P52789 (HXK2_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Hexokinase-2
EC=2.7.1.1

Alternative name(s):
Hexokinase type II
Short name=HK II
Muscle form hexokinase

Gene names

Name:

HK2

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	917 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Catalytic activity	ATP + D-hexose = ADP + D-hexose 6-phosphate.
Enzyme regulation	Hexokinase is an allosteric enzyme inhibited by its product Glc-6-P.
Pathway	Carbohydrate metabolism; hexose metabolism.
Subunit structure	Monomer By similarity.
Subcellular location	Mitochondrion outer membrane By similarity. Note: Its hydrophobic N-terminal sequence may be involved in membrane binding By similarity.
Tissue specificity	Predominant hexokinase isozyme expressed in insulin-responsive tissues such as skeletal muscle.
Domain	The N- and C-terminal halves of this hexokinase show extensive sequence similarity to each other. The catalytic activity is associated with the C-terminus while regulatory function is associated with the N-terminus. Each domain can bind a single glucose and Gluc-6-P molecule.
Polymorphism	Although found in NIDDM patients, genetic variations of HK2 do not contribute to the disease.
Miscellaneous	In vertebrates there are four major glucose-phosphorylating isoenzymes, designated hexokinase I, II, III and IV (glucokinase).
Sequence similarities	Belongs to the hexokinase family.

Ontologies

Keywords
Biological process	Glycolysis
Cellular component	Membrane Mitochondrion Mitochondrion outer membrane
Coding sequence diversity	Polymorphism
Domain	Repeat
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Allosteric enzyme Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	apoptotic mitochondrial changes Inferred from direct assay PubMed 18350175. Source: MGI cellular glucose homeostasis Inferred from Biological aspect of Ancestor. Source: RefGenome glucose transport Traceable author statement. Source: Reactome glycolysis Inferred from Biological aspect of Ancestor. Source: RefGenome lactation Inferred from electronic annotation. Source: Compara regulation of glucose import Inferred from electronic annotation. Source: Compara small molecule metabolic process Traceable author statement. Source: Reactome transmembrane transport Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome mitochondrial outer membrane Inferred from direct assay PubMed 18350175. Source: MGI
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW fructokinase activity Inferred from Biological aspect of Ancestor. Source: RefGenome glucokinase activity Inferred from Biological aspect of Ancestor. Source: RefGenome glucose binding Inferred from electronic annotation. Source: Compara mannokinase activity Inferred from Biological aspect of Ancestor. Source: RefGenome
Complete GO annotation...

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 917

917

Hexokinase-2

PRO_0000197587

Regions

Nucleotide binding

84 – 89

6

ATP 1 Potential

Nucleotide binding

425 – 426

2

ATP 1 By similarity

Nucleotide binding

532 – 537

6

ATP 2 By similarity

Nucleotide binding

747 – 748

2

ATP 2 By similarity

Nucleotide binding

784 – 788

5

ATP 2 By similarity

Nucleotide binding

863 – 867

5

ATP 2 By similarity

Region

1 – 12

12

Hydrophobic

Region

13 – 475

463

Regulatory

Region

84 – 88

5

Glucose-6-phosphate 1 binding

Region

155 – 156

2

Substrate 1 binding

Region

172 – 173

2

Substrate 1 binding

Region

208 – 209

2

Substrate 1 binding

Region

291 – 294

4

Substrate 1 binding

Region

413 – 415

3

Glucose-6-phosphate 1 binding

Region

476 – 917

442

Catalytic

Region

532 – 536

5

Glucose-6-phosphate 2 binding

Region

603 – 604

2

Substrate 2 binding

Region

620 – 621

2

Substrate 2 binding

Region

656 – 657

2

Substrate 2 binding

Region

682 – 683

2

Substrate 2 binding

Region

739 – 742

4

Substrate 2 binding

Region

861 – 863

3

Glucose-6-phosphate 2 binding

Sites

Binding site

30

1

ATP 1 By similarity

Binding site

209

1

Glucose-6-phosphate 1

Binding site

232

1

Glucose-6-phosphate 1

Binding site

235

1

Substrate 1

Binding site

260

1

Substrate 1

Binding site

449

1

Glucose-6-phosphate 1

Binding site

558

1

ATP Potential

Binding site

657

1

Glucose-6-phosphate 2

Binding site

680

1

ATP 2 By similarity

Binding site

680

1

Glucose-6-phosphate 2

Binding site

708

1

Substrate 2

Binding site

897

1

Glucose-6-phosphate 2

Amino acid modifications

Modified residue

461

1

Phosphotyrosine By similarity

Natural variations

Natural variant

142

1

Q → H Does not affect activity. Ref.2 Ref.4 Ref.11 Ref.12
Corresponds to variant rs2229621 [ dbSNP | Ensembl ].

