P50053 (KHK_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Ketohexokinase
EC=2.7.1.3

Alternative name(s):
Hepatic fructokinase

Gene names

Name:

KHK

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	298 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Catalytic activity	ATP + D-fructose = ADP + D-fructose 1-phosphate.
Enzyme regulation	Requires potassium. Inhibition by ADP.
Pathway	Carbohydrate metabolism; fructose metabolism.
Subunit structure	Homodimer. Ref.7
Tissue specificity	Most abundant in liver, kidney, gut, spleen and pancreas. Low levels also found in adrenal, muscle, brain and eye.
Involvement in disease	Fructosuria (FRUCT) [MIM:229800]: Benign defect of intermediary metabolism. Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.7
Sequence similarities	Belongs to the carbohydrate kinase PfkB family.

Ontologies

Keywords
Biological process	Carbohydrate metabolism
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	fructose catabolic process Traceable author statement. Source: Reactome small molecule metabolic process Traceable author statement. Source: Reactome
Cellular_component	cytosol Traceable author statement. Source: Reactome
Molecular_function	ATP binding Inferred from electronic annotation. Source: UniProtKB-KW ketohexokinase activity Traceable author statement Ref.1. Source: ProtInc
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ARRB1	P49407	1	EBI-1053974,EBI-743313
CD2BP2	O95400	1	EBI-1053974,EBI-768015
CDK5RAP3	Q96JB5	1	EBI-1053974,EBI-718818
DEDD	O75618	1	EBI-1053974,EBI-1043164
LCN1	P31025	1	EBI-1053974,EBI-1052433
LYZ	P61626	1	EBI-1053974,EBI-355360
RNPS1	Q15287	1	EBI-1053974,EBI-395959
SNRPB	P14678	1	EBI-1053974,EBI-372458

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform A (identifier: P50053-1)

Also known as: Central; hepatic/renal/intestinal;

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform C (identifier: P50053-2)

Also known as: Peripheral;

The sequence of this isoform differs from the canonical sequence as follows:
     72-115: VLDDLRRYSV...GSRTILYYDR → LVADFRRRGV...GNRTIVLHDT

Note: More widely distributed but with a low expression level.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 298

298

Ketohexokinase

PRO_0000080088

Regions

Nucleotide binding

255 – 258

4

ATP

Sites

Binding site

15

1

D-fructose

Binding site

41

1

D-fructose; via amide nitrogen

Binding site

42

1

D-fructose

Binding site

45

1

D-fructose

Binding site

108

1

ATP

Binding site

258

1

D-fructose

Amino acid modifications

Modified residue

169

1

Phosphoserine By similarity

Natural variations

Alternative sequence

72 – 115

44

VLDDL…LYYDR → LVADFRRRGVDVSQVAWQSK GDTPSSCCIINNSNGNRTIV LHDT in isoform C.

VSP_004669

Natural variant

40

1

G → R in FRUCT. Ref.1

VAR_006072

Natural variant

43

1

A → T in FRUCT. Ref.1

VAR_006073

Natural variant

49

1

V → I. Ref.1
Corresponds to variant rs2304681 [ dbSNP | Ensembl ].

VAR_006074

Natural variant

159

1

R → G Either a polymorphism or a cloning artifact.

VAR_006075

Secondary structure

1

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298

Helix Strand Turn

Details...

