ID   HXK2_EQUGR              Reviewed;         917 AA.
AC   A2PYL8;
DT   01-MAY-2007, integrated into UniProtKB/Swiss-Prot.
DT   06-MAR-2007, sequence version 1.
DT   04-NOV-2026, entry version 62.
DE   RecName: Full=Hexokinase-2 {ECO:0000305};
DE            EC=2.7.1.1 {ECO:0000250|UniProtKB:P52789};
DE   AltName: Full=Hexokinase type II {ECO:0000303|PubMed:17454005};
DE            Short=HK II {ECO:0000303|PubMed:17454005};
GN   Name=HK2 {ECO:0000250|UniProtKB:P52789};
OS   Equus grevyi (Grevy's zebra).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Laurasiatheria; Perissodactyla; Equidae; Equus.
OX   NCBI_TaxID=9792;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Hair root;
RX   PubMed=17454005; DOI=10.1080/10425170601136648;
RA   Sato T., Itou T., Sato G., Kobayashi Y., Endo H., Sakai T.;
RT   "Sequencing of cDNA and proximal promoter of equine hexokinase II gene.";
RL   DNA Seq. 18:203-208(2007).
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). Mediates the initial step of
CC       glycolysis by catalyzing phosphorylation of D-glucose to D-glucose 6-
CC       phosphate. Plays a key role in maintaining the integrity of the outer
CC       mitochondrial membrane by preventing the release of apoptogenic
CC       molecules from the intermembrane space and subsequent apoptosis.
CC       {ECO:0000250|UniProtKB:P52789}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a D-hexose + ATP = a D-hexose 6-phosphate + ADP + H(+);
CC         Xref=Rhea:RHEA:22740, ChEBI:CHEBI:4194, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:30616, ChEBI:CHEBI:229467, ChEBI:CHEBI:456216;
CC         EC=2.7.1.1; Evidence={ECO:0000250|UniProtKB:P52789};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:22741;
CC         Evidence={ECO:0000250|UniProtKB:P52789};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=D-fructose + ATP = D-fructose 6-phosphate + ADP + 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=D-glucose + ATP = D-glucose 6-phosphate + ADP + 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:0000250|UniProtKB:P52789};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17826;
CC         Evidence={ECO:0000250|UniProtKB:P52789};
CC   -!- ACTIVITY REGULATION: Hexokinase activity is specifically inhibited by
CC       2,6-disubstituted glucosamines. {ECO:0000250|UniProtKB:P52789}.
CC   -!- PATHWAY: Carbohydrate metabolism; hexose metabolism.
CC       {ECO:0000250|UniProtKB:P52789}.
CC   -!- PATHWAY: Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-
CC       phosphate and glycerone phosphate from D-glucose: step 1/4.
CC       {ECO:0000250|UniProtKB:P52789}.
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}.
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DR   EMBL; AB248870; BAF45852.1; -; mRNA.
DR   SMR; A2PYL8; -.
DR   UniPathway; UPA00109; UER00180.
DR   UniPathway; UPA00242; -.
DR   CDD; cd24128; ASKHA_NBD_HK2_meta_rpt2; 1.
DR   FunFam; 3.40.367.20:FF:000001; Hexokinase 1; 1.
DR   FunFam; 3.40.367.20:FF:000020; Hexokinase-1; 1.
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   GO; GO:0005829; C:cytosol; IEA:UniProtKB-SubCell.
DR   GO; GO:0005741; C:mitochondrial outer membrane; ISS:UniProtKB.
DR   GO; GO:0005524; F:ATP binding; IEA:InterPro.
DR   GO; GO:0005536; F:D-glucose binding; IEA:InterPro.
DR   GO; GO:0008865; F:fructokinase activity; ISS:UniProtKB.
DR   GO; GO:0004340; F:glucokinase activity; ISS:UniProtKB.
DR   GO; GO:0004396; F:hexokinase activity; ISS:UniProtKB.
DR   GO; GO:0046835; P:carbohydrate phosphorylation; IEA:TreeGrafter.
DR   GO; GO:0006002; P:fructose 6-phosphate metabolic process; ISS:UniProtKB.
DR   GO; GO:0051156; P:glucose 6-phosphate metabolic process; ISS:UniProtKB.
DR   GO; GO:0006006; P:glucose metabolic process; IEA:TreeGrafter.
DR   GO; GO:0006096; P:glycolytic process; IEA:UniProtKB-UniPathway.
DR   GO; GO:0001678; P:intracellular glucose homeostasis; IEA:InterPro.
DR   AlphaFoldDB; A2PYL8; -.
PE   2: Evidence at transcript level;
KW   Acetylation; Allosteric enzyme; ATP-binding; Cytoplasm; Glycolysis; Kinase;
KW   Membrane; Mitochondrion; Mitochondrion outer membrane; Nucleotide-binding;
KW   Repeat; Transferase.
FT   CHAIN           1..917
FT                   /note="Hexokinase-2"
FT                   /id="PRO_0000286049"
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         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;  102654 MW;  65C12AFAB051F95F CRC64;
     MIASHLLAYF FTELNHDQVQ KVDQYLYHMR LSDETLLEIS KRFRKEMEKG LAATTHPTAS
     VKMLPTFVRS TPDGTEHGEF LALDLGGTNF RVLRVRVTDN GLQKVEMENQ IYAIPEDIMQ
     GSGTQLFDHI AGCLANFMDK LQIKDKKLPL GFTFSFPCIQ TKLDESFLVS WTKGFKSRGV
     EGRDVVTLIR KAIQRRGDFD IDIVAMVNDT VATMMTCGYD DQNCEIGLIV GMGSNACYME
     EMRYIDTVEG DEGRMCINME WGAFGDDGTL DDIRTEFDQE IDMGSLNPGQ QLFEKMISGM
     YMGELVRLIL VKMAKEELLF RGKLSPELLT TGRFETKDVS EIEGEKDGIQ KAREVLVRLG
     MDPTQEDCVA THRICQIVST RSASLCAATL AAVLQRIKEN KGEERLRSTI GVDGSVYKKH
     PHFAKRLQKT VRRLVPNCDI RFLCSEDGSG KGAAMVTAVA YRLAYQHRAR LKTLEPLKLS
     REQLLEVKRR MKVEMERGLS KETHASAPVK MLPTYVCATP DGTEKGDFLA LDLGGTNFRV
     LLVRVRNGKR RGVEMHNKIY SIPQDIMHGT GDELFDHIVQ CIADFLEYMG MKGVSLPLGF
     TFSFPCQQNR LDESILLKWT KGFKASGCEG EDVVTLLKEA IHRREEFDLD VVAVVNDTVG
     TMMTCGYEDP HCEVGLIVGT GSNACYMEEM RNVELVEGEE GRMCVNTEWG AFGDNGCLDD
     FCTEFDVAVD ELSLNPGKQR FEKMMSGMYL GEIVRNILID FTKRGLLFRG RISERLKTRG
     IFETKFLSQI ESDCLALQQV RAILQHLGLE STCDDSIIVK EVCTVVAQRA AQLCGAGMAA
     VVDKIRENRG LDTLKVTVGV DGTLYKLHPH FAKVMRETVK DLAPKCDVSF LESEDGSGKG
     AALITAVACR IREAGQR
//