VAR_003691

Natural variant

148

1

L → F. Ref.12

VAR_010577

Natural variant

274

1

R → C. Ref.4
Corresponds to variant rs28363006 [ dbSNP | Ensembl ].

VAR_020504

Natural variant

314

1

A → P. Ref.4
Corresponds to variant rs28363015 [ dbSNP | Ensembl ].

VAR_020505

Natural variant

314

1

A → V. Ref.10

VAR_010578

Natural variant

331

1

T → I. Ref.4
Corresponds to variant rs28363016 [ dbSNP | Ensembl ].

VAR_020506

Natural variant

353

1

R → C. Ref.10

VAR_010579

Natural variant

387

1

A → S. Ref.4
Corresponds to variant rs28363029 [ dbSNP | Ensembl ].

VAR_020507

Natural variant

497

1

R → Q. Ref.12
Corresponds to variant rs2229625 [ dbSNP | Ensembl ].

VAR_010580

Natural variant

775

1

R → Q. Ref.10

VAR_010581

Natural variant

801

1

R → Q. Ref.4
Corresponds to variant rs28363057 [ dbSNP | Ensembl ].

VAR_020508

Natural variant

844

1

R → K. Ref.4 Ref.12
Corresponds to variant rs2229629 [ dbSNP | Ensembl ].

VAR_010582

Natural variant

881

1

D → N. Ref.4
Corresponds to variant rs28363065 [ dbSNP | Ensembl ].

VAR_020509

Experimental info

Sequence conflict

803

1

I → T in CAA86511. Ref.1

Sequence conflict

870

1

Missing in CAA86476. Ref.2

Secondary structure

1

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917

Helix Strand Turn

Details...

