KIME_HUMAN
ID KIME_HUMAN Reviewed; 396 AA.
AC Q03426;
DT 01-OCT-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1993, sequence version 1.
DT 03-AUG-2022, entry version 222.
DE RecName: Full=Mevalonate kinase {ECO:0000305};
DE Short=MK;
DE EC=2.7.1.36 {ECO:0000269|PubMed:11278915, ECO:0000269|PubMed:18302342, ECO:0000269|PubMed:9325256, ECO:0000269|PubMed:9392419};
GN Name=MVK {ECO:0000312|HGNC:HGNC:7530};
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND VARIANT MEVA THR-301.
RX PubMed=1377680; DOI=10.1016/s0021-9258(18)42199-0;
RA Schafer B.L., Bishop R.W., Kratunis V.J., Kalinowski S.S., Mosley S.T.,
RA Gibson K.M., Tanaka R.D.;
RT "Molecular cloning of human mevalonate kinase and identification of a
RT missense mutation in the genetic disease mevalonic aciduria.";
RL J. Biol. Chem. 267:13229-13238(1992).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Hepatoma;
RX PubMed=8302606;
RA Graef E., Caselmann W.H., Wells J., Koshy R.;
RT "Insertional activation of mevalonate kinase by hepatitis B virus DNA in a
RT human hepatoma cell line.";
RL Oncogene 9:81-87(1994).
RN [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], VARIANTS HIDS PRO-20; PRO-39; LEU-135;
RP THR-148; THR-268 AND ILE-377, AND VARIANTS MEVA PRO-20; PHE-264; THR-268;
RP MET-310 AND THR-334.
RX PubMed=11313768; DOI=10.1038/sj.ejhg.5200595;
RA Houten S.M., Koster J., Romeijn G.-J., Frenkel J., Di Rocco M., Caruso U.,
RA Landrieu P., Kelley R.I., Kuis W., Poll-The B.T., Gibson K.M.,
RA Wanders R.J.A., Waterham H.R.;
RT "Organization of the mevalonate kinase (MVK) gene and identification of
RT novel mutations causing mevalonic aciduria and hyperimmunoglobulinaemia D
RT and periodic fever syndrome.";
RL Eur. J. Hum. Genet. 9:253-259(2001).
RN [4]
RP ERRATUM OF PUBMED:11313768.
RA Houten S.M., Koster J., Romeijn G.-J., Frenkel J., Di Rocco M., Caruso U.,
RA Landrieu P., Kelley R.I., Kuis W., Poll-The B.T., Gibson K.M.,
RA Wanders R.J.A., Waterham H.R.;
RL Eur. J. Hum. Genet. 9:651-651(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Skin;
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 project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, PROBABLE
RP ACTIVE SITE, ACTIVITY REGULATION, SUBUNIT, AND MUTAGENESIS OF GLU-19;
RP GLU-193; ASP-204 AND GLU-296.
RX PubMed=9325256; DOI=10.1074/jbc.272.41.25449;
RA Potter D., Miziorko H.M.;
RT "Identification of catalytic residues in human mevalonate kinase.";
RL J. Biol. Chem. 272:25449-25454(1997).
RN [7]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=9392419;
RA Hinson D.D., Chambliss K.L., Toth M.J., Tanaka R.D., Gibson K.M.;
RT "Post-translational regulation of mevalonate kinase by intermediates of the
RT cholesterol and nonsterol isoprene biosynthetic pathways.";
RL J. Lipid Res. 38:2216-2223(1997).
RN [8]
RP MUTAGENESIS OF SER-145; SER-146; SER-201 AND THR-243, FUNCTION, CATALYTIC
RP ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=11278915; DOI=10.1074/jbc.m011478200;
RA Cho Y.K., Rios S.E., Kim J.J., Miziorko H.M.;
RT "Investigation of invariant serine/threonine residues in mevalonate kinase.
RT Tests of the functional significance of a proposed substrate binding motif
RT and a site implicated in human inherited disease.";
RL J. Biol. Chem. 276:12573-12578(2001).
RN [9]
RP SUBCELLULAR LOCATION.