Beta strand

5 – 10

6

Beta strand

13 – 22

10

Beta strand

29 – 31

3

Beta strand

33 – 41

9

Helix

42 – 53

12

Beta strand

57 – 63

7

Helix

67 – 78

12

Beta strand

86 – 88

3

Beta strand

90 – 92

3

Beta strand

96 – 102

7

Turn

103 – 105

3

Beta strand

108 – 113

6

Helix

122 – 126

5

Helix

130 – 132

3

Beta strand

133 – 139

7

Helix

143 – 157

15

Helix

162 – 164

3

Beta strand

167 – 172

6

Helix

177 – 184

8

Beta strand

185 – 191

7

Helix

193 – 198

6

Helix

204 – 211

8

Helix

212 – 214

3

Beta strand

220 – 224

5

Helix

226 – 228

3

Beta strand

230 – 233

4

Beta strand

239 – 242

4

Helix

256 – 269

14

Helix

274 – 289

16

Beta strand

291 – 294

4

Helix

295 – 297

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform A (Central) (hepatic/renal/intestinal) [UniParc]. Last modified October 1, 1996. Version 1. Checksum: 1BA47BDC60C1B89F	FASTA	298	32,730
	10 20 30 40 50 60 MEEKQILCVG LVVLDVISLV DKYPKEDSEI RCLSQRWQRG GNASNSCTVL SLLGAPCAFM 70 80 90 100 110 120 GSMAPGHVAD FVLDDLRRYS VDLRYTVFQT TGSVPIATVI INEASGSRTI LYYDRSLPDV 130 140 150 160 170 180 SATDFEKVDL TQFKWIHIEG RNASEQVKML QRIDAHNTRQ PPEQKIRVSV EVEKPREELF 190 200 210 220 230 240 QLFGYGDVVF VSKDVAKHLG FQSAEEALRG LYGRVRKGAV LVCAWAEEGA DALGPDGKLL 250 260 270 280 290 HSDAFPPPRV VDTLGAGDTF NASVIFSLSQ GRSVQEALRF GCQVAGKKCG LQGFDGIV
	Isoform C (Peripheral) [UniParc]. Checksum: BE77FC325CAC5721	FASTA	298	32,523
	10 20 30 40 50 60 MEEKQILCVG LVVLDVISLV DKYPKEDSEI RCLSQRWQRG GNASNSCTVL SLLGAPCAFM 70 80 90 100 110 120 GSMAPGHVAD FLVADFRRRG VDVSQVAWQS KGDTPSSCCI INNSNGNRTI VLHDTSLPDV 130 140 150 160 170 180 SATDFEKVDL TQFKWIHIEG RNASEQVKML QRIDAHNTRQ PPEQKIRVSV EVEKPREELF 190 200 210 220 230 240 QLFGYGDVVF VSKDVAKHLG FQSAEEALRG LYGRVRKGAV LVCAWAEEGA DALGPDGKLL 250 260 270 280 290 HSDAFPPPRV VDTLGAGDTF NASVIFSLSQ GRSVQEALRF GCQVAGKKCG LQGFDGIV

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Molecular basis of essential fructosuria: molecular cloning and mutational analysis of human ketohexokinase (fructokinase)." Bonthron D.T., Brady N., Donaldson I.A., Steinmann B. Hum. Mol. Genet. 3:1627-1631(1994) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], VARIANTS FRUCT ARG-40 AND THR-43, VARIANT ILE-49.
[2]	"Cloning of human full open reading frames in Gateway(TM) system entry vector (pDONR201)." Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B. Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[3]	"Generation and annotation of the DNA sequences of human chromosomes 2 and 4." Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L., Du H. , Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H., Wilson R.K. Nature 434:724-731(2005) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	Mural R.J., Istrail S., Sutton 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].
[5]	"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: Lung.
[6]	"Structure and alternative splicing of the ketohexokinase gene." Hayward B.E., Bonthron D.T. Eur. J. Biochem. 257:85-91(1998) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-26 AND 71-298, ALTERNATIVE SPLICING.
[7]	"Structures of alternatively spliced isoforms of human ketohexokinase." Trinh C.H., Asipu A., Bonthron D.T., Phillips S.E. Acta Crystallogr. D 65:201-211(2009) [PubMed] [Europe PMC] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEX WITH FRUCTOSE AND AMP-PNP, X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS) OF ISOFORM C, SUBUNIT, SUBSTRATE-BINDING SITES.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

X78678 mRNA. Translation: CAA55347.1.
X78677 mRNA. Translation: CAA55346.1.
CR456801 mRNA. Translation: CAG33082.1.
AC013403 Genomic DNA. Translation: AAX93167.1.
CH471053 Genomic DNA. Translation: EAX00643.1.
BC006233 mRNA. Translation: AAH06233.1.
Y09336 Genomic DNA. Translation: CAA70516.1.
Y09341 Genomic DNA. Translation: CAA70522.1.
Y09341 Genomic DNA. Translation: CAA70523.1.
Y09340 Genomic DNA. Translation: CAA70521.1.
AJ005168 Genomic DNA. Translation: CAA06409.1.

