ID KHK_HUMAN Reviewed; 298 AA. AC P50053; Q6IBK2; Q99532; Q9BRJ3; Q9UMN1; DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot. DT 29-APR-2015, sequence version 2. DT 08-MAY-2019, entry version 183. DE RecName: Full=Ketohexokinase {ECO:0000312|HGNC:HGNC:6315}; DE EC=2.7.1.3 {ECO:0000269|PubMed:12941785}; DE AltName: Full=Hepatic fructokinase; GN Name=KHK {ECO:0000312|HGNC:HGNC:6315}; OS Homo sapiens (Human). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; OC Catarrhini; Hominidae; Homo. OX NCBI_TaxID=9606; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA], VARIANTS FRUCT ARG-40 AND THR-43, AND RP VARIANT ILE-49. RX PubMed=7833921; DOI=10.1093/hmg/3.9.1627; RA Bonthron D.T., Brady N., Donaldson I.A., Steinmann B.; RT "Molecular basis of essential fructosuria: molecular cloning and RT mutational analysis of human ketohexokinase (fructokinase)."; RL Hum. Mol. Genet. 3:1627-1631(1994). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.; RT "Cloning of human full open reading frames in Gateway(TM) system entry RT vector (pDONR201)."; RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases. RN [3] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=15815621; DOI=10.1038/nature03466; RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M., RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J., RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C., RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J., RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A., RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K., RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M., RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K., RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C., RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M., RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E., RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P., RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A., RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A., RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T., RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D., RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X., RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C., RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S., RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., RA Waterston R.H., Wilson R.K.; RT "Generation and annotation of the DNA sequences of human chromosomes 2 RT and 4."; RL Nature 434:724-731(2005). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R., RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., RA Venter J.C.; RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases. RN [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. RC TISSUE=Lung; 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 RT project: the Mammalian Gene Collection (MGC)."; RL Genome Res. 14:2121-2127(2004). RN [6] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-26 AND 71-298, ALTERNATIVE RP SPLICING, AND TISSUE SPECIFICITY. RX PubMed=9799106; DOI=10.1046/j.1432-1327.1998.2570085.x; RA Hayward B.E., Bonthron D.T.; RT "Structure and alternative splicing of the ketohexokinase gene."; RL Eur. J. Biochem. 