RX PubMed=14730012; DOI=10.1242/jcs.00910;
RA Hogenboom S., Tuyp J.J., Espeel M., Koster J., Wanders R.J., Waterham H.R.;
RT "Mevalonate kinase is a cytosolic enzyme in humans.";
RL J. Cell Sci. 117:631-639(2004).
RN [10]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T.,
RA Bennett K.L., Superti-Furga G., Colinge J.;
RT "Initial characterization of the human central proteome.";
RL BMC Syst. Biol. 5:17-17(2011).
RN [11]
RP INVOLVEMENT IN POROK3, AND VARIANTS POROK3 ARG-12; PRO-41; ARG-202;
RP PRO-255; PRO-279; ASP-291; ARG-312; SER-365 AND SER-376.
RX PubMed=22983302; DOI=10.1038/ng.2409;
RA Zhang S.Q., Jiang T., Li M., Zhang X., Ren Y.Q., Wei S.C., Sun L.D.,
RA Cheng H., Li Y., Yin X.Y., Hu Z.M., Wang Z.Y., Liu Y., Guo B.R., Tang H.Y.,
RA Tang X.F., Ding Y.T., Wang J.B., Li P., Wu B.Y., Wang W., Yuan X.F.,
RA Hou J.S., Ha W.W., Wang W.J., Zhai Y.J., Wang J., Qian F.F., Zhou F.S.,
RA Chen G., Zuo X.B., Zheng X.D., Sheng Y.J., Gao J.P., Liang B., Li P.,
RA Zhu J., Xiao F.L., Wang P.G., Cui Y., Li H., Liu S.X., Gao M., Fan X.,
RA Shen S.K., Zeng M., Sun G.Q., Xu Y., Hu J.C., He T.T., Li Y.R., Yang H.M.,
RA Wang J., Yu Z.Y., Zhang H.F., Hu X., Yang K., Wang J., Zhao S.X.,
RA Zhou Y.W., Liu J.J., Du W.D., Zhang L., Xia K., Yang S., Wang J.,
RA Zhang X.J.;
RT "Exome sequencing identifies MVK mutations in disseminated superficial
RT actinic porokeratosis.";
RL Nat. Genet. 44:1156-1160(2012).
RN [12]
RP INVOLVEMENT IN POROK3.
RX PubMed=24781643; DOI=10.1007/s00403-014-1465-7;
RA Zeng K., Zhang Q.G., Li L., Duan Y., Liang Y.H.;
RT "Splicing mutation in MVK is a cause of porokeratosis of Mibelli.";
RL Arch. Dermatol. Res. 306:749-755(2014).
RN [13] {ECO:0007744|PDB:2R3V}
RP X-RAY CRYSTALLOGRAPHY (2.50 ANGSTROMS), FUNCTION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, AND MUTAGENESIS OF
RP ILE-56; THR-104; TYR-149 AND ILE-196.
RX PubMed=18302342; DOI=10.1021/bi7024386;
RA Fu Z., Voynova N.E., Herdendorf T.J., Miziorko H.M., Kim J.J.;
RT "Biochemical and structural basis for feedback inhibition of mevalonate
RT kinase and isoprenoid metabolism.";
RL Biochemistry 47:3715-3724(2008).
RN [14]
RP VARIANTS MEVA ILE-243; PHE-264; PRO-265 AND THR-268.
RX PubMed=10417275; DOI=10.1086/302489;
RA Hinson D.D., Ross R.M., Krisans S., Shaw J.L., Kozich V., Rolland M.-O.,
RA Divry P., Mancini J., Hoffmann G.F., Gibson K.M.;
RT "Identification of a mutation cluster in mevalonate kinase deficiency,
RT including a new mutation in a patient of Mennonite ancestry.";
RL Am. J. Hum. Genet. 65:327-335(1999).
RN [15]
RP VARIANTS MEVA MET-310 AND THR-334.
RX PubMed=10401001; DOI=10.1093/hmg/8.8.1523;
RA Houten S.M., Romeijn G.J., Koster J., Gray R.G.F., Darbyshire P.,
RA Smit G.P.A., de Klerk J.B.C., Duran R., Gibson K.M., Wanders R.J.A.,
RA Waterham H.R.;
RT "Identification and characterization of three novel missense mutations in
RT mevalonate kinase cDNA causing mevalonic aciduria, a disorder of isoprene
RT biosynthesis.";
RL Hum. Mol. Genet. 8:1523-1528(1999).