IPI

IPI00029488.
IPI00216136.

RefSeq

NP_000212.1. NM_000221.2.
NP_006479.1. NM_006488.2.

UniGene

Hs.567297.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2HLZ	X-ray	1.85	A/B/C/D	5-298	[»]
2HQQ	X-ray	1.86	A	1-298	[»]
2HW1	X-ray	2.10	A	1-298	[»]
3B3L	X-ray	2.90	A/B/C/D	1-298	[»]
3NBV	X-ray	2.30	A/B	5-298	[»]
3NBW	X-ray	2.34	A/B	5-298	[»]
3NC2	X-ray	2.50	A/B	5-298	[»]
3NC9	X-ray	2.40	A/B	5-298	[»]
3NCA	X-ray	2.60	A/B	5-298	[»]
3Q92	X-ray	2.80	A/B	5-298	[»]
3QA2	X-ray	2.52	A/B	5-298	[»]
3QAI	X-ray	2.70	A/B	5-298	[»]
3RO4	X-ray	2.60	A/B	5-298	[»]

ProteinModelPortal

P50053.

ModBase

Search...

Protein-protein interaction databases

STRING

9606.ENSP00000260598.

PTM databases

PhosphoSite

P50053.

Polymorphism databases

DMDM

1730044.

2D gel databases

REPRODUCTION-2DPAGE

IPI00029488.

Proteomic databases

PaxDb

P50053.

PRIDE

P50053.

Protocols and materials databases

DNASU

3795.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000260598; ENSP00000260598; ENSG00000138030.
ENST00000260599; ENSP00000260599; ENSG00000138030.

GeneID

3795.

KEGG

hsa:3795.

UCSC

uc002ril.2. human.
uc002rim.2. human.

Organism-specific databases

CTD

3795.

GeneCards

GC02P027309.

HGNC

HGNC:6315. KHK.

HPA

HPA007040.

MIM

229800. phenotype.
614058. gene.

neXtProt

NX_P50053.

Orphanet

2056. Fructosuria.

PharmGKB

PA30095.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG0524.

HOGENOM

HOG000212926.

HOVERGEN

HBG003335.

InParanoid

P50053.

KO

K00846.

OMA

FMAGFIY.

OrthoDB

EOG4F7NKS.

Enzyme and pathway databases

BioCyc

MetaCyc:HS06437-MONOMER.

BRENDA

2.7.1.3. 2681.

Reactome

REACT_111217. Metabolism.

SABIO-RK

P50053.

UniPathway

UPA00202.

Gene expression databases

ArrayExpress

P50053.

Bgee

P50053.

CleanEx

HS_KHK.

Genevestigator

P50053.

GermOnline

ENSG00000138030. Homo sapiens.

Family and domain databases

InterPro

IPR011611. PfkB_dom.
[Graphical view]

Pfam

PF00294. PfkB. 1 hit.
[Graphical view]

PROSITE

PS00583. PFKB_KINASES_1. False negative.
PS00584. PFKB_KINASES_2. False negative.
[Graphical view]

ProtoNet

Search...

Other

BindingDB

P50053.

ChEMBL

CHEMBL1275212.

EvolutionaryTrace

P50053.

GenomeRNAi

3795.

NextBio

14897.

SOURCE

Search...

Entry information

Entry name

KHK_HUMAN

Accession

Primary (citable) accession number: P50053
Secondary accession number(s): Q6IBK2 , Q99532, Q9BRJ3, Q9UMN1

Entry history

Integrated into UniProtKB/Swiss-Prot:	October 1, 1996
Last sequence update:	October 1, 1996
Last modified:	May 1, 2013
This is version 124 of the entry and version 1 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.