N; -. DR IntAct; P27881; 3. DR STRING; 10116.ENSRNOP00000008813; -. DR BindingDB; P27881; -. DR ChEMBL; CHEMBL5063; -. DR iPTMnet; P27881; -. DR PhosphoSitePlus; P27881; -. DR jPOST; P27881; -. DR PaxDb; 10116-ENSRNOP00000008813; -. DR Ensembl; ENSRNOT00000008813.4; ENSRNOP00000008813.1; ENSRNOG00000006116.4. DR Ensembl; ENSRNOT00055020846; ENSRNOP00055016824; ENSRNOG00055012250. DR Ensembl; ENSRNOT00060003434; ENSRNOP00060002347; ENSRNOG00060002196. DR Ensembl; ENSRNOT00065027778; ENSRNOP00065021899; ENSRNOG00065016667. DR GeneID; 25059; -. DR KEGG; rno:25059; -. DR UCSC; RGD:2797; rat. DR AGR; RGD:2797; -. DR CTD; 3099; -. DR RGD; 2797; Hk2. DR eggNOG; KOG1369; Eukaryota. DR GeneTree; ENSGT00950000182787; -. DR HOGENOM; CLU_014393_1_0_1; -. DR InParanoid; P27881; -. DR OMA; SYLVSWT; -. DR OrthoDB; 5481886at2759; -. DR PhylomeDB; P27881; -. DR TreeFam; TF314238; -. DR BRENDA; 2.7.1.1; 5301. DR Reactome; R-RNO-70171; Glycolysis. DR SABIO-RK; P27881; -. DR UniPathway; UPA00109; UER00180. DR UniPathway; UPA00242; -. DR PRO; PR:P27881; -. DR Proteomes; UP000002494; Chromosome 4. DR Bgee; ENSRNOG00000006116; Expressed in skeletal muscle tissue and 19 other cell types or tissues. DR GO; GO:0005813; C:centrosome; IEA:Ensembl. DR GO; GO:0005829; C:cytosol; IBA:GO_Central. DR GO; GO:0005741; C:mitochondrial outer membrane; ISO:RGD. DR GO; GO:0005739; C:mitochondrion; IBA:GO_Central. DR GO; GO:0016529; C:sarcoplasmic reticulum; IDA:RGD. DR GO; GO:0005524; F:ATP binding; IDA:RGD. DR GO; GO:0008865; F:fructokinase activity; IDA:UniProtKB. DR GO; GO:0004340; F:glucokinase activity; IDA:UniProtKB. DR GO; GO:0005536; F:glucose binding; IDA:RGD. DR GO; GO:0004396; F:hexokinase activity; IDA:RGD. DR GO; GO:0008637; P:apoptotic mitochondrial changes; ISO:RGD. DR GO; GO:0046835; P:carbohydrate phosphorylation; IDA:RGD. DR GO; GO:1990830; P:cellular response to leukemia inhibitory factor; ISO:RGD. DR GO; GO:0072655; P:establishment of protein localization to mitochondrion; ISO:RGD. DR GO; GO:0006002; P:fructose 6-phosphate metabolic process; IDA:UniProtKB. DR GO; GO:0051156; P:glucose 6-phosphate metabolic process; IDA:UniProtKB. DR GO; GO:0006007; P:glucose catabolic process; TAS:RGD. DR GO; GO:0006006; P:glucose metabolic process; ISO:RGD. 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; IEP:RGD. DR GO; GO:0072656; P:maintenance of protein location in mitochondrion; ISO:RGD. DR GO; GO:0035795; P:negative regulation of mitochondrial membrane permeability; ISO:RGD. DR GO; GO:2000378; P:negative regulation of reactive oxygen species metabolic process; ISO:RGD. DR GO; GO:0045766; P:positive regulation of angiogenesis; ISO:RGD. DR GO; GO:1904925; P:positive regulation of autophagy of mitochondrion in response to mitochondrial depolarization; ISO:RGD. DR GO; GO:0046324; P:regulation of glucose import; ISO:RGD. DR GO; GO:0001666; P:response to hypoxia; IEP:RGD. DR GO; GO:0002931; P:response to ischemia; IDA:RGD. 