RN [16]
RP VARIANTS HIDS PRO-20; THR-268 AND ILE-377.
RX PubMed=10369261; DOI=10.1038/9691;
RA Houten S.M., Kuis W., Duran M., de Koning T.J., van Royen-Kerkhof A.,
RA Romeijn G.J., Frenkel J., Dorland L., de Barse M.M.J., Huijbers W.A.R.,
RA Rijkers G.T., Waterham H.R., Wanders R.J.A., Poll-The B.T.;
RT "Mutations in MVK, encoding mevalonate kinase, cause
RT hyperimmunoglobulinaemia D and periodic fever syndrome.";
RL Nat. Genet. 22:175-177(1999).
RN [17]
RP VARIANTS HIDS LEU-167; THR-268 AND ILE-377.
RX PubMed=10369262; DOI=10.1038/9696;
RA Drenth J.P.H., Cuisset L., Grateau G., Vasseur C.,
RA van der Velde-Visser S.D., de Jong J.G.N., Beckmann J.S.,
RA van der Meer J.W.M., Delpech M.;
RT "Mutations in the gene encoding mevalonate kinase cause hyper-IgD and
RT periodic fever syndrome.";
RL Nat. Genet. 22:178-181(1999).
RN [18]
RP VARIANTS HIDS ASN-20; PRO-20; PRO-39; LEU-150; LEU-167; ARG-202; GLN-215;
RP THR-268; SER-309; ARG-326 AND ILE-377, VARIANT MEVA THR-334, AND VARIANT
RP ASN-52.
RX PubMed=11313769; DOI=10.1038/sj.ejhg.5200614;
RA Cuisset L., Drenth J.P.H., Simon A., Vincent M.-F.,
RA van der Velde-Visser S.D., van der Meer J.W.M., Grateau G., Delpech M.;
RT "Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD
RT and periodic fever syndrome.";
RL Eur. J. Hum. Genet. 9:260-266(2001).
RN [19]
RP VARIANTS HIDS GLN-20; ILE-132; THR-148; ARG-171; GLU-211; GLN-215; ILE-250;
RP ARG-265; THR-268; MET-310; VAL-376 AND ILE-377, AND VARIANTS ASN-52 AND
RP MET-356.
RX PubMed=15536479; DOI=10.1038/sj.ejhg.5201323;
RA D'Osualdo A., Picco P., Caroli F., Gattorno M., Giacchino R., Fortini P.,
RA Corona F., Tommasini A., Salvi G., Specchia F., Obici L., Meini A.,
RA Ricci A., Seri M., Ravazzolo R., Martini A., Ceccherini I.;
RT "MVK mutations and associated clinical features in Italian patients
RT affected with autoinflammatory disorders and recurrent fever.";
RL Eur. J. Hum. Genet. 13:314-320(2005).
CC -!- FUNCTION: Catalyzes the phosphorylation of mevalonate to mevalonate 5-
CC phosphate, a key step in isoprenoid and cholesterol biosynthesis
CC (PubMed:9325256, PubMed:18302342, PubMed:9392419, PubMed:11278915).