Helix

19 – 25

7

Helix

27 – 29

3

Helix

33 – 51

19

Turn

53 – 55

3

Helix

56 – 58

3

Beta strand

78 – 97

20

Beta strand

106 – 112

7

Helix

116 – 119

4

Helix

123 – 141

19

Beta strand

148 – 154

7

Helix

185 – 194

10

Beta strand

201 – 207

7

Helix

209 – 218

10

Beta strand

224 – 241

18

Helix

242 – 244

3

Beta strand

252 – 258

7

Helix

261 – 263

3

Turn

264 – 267

4

Turn

269 – 273

5

Helix

276 – 283

8

Beta strand

285 – 287

3

Helix

292 – 295

4

Turn

299 – 301

3

Helix

302 – 315

14

Helix

320 – 322

3

Helix

326 – 329

4

Helix

336 – 344

9

Beta strand

345 – 347

3

Helix

348 – 358

11

Helix

365 – 401

37

Beta strand

404 – 413

10

Helix

415 – 419

5

Beta strand

420 – 422

3

Helix

423 – 434

12

Beta strand

438 – 444

7

Helix

449 – 474

26

Helix

475 – 477

3

Helix

481 – 499

19

Helix

501 – 504

4

Beta strand

527 – 536

10

Beta strand

539 – 545

7

Beta strand

553 – 559

7

Helix

564 – 568

5

Helix

571 – 588

18

Beta strand

597 – 602

6

Beta strand

606 – 610

5

Beta strand

613 – 616

4

Helix

633 – 642

10

Beta strand

650 – 655

6

Helix

657 – 666

10

Beta strand

672 – 689

18

Turn

690 – 692

3

Beta strand

699 – 706

8

Helix

709 – 711

3

Turn

712 – 715

4

Turn

717 – 721

5

Helix

724 – 731

8

Beta strand

733 – 735

3

Helix

742 – 744

3

Turn

747 – 749

3

Helix

750 – 763

14

Helix

768 – 770

3

Turn

774 – 776

3

Helix

785 – 788

4

Turn

789 – 791

3

Helix

797 – 806

10

Helix

813 – 848

36

Beta strand

852 – 861

10

Helix

863 – 867

5

Helix

871 – 882

12

Beta strand

886 – 892

7

Helix

897 – 911

15

Sequences

	Sequence		Length	Mass (Da)
	P52789 [UniParc]. Last modified December 7, 2004. Version 2. Checksum: F17CE1938CF13880	FASTA	917	102,380
	10 20 30 40 50 60 MIASHLLAYF FTELNHDQVQ KVDQYLYHMR LSDETLLEIS KRFRKEMEKG LGATTHPTAA 70 80 90 100 110 120 VKMLPTFVRS TPDGTEHGEF LALDLGGTNF RVLWVKVTDN GLQKVEMENQ IYAIPEDIMR 130 140 150 160 170 180 GSGTQLFDHI AECLANFMDK LQIKDKKLPL GFTFSFPCHQ TKLDESFLVS WTKGFKSSGV 190 200 210 220 230 240 EGRDVVALIR KAIQRRGDFD IDIVAVVNDT VGTMMTCGYD DHNCEIGLIV GTGSNACYME 250 260 270 280 290 300 EMRHIDMVEG DEGRMCINME WGAFGDDGSL NDIRTEFDQE IDMGSLNPGK QLFEKMISGM 310 320 330 340 350 360 YMGELVRLIL VKMAKEELLF GGKLSPELLN TGRFETKDIS DIEGEKDGIR KAREVLMRLG 370 380 390 400 410 420 LDPTQEDCVA THRICQIVST RSASLCAATL AAVLQRIKEN KGEERLRSTI GVDGSVYKKH 430 440 450 460 470 480 PHFAKRLHKT VRRLVPGCDV RFLRSEDGSG KGAAMVTAVA YRLADQHRAR QKTLEHLQLS 490 500 510 520 530 540 HDQLLEVKRR MKVEMERGLS KETHASAPVK MLPTYVCATP DGTEKGDFLA LDLGGTNFRV 550 560 570 580 590 600 LLVRVRNGKW GGVEMHNKIY AIPQEVMHGT GDELFDHIVQ CIADFLEYMG MKGVSLPLGF 610 620 630 640 650 660 TFSFPCQQNS LDESILLKWT KGFKASGCEG EDVVTLLKEA IHRREEFDLD VVAVVNDTVG 670 680 690 700 710 720 TMMTCGFEDP HCEVGLIVGT GSNACYMEEM RNVELVEGEE GRMCVNMEWG AFGDNGCLDD 730 740 750 760 770 780 FRTEFDVAVD ELSLNPGKQR FEKMISGMYL GEIVRNILID FTKRGLLFRG RISERLKTRG 790 800 810 820 830 840 IFETKFLSQI ESDCLALLQV RAILQHLGLE STCDDSIIVK EVCTVVARRA AQLCGAGMAA 850 860 870 880 890 900 VVDRIRENRG LDALKVTVGV DGTLYKLHPH FAKVMHETVK DLAPKCDVSF LQSEDGSGKG 910 AALITAVACR IREAGQR

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Human hexokinase II: sequence and homology to other hexokinases." Deeb S.S., Malkki M., Laakso M. Biochem. Biophys. Res. Commun. 197:68-74(1993) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Skeletal muscle.
[2]	"Human hexokinase II gene: exon-intron organization, mutation screening in NIDDM, and its relationship to muscle hexokinase activity." Lehto M., Huang X., Davis E.M., Le Beau M.M., Laurila E., Eriksson K.F., Bell G.I., Groop L.C. Diabetologia 38:1466-1474(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANT HIS-142. Tissue: Blood, Muscle and Placenta.
[3]	Malkki M., Heikkinen S., Deeb S.S., Laakso M. Submitted (MAY-1999) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA]. Tissue: Skeletal muscle.
[4]	NIEHS SNPs program Submitted (MAY-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS HIS-142; CYS-274; PRO-314; ILE-331; SER-387; GLN-801; LYS-844 AND ASN-881.
[5]	Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C. Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Placenta and Testis.
[7]	"Steady state transcript levels of the type II hexokinase and type 1 glucose transporter in human tumor cell lines." Shinohara Y., Yamamoto K., Kogure K., Ichihara J., Terada H. Cancer Lett. 82:27-32(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 614-739.
[8]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[9]	"Crystal structure of human hexokinase II." Structural genomics consortium (SGC) Submitted (DEC-2006) to the PDB data bank Cited for: X-RAY CRYSTALLOGRAPHY (2.45 ANGSTROMS) OF 17-916 IN COMPLEX WITH GLUCOSE AND GLUCOSE-6-PHOSPHATE.
[10]	"Amino acid substitutions in hexokinase II among patients with NIDDM." Laakso M., Malkki M., Deeb S.S. Diabetes 44:330-334(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS VAL-314; CYS-353 AND GLN-775.
[11]	"Analysis of the hexokinase II gene in subjects with insulin resistance and NIDDM and detection of a Gln142-->His substitution." Vidal-Puig A., Printz R.L., Stratton I.M., Granner D.K., Moller D.E. Diabetes 44:340-346(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT HIS-142.
[12]	"Identification of four amino acid substitutions in hexokinase II and studies of relationships to NIDDM, glucose effectiveness, and insulin sensitivity." Echwald S.M., Bjoerbaek C., Hansen T., Clausen J.O., Vestergaard H., Zierath J.R., Printz R.L., Granner D.K., Pedersen O. Diabetes 44:347-353(1995) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANTS HIS-142; PHE-148; GLN-497 AND LYS-844.
+	Additional computationally mapped references.