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; P27881; RN. PE 1: Evidence at protein level; KW Acetylation; Allosteric enzyme; ATP-binding; Cytoplasm; KW Direct protein sequencing; Glycolysis; Kinase; Membrane; Mitochondrion; KW Mitochondrion outer membrane; Nucleotide-binding; Reference proteome; KW Repeat; Transferase. FT CHAIN 1..917 FT /note="Hexokinase-2" FT /id="PRO_0000197589" 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:0000250|UniProtKB:P52789" 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:0000250|UniProtKB:P52789" FT BINDING 155..156 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 172..173 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 208..209 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 209 FT /ligand="D-glucose 6-phosphate" FT /ligand_id="ChEBI:CHEBI:61548" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 232 FT /ligand="D-glucose 6-phosphate" FT /ligand_id="ChEBI:CHEBI:61548" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 235 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 260 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 291..294 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 413..415 FT /ligand="D-glucose 6-phosphate" FT /ligand_id="ChEBI:CHEBI:61548" FT /ligand_label="1" FT /evidence="ECO:0000250|UniProtKB:P52789" 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:0000250|UniProtKB:P52789" 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:0000250|UniProtKB:P52789" FT BINDING 603..604 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 620..621 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 656..657 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 657 FT /ligand="D-glucose 6-phosphate" FT /ligand_id="ChEBI:CHEBI:61548" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P52789" 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:0000250|UniProtKB:P52789" FT BINDING 682..683 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 708 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P52789" FT BINDING 739..742 FT /ligand="D-glucose" FT /ligand_id="ChEBI:CHEBI:4167" FT /ligand_label="2" FT /evidence="ECO:0000250|UniProtKB:P52789" 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:0000250|UniProtKB:P52789" 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:0000250|UniProtKB:P52789" FT MOD_RES 1 FT /note="N-acetylmethionine" FT /evidence="ECO:0000250|UniProtKB:P52789" SQ SEQUENCE 917 AA; 102544 MW; 764EC189C0F90987 CRC64; MIASHMIACL FTELNQNQVQ KVDQFLYHMR LSDETLLEIS RRFRKEMEKG LGATTHPTAA VKMLPTFVRS TPDGTEHGEF LALDLGGTNF RVLRVRVTDN GLQRVEMENQ IYAIPEDIMR GSGTQLFDHI AECLANFMDK LQIKEKKLPL GFTFSFPCHQ TKLDESFLVS WTKGFKSSGV EGRDVVDLIR KAIQRRGDFD IDIVAVVNDT VGTMMTCGYD DQNCEIGLIV GTGSNACYME EMRHIDMVEG DEGRMCINME WGAFGDDGTL NDIRTEFDRE IDMGSLNPGK QLFEKMISGM YMGELVRLIL VKMAKAELLF QGKLSPELLT TGSFETKDVS DIEEDKDGIE KAYQILMRLG LNPLQEDCVA THRICQIVST RSASLCAATL AAVLWRIKEN KGEERLRSTI GVDGSVYKKH PHFAKRLHKA VRRLVPDCDV RFLRSEDGSG KGAAMVTAVA YRLADQHRAR QKTLESLKLS HEQLLEVKRR MKVEMEQGLS KETHAVAPVK MLPTYVCATP DGTEKGDFLA LDLGGTNFRV LLVRVRNGKR RGVEMHNKIY SIPQEVMHGT GEELFDHIVQ CIADFLEYMG MKGVSLPLGF TFSFPCQQNS LDQSILLKWT KGFKASGCEG EDVVTLLKEA IHRREEFDLD VVAVVNDTVG TMMTCGYEDP HCEVGLIVGT GSNACYMEEM RNVELVDGEE GRMCVNMEWG AFGDNGCLDD LRTVFDVAVD ELSLNPGKQR FEKMISGMYL GEIVRNILID FTKRGLLFRG RISERLKTRG IFETKFLSQI ESDCLALLQV RAILRHLGLE STCDDSIIVK EVCTVVARRA AQLCGAGMAA VVDKIRENRG LDNLKVTVGV DGTLYKLHPH FAKVMHETVR DLAPKCDVSF LESEDGSGKG AALITAVACR IREAGQR //