CC {ECO:0000269|PubMed:11278915, ECO:0000269|PubMed:18302342,
CC ECO:0000269|PubMed:9325256, ECO:0000269|PubMed:9392419}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-mevalonate + ATP = (R)-5-phosphomevalonate + ADP + H(+);
CC Xref=Rhea:RHEA:17065, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:36464, ChEBI:CHEBI:58146, ChEBI:CHEBI:456216;
CC EC=2.7.1.36; Evidence={ECO:0000269|PubMed:11278915,
CC ECO:0000269|PubMed:18302342, ECO:0000269|PubMed:9325256,
CC ECO:0000269|PubMed:9392419};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000250|UniProtKB:P17256};
CC -!- ACTIVITY REGULATION: Farnesyl pyrophosphate and geranyl pyrophosphate
CC inhibit mevalonate kinase activity by binding competitively at the ATP-
CC binding sites. {ECO:0000269|PubMed:18302342,
CC ECO:0000269|PubMed:9392419}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=74 uM for ATP {ECO:0000269|PubMed:9325256};
CC KM=178 uM for ATP {ECO:0000269|PubMed:18302342};
CC KM=12.2 uM for adenosine 5-O-[S-(acetamidoproxyl)-3-thiotriphosphate]
CC {ECO:0000269|PubMed:11278915};
CC KM=24 uM for (R)-mevalonate {ECO:0000269|PubMed:9325256};
CC KM=40 uM for (R)-mevalonate {ECO:0000269|PubMed:18302342};
CC Vmax=37 umol/min/mg enzyme with (R)-mevalonate as substrate
CC {ECO:0000269|PubMed:9325256};
CC Vmax=28 umol/min/mg enzyme with (R)-mevalonate as substrate
CC {ECO:0000269|PubMed:18302342};
CC -!- PATHWAY: Isoprenoid biosynthesis; isopentenyl diphosphate biosynthesis
CC via mevalonate pathway; isopentenyl diphosphate from (R)-mevalonate:
CC step 1/3. {ECO:0000305}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:9325256}.
CC -!- INTERACTION:
CC Q03426; Q03426: MVK; NbExp=12; IntAct=EBI-740630, EBI-740630;
CC Q03426; Q9NUX5: POT1; NbExp=2; IntAct=EBI-740630, EBI-752420;
CC Q03426; Q8WVD5: RNF141; NbExp=3; IntAct=EBI-740630, EBI-4308142;
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14730012}.
CC Peroxisome {ECO:0000250|UniProtKB:P17256}.
CC -!- DISEASE: Mevalonic aciduria (MEVA) [MIM:610377]: Accumulation of
CC mevalonic acid which causes a variety of symptoms such as psychomotor
CC retardation, dysmorphic features, cataracts, hepatosplenomegaly,
CC lymphadenopathy, anemia, hypotonia, myopathy, and ataxia.
CC {ECO:0000269|PubMed:10401001, ECO:0000269|PubMed:10417275,
CC ECO:0000269|PubMed:11313768, ECO:0000269|PubMed:11313769,
CC ECO:0000269|PubMed:1377680}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS)
CC [MIM:260920]: Autosomal recessive disease characterized by recurrent
CC episodes of unexplained high fever associated with skin rash, diarrhea,
CC adenopathy (swollen, tender lymph nodes), arthralgias and/or arthritis.
CC Concentration of IgD, and often IgA, are above normal.
CC {ECO:0000269|PubMed:10369261, ECO:0000269|PubMed:10369262,
CC ECO:0000269|PubMed:11313768, ECO:0000269|PubMed:11313769,
CC ECO:0000269|PubMed:15536479}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- DISEASE: Porokeratosis 3, multiple types (POROK3) [MIM:175900]: A form
CC of porokeratosis, a disorder of faulty keratinization characterized by
CC one or more atrophic patches surrounded by a distinctive hyperkeratotic
CC ridgelike border called the cornoid lamella. The keratotic lesions can
CC progress to overt cutaneous neoplasms, typically squamous cell
CC carcinomas. Multiple clinical variants of porokeratosis are recognized,
CC including porokeratosis of Mibelli, linear porokeratosis, disseminated
CC superficial actinic porokeratosis, palmoplantar porokeratosis, and
CC punctate porokeratosis. Different clinical presentations can be
CC observed among members of the same family. Individuals expressing more
CC than one variant have also been reported. {ECO:0000269|PubMed:22983302,
CC ECO:0000269|PubMed:24781643}. Note=The disease is caused by variants
CC affecting the gene represented in this entry.
CC -!- SIMILARITY: Belongs to the GHMP kinase family. Mevalonate kinase
CC subfamily. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=CAA53059.1; Type=Erroneous initiation; Note=Extended N-terminus.; Evidence={ECO:0000305};
CC -!- WEB RESOURCE: Name=INFEVERS; Note=Repertory of FMF and hereditary
CC autoinflammatory disorders mutations;
CC URL="https://infevers.umai-montpellier.fr/web/search.php?n=3";
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DR EMBL; M88468; AAB59362.1; -; mRNA.