257:85-91(1998). RN [7] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., RA Wang L., Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human RT liver phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [8] RP X-RAY CRYSTALLOGRAPHY (2.10 ANGSTROMS) IN COMPLEX WITH FRUCTOSE AND RP AMP-PNP, X-RAY CRYSTALLOGRAPHY (1.86 ANGSTROMS) OF ISOFORM A, SUBUNIT, RP AND SUBSTRATE-BINDING SITES. RX PubMed=19237742; DOI=10.1107/S0907444908041115; RA Trinh C.H., Asipu A., Bonthron D.T., Phillips S.E.; RT "Structures of alternatively spliced isoforms of human RT ketohexokinase."; RL Acta Crystallogr. D 65:201-211(2009). RN [9] RP CHARACTERIZATION OF VARIANTS FRUCT ARG-40 AND THR-43, FUNCTION, RP BIOPHYSICOCHEMICAL PROPERTIES, AND CATALYTIC ACTIVITY. RX PubMed=12941785; DOI=10.2337/diabetes.52.9.2426; RA Asipu A., Hayward B.E., O'Reilly J., Bonthron D.T.; RT "Properties of normal and mutant recombinant human ketohexokinases and RT implications for the pathogenesis of essential fructosuria."; RL Diabetes 52:2426-2432(2003). CC -!- FUNCTION: Catalyzes the phosphorylation of the ketose sugar CC fructose to fructose-1-phosphate. {ECO:0000269|PubMed:12941785}. CC -!- CATALYTIC ACTIVITY: CC Reaction=ATP + beta-D-fructose = ADP + beta-D-fructose 1-phosphate CC + H(+); Xref=Rhea:RHEA:18145, ChEBI:CHEBI:15378, CC ChEBI:CHEBI:28645, ChEBI:CHEBI:30616, ChEBI:CHEBI:138881, CC ChEBI:CHEBI:456216; EC=2.7.1.3; CC Evidence={ECO:0000269|PubMed:12941785}; CC -!- ACTIVITY REGULATION: Requires potassium. Inhibition by ADP. CC -!- BIOPHYSICOCHEMICAL PROPERTIES: CC Kinetic parameters: CC KM=0.8 mM for D-fructose (at 25 degrees Celsius) CC {ECO:0000269|PubMed:12941785}; CC KM=0.15 mM for Mg-ATP (at 25 degrees Celsius) CC {ECO:0000269|PubMed:12941785}; CC Note=kcat is 7.6 sec(-1). {ECO:0000269|PubMed:12941785}; CC -!- PATHWAY: Carbohydrate metabolism; fructose metabolism. CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:19237742}. CC -!- INTERACTION: CC Q9NQ69:LHX9; NbExp=3; IntAct=EBI-12204387, EBI-10175218; CC P60891-1:PRPS1; NbExp=4; IntAct=EBI-12204387, EBI-16205225; CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=C {ECO:0000269|PubMed:9799106}; Synonyms=Central, CC hepatic/renal/intestinal {ECO:0000269|PubMed:9799106}; CC IsoId=P50053-1; Sequence=Displayed; CC Name=A {ECO:0000269|PubMed:9799106}; Synonyms=Peripheral CC {ECO:0000269|PubMed:9799106}; CC IsoId=P50053-2; Sequence=VSP_004669; CC Note=More widely distributed but with a low expression level. CC KM=7 mM for D-fructose (at 25 degrees Celsius). KM=036 mM for CC Mg-ATP (at 25 degrees Celsius). kcat is 6.9 sec(-1). CC {ECO:0000269|PubMed:12941785}; CC -!- TISSUE SPECIFICITY: Most abundant in liver, kidney, gut, spleen CC and pancreas. Low levels also found in adrenal, muscle, brain and CC eye. {ECO:0000269|PubMed:9799106}. CC -!- DISEASE: Fructosuria (FRUCT) [MIM:229800]: Benign defect of CC intermediary metabolism. {ECO:0000269|PubMed:12941785, CC ECO:0000269|PubMed:7833921}. Note=The disease is caused by CC mutations affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the carbohydrate kinase PfkB family. CC {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; X78678; CAA55347.1; -; mRNA. DR EMBL; X78677; CAA55346.1; -; mRNA. DR EMBL; CR456801; CAG33082.1; -; mRNA. DR EMBL; AC013403; AAX93167.1; -; Genomic_DNA. DR EMBL; CH471053; EAX00643.1; -; Genomic_DNA. DR EMBL; BC006233; AAH06233.1; -; mRNA. DR EMBL; Y09336; CAA70516.1; -; Genomic_DNA. DR EMBL; Y09341; CAA70522.1; -; Genomic_DNA. DR EMBL; Y09341; CAA70523.1; -; Genomic_DNA. DR EMBL; Y09340; CAA70521.1; -; Genomic_DNA. DR EMBL; AJ005168; CAA06409.1; -; Genomic_DNA. DR CCDS; CCDS1734.1; -. [P50053-2] DR CCDS; CCDS1735.1; -. [P50053-1] DR RefSeq; NP_000212.1; NM_000221.2. [P50053-2] DR