Web resources

NIEHS-SNPs

Wikipedia

Hexokinase entry

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

Z46376 mRNA. Translation: CAA86511.1.
Z46354 , Z46355, Z46604, Z46356, Z46357, Z46358, Z46359, Z46360, Z46361, Z46362, Z46363, Z46364, Z46365, Z46366, Z46367, Z46368, Z46369 Genomic DNA. Translation: CAA86476.2.
AF148513 mRNA. Translation: AAD30174.1.
AY623118 Genomic DNA. Translation: AAT38114.1.
CH471053 Genomic DNA. Translation: EAW99601.1.
CH471053 Genomic DNA. Translation: EAW99602.1.
BC021116 mRNA. Translation: AAH21116.1.
BC064369 mRNA. Translation: AAH64369.1.
D25412 Genomic DNA. Translation: BAA04999.1.

IPI

IPI00102864.

PIR

JC2025. S48809.

RefSeq

NP_000180.2. NM_000189.4.

UniGene

Hs.406266.
Hs.591588.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2NZT	X-ray	2.45	A/B	17-916	[»]

ProteinModelPortal

P52789.

ModBase

Search...

Protein-protein interaction databases

IntAct

P52789. 4 interactions.

MINT

MINT-1461614.

STRING

9606.ENSP00000290573.

PTM databases

PhosphoSite

P52789.

Polymorphism databases

DMDM

56405344.

Proteomic databases

PaxDb

P52789.

PeptideAtlas

P52789.

PRIDE

P52789.

Protocols and materials databases

DNASU

3099.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000290573; ENSP00000290573; ENSG00000159399.
ENST00000535740; ENSP00000438556; ENSG00000159399.

GeneID

3099.

KEGG

hsa:3099.

UCSC

uc002snd.3. human.

Organism-specific databases

CTD

3099.

GeneCards

GC02P075059.

H-InvDB

HIX0030207.

HGNC

HGNC:4923. HK2.

HPA

HPA028587.

MIM

601125. gene.

neXtProt

NX_P52789.

PharmGKB

PA29301.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5026.

HOGENOM

HOG000162671.

HOVERGEN

HBG005020.

InParanoid

P52789.

KO

K00844.

OMA

SKETHAI.

OrthoDB

EOG47WNMX.

PhylomeDB

P52789.

Enzyme and pathway databases

Pathway_Interaction_DB

hif1_tfpathway. HIF-1-alpha transcription factor network.

Reactome

REACT_111217. Metabolism.
REACT_15518. Transmembrane transport of small molecules.

SABIO-RK

P52789.

UniPathway

UPA00242.

Gene expression databases

ArrayExpress

P52789.

Bgee

P52789.

CleanEx

HS_HK2.

Genevestigator

P52789.

GermOnline

ENSG00000159399. Homo sapiens.

Family and domain databases

InterPro

IPR001312. Hexokinase.
IPR022673. Hexokinase_C.
IPR019807. Hexokinase_CS.
IPR022672. Hexokinase_N.
[Graphical view]

PANTHER

PTHR19443. PTHR19443. 1 hit.

Pfam

PF00349. Hexokinase_1. 2 hits.
PF03727. Hexokinase_2. 2 hits.
[Graphical view]

PRINTS

PR00475. HEXOKINASE.

PROSITE

PS00378. HEXOKINASES. 2 hits.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P52789.

ChEMBL

CHEMBL2640.

EvolutionaryTrace

P52789.

GenomeRNAi

3099.

NextBio

12305.

SOURCE

Search...

Entry information

Entry name

HXK2_HUMAN

Accession

Primary (citable) accession number: P52789
Secondary accession number(s): D6W5J2, Q8WU87, Q9UN82

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	December 7, 2004
Last modified:	May 1, 2013
This is version 132 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.