DR EMBL; X75311; CAA53060.1; -; mRNA.
DR EMBL; X75311; CAA53059.1; ALT_INIT; mRNA.
DR EMBL; AF217535; AAF82407.1; -; Genomic_DNA.
DR EMBL; AF217528; AAF82407.1; JOINED; Genomic_DNA.
DR EMBL; AF217529; AAF82407.1; JOINED; Genomic_DNA.
DR EMBL; AF217530; AAF82407.1; JOINED; Genomic_DNA.
DR EMBL; AF217531; AAF82407.1; JOINED; Genomic_DNA.
DR EMBL; AF217532; AAF82407.1; JOINED; Genomic_DNA.
DR EMBL; AF217533; AAF82407.1; JOINED; Genomic_DNA.
DR EMBL; AF217534; AAF82407.1; JOINED; Genomic_DNA.
DR EMBL; BC016140; AAH16140.1; -; mRNA.
DR CCDS; CCDS9132.1; -.
DR PIR; A42919; A42919.
DR RefSeq; NP_000422.1; NM_000431.3.
DR RefSeq; NP_001107657.1; NM_001114185.2.
DR RefSeq; NP_001288111.1; NM_001301182.1.
DR RefSeq; XP_016874803.1; XM_017019314.1.
DR PDB; 2R3V; X-ray; 2.50 A; A/B/C/D=1-396.
DR PDBsum; 2R3V; -.
DR AlphaFoldDB; Q03426; -.
DR SMR; Q03426; -.
DR BioGRID; 110683; 34.
DR IntAct; Q03426; 16.
DR STRING; 9606.ENSP00000443551; -.
DR DrugBank; DB04695; Farnesyl thiopyrophosphate.
DR GuidetoPHARMACOLOGY; 640; -.
DR SwissLipids; SLP:000001240; -.
DR iPTMnet; Q03426; -.
DR PhosphoSitePlus; Q03426; -.
DR BioMuta; MVK; -.
DR DMDM; 417215; -.
DR EPD; Q03426; -.
DR jPOST; Q03426; -.
DR MassIVE; Q03426; -.
DR MaxQB; Q03426; -.
DR PaxDb; Q03426; -.
DR PeptideAtlas; Q03426; -.
DR PRIDE; Q03426; -.
DR ProteomicsDB; 58211; -.
DR Antibodypedia; 2047; 398 antibodies from 32 providers.
DR DNASU; 4598; -.
DR Ensembl; ENST00000228510.8; ENSP00000228510.3; ENSG00000110921.14.
DR Ensembl; ENST00000539575.4; ENSP00000443551.2; ENSG00000110921.14.
DR GeneID; 4598; -.
DR KEGG; hsa:4598; -.
DR MANE-Select; ENST00000228510.8; ENSP00000228510.3; NM_000431.4; NP_000422.1.
DR UCSC; uc009zvk.4; human.
DR CTD; 4598; -.
DR DisGeNET; 4598; -.
DR GeneCards; MVK; -.
DR HGNC; HGNC:7530; MVK.
DR HPA; ENSG00000110921; Tissue enhanced (liver).
DR MalaCards; MVK; -.
DR MIM; 175900; phenotype.
DR MIM; 251170; gene.
DR MIM; 260920; phenotype.
DR MIM; 610377; phenotype.
DR neXtProt; NX_Q03426; -.
DR OpenTargets; ENSG00000110921; -.
DR Orphanet; 79152; Disseminated superficial actinic porokeratosis.
DR Orphanet; 343; Hyperimmunoglobulinemia D with periodic fever.
DR Orphanet; 29; Mevalonic aciduria.
DR Orphanet; 735; Porokeratosis of Mibelli.
DR PharmGKB; PA31331; -.
DR VEuPathDB; HostDB:ENSG00000110921; -.
DR eggNOG; KOG1511; Eukaryota.
DR GeneTree; ENSGT00950000183187; -.
DR HOGENOM; CLU_017814_0_1_1; -.
DR InParanoid; Q03426; -.
DR OMA; NTVCTYG; -.
DR OrthoDB; 762492at2759; -.
DR PhylomeDB; Q03426; -.
DR TreeFam; TF313775; -.