RefSeq; NP_006479.1; NM_006488.2. [P50053-1] DR PDB; 2HLZ; X-ray; 1.85 A; A/B/C/D=5-298. DR PDB; 2HQQ; X-ray; 1.86 A; A=1-298. DR PDB; 2HW1; X-ray; 2.10 A; A=1-298. DR PDB; 3B3L; X-ray; 2.90 A; A/B/C/D=1-298. DR PDB; 3NBV; X-ray; 2.30 A; A/B=5-298. DR PDB; 3NBW; X-ray; 2.34 A; A/B=5-298. DR PDB; 3NC2; X-ray; 2.50 A; A/B=5-298. DR PDB; 3NC9; X-ray; 2.40 A; A/B=5-298. DR PDB; 3NCA; X-ray; 2.60 A; A/B=5-298. DR PDB; 3Q92; X-ray; 2.80 A; A/B=5-298. DR PDB; 3QA2; X-ray; 2.52 A; A/B=5-298. DR PDB; 3QAI; X-ray; 2.70 A; A/B=5-298. DR PDB; 3RO4; X-ray; 2.60 A; A/B=5-298. DR PDB; 5WBM; X-ray; 2.16 A; A/B=5-298. DR PDB; 5WBO; X-ray; 2.25 A; A/B=5-298. DR PDB; 5WBP; X-ray; 2.74 A; A/B=5-298. DR PDB; 5WBQ; X-ray; 2.40 A; A/B=5-298. DR PDB; 5WBR; X-ray; 2.58 A; A/B=5-298. DR PDB; 5WBZ; X-ray; 2.40 A; A/B=5-298. DR PDBsum; 2HLZ; -. DR PDBsum; 2HQQ; -. DR PDBsum; 2HW1; -. DR PDBsum; 3B3L; -. DR PDBsum; 3NBV; -. DR PDBsum; 3NBW; -. DR PDBsum; 3NC2; -. DR PDBsum; 3NC9; -. DR PDBsum; 3NCA; -. DR PDBsum; 3Q92; -. DR PDBsum; 3QA2; -. DR PDBsum; 3QAI; -. DR PDBsum; 3RO4; -. DR PDBsum; 5WBM; -. DR PDBsum; 5WBO; -. DR PDBsum; 5WBP; -. DR PDBsum; 5WBQ; -. DR PDBsum; 5WBR; -. DR PDBsum; 5WBZ; -. DR SMR; P50053; -. DR BioGrid; 109996; 21. DR DIP; DIP-50184N; -. DR IntAct; P50053; 4. DR STRING; 9606.ENSP00000260599; -. DR BindingDB; P50053; -. DR ChEMBL; CHEMBL1275212; -. DR iPTMnet; P50053; -. DR PhosphoSitePlus; P50053; -. DR BioMuta; KHK; -. DR DMDM; 1730044; -. DR REPRODUCTION-2DPAGE; IPI00029488; -. DR EPD; P50053; -. DR jPOST; P50053; -. DR MaxQB; P50053; -. DR PaxDb; P50053; -. DR PeptideAtlas; P50053; -. DR PRIDE; P50053; -. DR ProteomicsDB; 56192; -. DR ProteomicsDB; 56193; -. [P50053-2] DR DNASU; 3795; -. DR Ensembl; ENST00000260598; ENSP00000260598; ENSG00000138030. [P50053-1] DR Ensembl; ENST00000260599; ENSP00000260599; ENSG00000138030. [P50053-2] DR GeneID; 3795; -. DR KEGG; hsa:3795; -. DR UCSC; uc002ril.3; human. [P50053-1] DR CTD; 3795; -. DR DisGeNET; 3795; -. DR GeneCards; KHK; -. DR HGNC; HGNC:6315; KHK. DR HPA; HPA007040; -. DR MalaCards; KHK; -. DR MIM; 229800; phenotype. DR MIM; 614058; gene. DR neXtProt; NX_P50053; -. DR OpenTargets; ENSG00000138030; -. DR Orphanet; 2056; Essential fructosuria. DR PharmGKB; PA30095; -. DR eggNOG; KOG2947; Eukaryota. DR eggNOG; ENOG4111F4Q; LUCA. DR GeneTree; ENSGT00390000007458; -. DR HOGENOM; HOG000212926; -. DR InParanoid; P50053; -. DR KO; K00846; -. DR OMA; CNKDYPQ; -. DR OrthoDB; 720391at2759; -. DR TreeFam; TF323942; -. DR BioCyc; MetaCyc:HS06437-MONOMER; -. DR BRENDA; 2.7.1.3; 2681. DR Reactome; R-HSA-5657562; Essential fructosuria. DR Reactome; R-HSA-70350; Fructose catabolism. DR SABIO-RK; P50053; -. DR UniPathway; UPA00202; -. DR EvolutionaryTrace; P50053; -. DR GenomeRNAi; 3795; -. DR PRO; PR:P50053; -. DR Proteomes; UP000005640; Chromosome 2. DR Bgee; ENSG00000138030; Expressed in 163 organ(s), highest expression level in right lobe of liver. DR ExpressionAtlas; P50053; baseline and differential. DR Genevisible; P50053; HS. DR GO; GO:0005737; C:cytoplasm; IDA:LIFEdb. DR GO; GO:0005829; C:cytosol; TAS:Reactome. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0005524; F:ATP binding; IEA:UniProtKB-KW. DR GO; GO:0019200; F:carbohydrate kinase activity; IBA:GO_Central. DR GO; GO:0004454; F:ketohexokinase activity; IDA:MGI. DR GO; GO:0061624; P:fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate; TAS:Reactome. DR GO; GO:0006000; P:fructose metabolic process; IBA:GO_Central. DR GO; GO:0070873; P:regulation of glycogen metabolic process; IBA:GO_Central. DR GO; GO:0009750; P:response to fructose; IBA:GO_Central. DR GO; GO:0009749; P:response to glucose; IBA:GO_Central. DR GO; GO:0032868; P:response to insulin; IBA:GO_Central. DR GO; GO:0009744; P:response to sucrose; IBA:GO_Central. DR GO; GO:0010043; P:response to zinc ion; IBA:GO_Central. DR CDD; cd01939; Ketohexokinase; 1. DR Gene3D; 3.40.1190.20; -; 1. DR InterPro; IPR034093; KHK. DR InterPro; IPR011611; PfkB_dom. DR InterPro; IPR029056; Ribokinase-like. DR Pfam; PF00294; PfkB; 1. DR SUPFAM; SSF53613; SSF53613; 1. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; ATP-binding; KW Carbohydrate metabolism; Complete proteome; Disease mutation; Kinase; KW Nucleotide-binding; Polymorphism; Reference proteome; Transferase. FT CHAIN 1 298 Ketohexokinase. FT /FTId=PRO_0000080088. FT NP_BIND 255 258 ATP. FT BINDING 15 15 D-fructose. FT BINDING 41 41 D-fructose; via amide nitrogen. FT BINDING 42 42 D-fructose. FT BINDING 45 45 D-fructose. FT BINDING 108 108 ATP. FT BINDING 258 258 D-fructose. FT VAR_SEQ 72 115 LVADFRRRGVDVSQVAWQSKGDTPSSCCIINNSNGNRTIVL FT HDT -> VLDDLRRYSVDLRYTVFQTTGSVPIATVIINEAS FT GSRTILYYDR (in isoform A). {ECO:0000305}. FT /FTId=VSP_004669. FT VARIANT 40 40 G -> R (in FRUCT; loss of ketohexokinase FT function; insoluble; dbSNP:rs104893643). FT {ECO:0000269|PubMed:12941785, FT ECO:0000269|PubMed:7833921}. FT /FTId=VAR_006072. FT VARIANT 43 43 A -> T (in FRUCT; no effect on FT ketohexokinase function; decreases enzyme FT activity but no effect in substrate FT affinity; decreases thermal stability; FT dbSNP:rs104893644). FT {ECO:0000269|PubMed:12941785, FT ECO:0000269|PubMed:7833921}. FT /FTId=VAR_006073. FT VARIANT 49 49 V -> I (in dbSNP:rs2304681). FT {ECO:0000269|PubMed:7833921}. FT /FTId=VAR_006074. FT STRAND 5 10 {ECO:0000244|PDB:2HLZ}. FT STRAND 13 22 {ECO:0000244|PDB:2HLZ}. FT STRAND 29 31 {ECO:0000244|PDB:2HLZ}. FT STRAND 33 41 {ECO:0000244|PDB:2HLZ}. FT HELIX 42 53 {ECO:0000244|PDB:2HLZ}. FT STRAND 57 63 {ECO:0000244|PDB:2HLZ}. FT HELIX 67 78 {ECO:0000244|PDB:2HLZ}. FT STRAND 86 88 {ECO:0000244|PDB:2HLZ}. FT STRAND 90 92 {ECO:0000244|PDB:2HQQ}. FT STRAND 96 102 {ECO:0000244|PDB:2HLZ}. FT TURN 103 105 {ECO:0000244|PDB:2HLZ}. FT STRAND 108 113 {ECO:0000244|PDB:2HLZ}. FT HELIX 122 126 {ECO:0000244|PDB:2HLZ}. FT HELIX 130 132 {ECO:0000244|PDB:2HLZ}. FT STRAND 133 139 {ECO:0000244|PDB:2HLZ}. FT HELIX 143 157 {ECO:0000244|PDB:2HLZ}. FT HELIX 162 164 {ECO:0000244|PDB:2HLZ}. FT STRAND 167 172 {ECO:0000244|PDB:2HLZ}. FT HELIX 177 184 {ECO:0000244|PDB:2HLZ}. FT STRAND 185 191 {ECO:0000244|PDB:2HLZ}. FT HELIX 193 198 {ECO:0000244|PDB:2HLZ}. FT HELIX 204 211 {ECO:0000244|PDB:2HLZ}. FT HELIX 212 214 {ECO:0000244|PDB:2HLZ}. FT STRAND 220 224 {ECO:0000244|PDB:2HLZ}. FT HELIX 226 228 {ECO:0000244|PDB:2HLZ}. FT STRAND 230 233 {ECO:0000244|PDB:2HLZ}. FT STRAND 239 242 {ECO:0000244|PDB:2HLZ}. FT HELIX 256 269 {ECO:0000244|PDB:2HLZ}. FT HELIX 274 289 {ECO:0000244|PDB:2HLZ}. FT STRAND 291 294 {ECO:0000244|PDB:2HLZ}. FT HELIX 295 297 {ECO:0000244|PDB:2HLZ}. SQ SEQUENCE 298 AA; 32523 MW; BE77FC325CAC5721 CRC64; MEEKQILCVG LVVLDVISLV DKYPKEDSEI RCLSQRWQRG GNASNSCTVL SLLGAPCAFM GSMAPGHVAD FLVADFRRRG VDVSQVAWQS KGDTPSSCCI INNSNGNRTI VLHDTSLPDV SATDFEKVDL TQFKWIHIEG RNASEQVKML QRIDAHNTRQ PPEQKIRVSV EVEKPREELF QLFGYGDVVF VSKDVAKHLG FQSAEEALRG LYGRVRKGAV LVCAWAEEGA DALGPDGKLL HSDAFPPPRV VDTLGAGDTF NASVIFSLSQ GRSVQEALRF GCQVAGKKCG LQGFDGIV //