DR BioCyc; MetaCyc:ENSG00000110921-MON; -.
DR BRENDA; 2.7.1.36; 2681.
DR PathwayCommons; Q03426; -.
DR Reactome; R-HSA-191273; Cholesterol biosynthesis.
DR Reactome; R-HSA-2426168; Activation of gene expression by SREBF (SREBP).
DR SABIO-RK; Q03426; -.
DR SignaLink; Q03426; -.
DR UniPathway; UPA00057; UER00098.
DR BioGRID-ORCS; 4598; 619 hits in 1081 CRISPR screens.
DR ChiTaRS; MVK; human.
DR EvolutionaryTrace; Q03426; -.
DR GeneWiki; Mevalonate_kinase; -.
DR GenomeRNAi; 4598; -.
DR Pharos; Q03426; Tchem.
DR PRO; PR:Q03426; -.
DR Proteomes; UP000005640; Chromosome 12.
DR RNAct; Q03426; protein.
DR Bgee; ENSG00000110921; Expressed in lower esophagus mucosa and 190 other tissues.
DR ExpressionAtlas; Q03426; baseline and differential.
DR Genevisible; Q03426; HS.
DR GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA.
DR GO; GO:0005777; C:peroxisome; ISS:UniProtKB.
DR GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR GO; GO:0004496; F:mevalonate kinase activity; IDA:UniProtKB.
DR GO; GO:0006695; P:cholesterol biosynthetic process; IDA:UniProtKB.
DR GO; GO:0019287; P:isopentenyl diphosphate biosynthetic process, mevalonate pathway; IBA:GO_Central.
DR GO; GO:0008299; P:isoprenoid biosynthetic process; IDA:UniProtKB.
DR GO; GO:0050728; P:negative regulation of inflammatory response; IMP:BHF-UCL.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR Gene3D; 3.30.230.10; -; 1.
DR Gene3D; 3.30.70.890; -; 1.
DR InterPro; IPR013750; GHMP_kinase_C_dom.
DR InterPro; IPR036554; GHMP_kinase_C_sf.
DR InterPro; IPR006204; GHMP_kinase_N_dom.
DR InterPro; IPR006203; GHMP_knse_ATP-bd_CS.
DR InterPro; IPR006205; Mev_gal_kin.
DR InterPro; IPR020568; Ribosomal_S5_D2-typ_fold.
DR InterPro; IPR014721; Ribosomal_S5_D2-typ_fold_subgr.
DR PANTHER; PTHR43290; PTHR43290; 1.
DR Pfam; PF08544; GHMP_kinases_C; 1.
DR Pfam; PF00288; GHMP_kinases_N; 1.
DR SUPFAM; SSF54211; SSF54211; 1.
DR SUPFAM; SSF55060; SSF55060; 1.
DR TIGRFAMs; TIGR00549; mevalon_kin; 1.
DR PROSITE; PS00627; GHMP_KINASES_ATP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Cataract; Cholesterol biosynthesis;
KW Cholesterol metabolism; Cytoplasm; Disease variant; Kinase;
KW Lipid biosynthesis; Lipid metabolism; Magnesium; Metal-binding;
KW Nucleotide-binding; Peroxisome; Reference proteome; Steroid biosynthesis;
KW Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transferase.
FT CHAIN 1..396
FT /note="Mevalonate kinase"
FT /id="PRO_0000156657"
FT ACT_SITE 146
FT /note="Proton donor"
FT /evidence="ECO:0000305|PubMed:11278915"
FT ACT_SITE 204
FT /note="Proton acceptor"
FT /evidence="ECO:0000305|PubMed:9325256"
FT BINDING 13
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P17256"
FT BINDING 55
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P17256"
FT BINDING 135
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P17256"
FT BINDING 140..146
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000250|UniProtKB:P17256"
FT BINDING 146
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P17256"
FT BINDING 193
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000250|UniProtKB:P17256"
FT VARIANT 12
FT /note="G -> R (in POROK3)"
FT /evidence="ECO:0000269|PubMed:22983302"
FT /id="VAR_075036"
FT VARIANT 20
FT /note="H -> N (in HIDS; dbSNP:rs11544299)"
FT /evidence="ECO:0000269|PubMed:11313769"
FT /id="VAR_010956"
FT VARIANT 20
FT /note="H -> P (in HIDS and MEVA; dbSNP:rs104895295)"
FT /evidence="ECO:0000269|PubMed:10369261,
FT ECO:0000269|PubMed:11313768, ECO:0000269|PubMed:11313769"
FT /id="VAR_004022"
FT VARIANT 20
FT /note="H -> Q (in HIDS; dbSNP:rs104895335)"
FT /evidence="ECO:0000269|PubMed:15536479"
FT /id="VAR_029519"
FT VARIANT 39
FT /note="L -> P (in HIDS; dbSNP:rs104895296)"
FT /evidence="ECO:0000269|PubMed:11313768,
FT ECO:0000269|PubMed:11313769"
FT /id="VAR_010957"
FT VARIANT 41
FT /note="L -> P (in POROK3; dbSNP:rs397514571)"
FT /evidence="ECO:0000269|PubMed:22983302"
FT /id="VAR_075037"
FT VARIANT 52
FT /note="S -> N (in dbSNP:rs7957619)"
FT /evidence="ECO:0000269|PubMed:11313769,
FT ECO:0000269|PubMed:15536479"
FT /id="VAR_010958"
FT VARIANT 132
FT /note="V -> I (in HIDS; dbSNP:rs104895336)"
FT /evidence="ECO:0000269|PubMed:15536479"
FT /id="VAR_029520"
FT VARIANT 135
FT /note="S -> L (in HIDS; dbSNP:rs104895297)"
FT /evidence="ECO:0000269|PubMed:11313768"
FT /id="VAR_010959"
FT VARIANT 148
FT /note="A -> T (in HIDS; dbSNP:rs104895298)"
FT /evidence="ECO:0000269|PubMed:11313768,
FT ECO:0000269|PubMed:15536479"
FT /id="VAR_010960"
FT VARIANT 150
FT /note="S -> L (in HIDS; dbSNP:rs747116992)"
FT /evidence="ECO:0000269|PubMed:11313769"
FT /id="VAR_010961"
FT VARIANT 167
FT /note="P -> L (in HIDS; dbSNP:rs104895300)"
FT /evidence="ECO:0000269|PubMed:10369262,
FT ECO:0000269|PubMed:11313769"
FT /id="VAR_004023"
FT VARIANT 171
FT /note="G -> R (in HIDS; dbSNP:rs104895337)"
FT /evidence="ECO:0000269|PubMed:15536479"
FT /id="VAR_029521"
FT VARIANT 202
FT /note="G -> R (in HIDS and POROK3; dbSNP:rs104895301)"
FT /evidence="ECO:0000269|PubMed:11313769,
FT ECO:0000269|PubMed:22983302"
FT /id="VAR_010962"
FT VARIANT 211
FT /note="G -> E (in HIDS; dbSNP:rs104895325)"
FT /evidence="ECO:0000269|PubMed:15536479"
FT /id="VAR_029522"
FT VARIANT 215
FT /note="R -> Q (in HIDS; dbSNP:rs104895303)"
FT /evidence="ECO:0000269|PubMed:11313769,
FT ECO:0000269|PubMed:15536479"
FT /id="VAR_010963"
FT VARIANT 243
FT /note="T -> I (in MEVA; dbSNP:rs104895314)"
FT /evidence="ECO:0000269|PubMed:10417275"
FT /id="VAR_010964"
FT VARIANT 250
FT /note="V -> I (in HIDS; dbSNP:rs104895339)"
FT /evidence="ECO:0000269|PubMed:15536479"
FT /id="VAR_029523"
FT VARIANT 255
FT /note="L -> P (in POROK3; dbSNP:rs397514570)"
FT /evidence="ECO:0000269|PubMed:22983302"
FT /id="VAR_075038"
FT VARIANT 264
FT /note="L -> F (in MEVA; dbSNP:rs104895315)"
FT /evidence="ECO:0000269|PubMed:10417275,
FT ECO:0000269|PubMed:11313768"
FT /id="VAR_010965"
FT VARIANT 265
FT /note="L -> P (in MEVA; dbSNP:rs104895316)"
FT /evidence="ECO:0000269|PubMed:10417275"
FT /id="VAR_010966"
FT VARIANT 265
FT /note="L -> R (in HIDS; dbSNP:rs104895316)"
FT /evidence="ECO:0000269|PubMed:15536479"
FT /id="VAR_029524"
FT VARIANT 268
FT /note="I -> T (in HIDS and MEVA; dbSNP:rs104895304)"
FT /evidence="ECO:0000269|PubMed:10369261,
FT ECO:0000269|PubMed:10369262, ECO:0000269|PubMed:10417275,
FT ECO:0000269|PubMed:11313768, ECO:0000269|PubMed:11313769,
FT ECO:0000269|PubMed:15536479"
FT /id="VAR_004024"
FT VARIANT 279
FT /note="L -> P (in POROK3)"
FT /evidence="ECO:0000269|PubMed:22983302"
FT /id="VAR_075039"
FT VARIANT 291
FT /note="Y -> D (in POROK3)"
FT /evidence="ECO:0000269|PubMed:22983302"
FT /id="VAR_075040"
FT VARIANT 301
FT /note="N -> T (in MEVA; diminished activity;
FT dbSNP:rs121917789)"
FT /evidence="ECO:0000269|PubMed:1377680"
FT /id="VAR_004025"
FT VARIANT 309
FT /note="G -> S (in HIDS; dbSNP:rs104895305)"
FT /evidence="ECO:0000269|PubMed:11313769"
FT /id="VAR_010967"
FT VARIANT 310
FT /note="V -> M (in MEVA and HIDS; dbSNP:rs104895319)"
FT /evidence="ECO:0000269|PubMed:10401001,
FT ECO:0000269|PubMed:11313768, ECO:0000269|PubMed:15536479"
FT /id="VAR_009068"
FT VARIANT 312
FT /note="H -> R (in POROK3)"
FT /evidence="ECO:0000269|PubMed:22983302"
FT /id="VAR_075041"
FT VARIANT 326
FT /note="G -> R (in HIDS; dbSNP:rs104895308)"
FT /evidence="ECO:0000269|PubMed:11313769"
FT /id="VAR_010968"
FT VARIANT 334
FT /note="A -> T (in MEVA; dbSNP:rs104895317)"
FT /evidence="ECO:0000269|PubMed:10401001,
FT ECO:0000269|PubMed:11313768, ECO:0000269|PubMed:11313769"
FT /id="VAR_004026"
FT VARIANT 335
FT /note="G -> S (in dbSNP:rs11614976)"
FT /id="VAR_029525"
FT VARIANT 356
FT /note="T -> M (in dbSNP:rs104895342)"
FT /evidence="ECO:0000269|PubMed:15536479"
FT /id="VAR_029526"
FT VARIANT 365
FT /note="F -> S (in POROK3; dbSNP:rs398122911)"
FT /evidence="ECO:0000269|PubMed:22983302"
FT /id="VAR_075042"
FT VARIANT 376
FT /note="G -> S (in POROK3; dbSNP:rs971159663)"
FT /evidence="ECO:0000269|PubMed:22983302"
FT /id="VAR_075043"
FT VARIANT 376
FT /note="G -> V (in HIDS; dbSNP:rs104895340)"
FT /evidence="ECO:0000269|PubMed:15536479"
FT /id="VAR_029527"
FT VARIANT 377
FT /note="V -> I (in HIDS; most frequent mutation;
FT dbSNP:rs28934897)"
FT /evidence="ECO:0000269|PubMed:10369261,
FT ECO:0000269|PubMed:10369262, ECO:0000269|PubMed:11313768,
FT ECO:0000269|PubMed:11313769, ECO:0000269|PubMed:15536479"
FT /id="VAR_004027"
FT MUTAGEN 19
FT /note="E->D: No change in protein stability. Weak decrease
FT in kinase activity. Approximately 2-fold decrease in Vmax.
FT Approximately 2-fold decrease affinity for ATP and
FT mevalonate."
FT /evidence="ECO:0000269|PubMed:9325256"
FT MUTAGEN 56
FT /note="I->A: No effect on kinase activity. Approximately
FT 4- and 5-fold decrease affinities for ATP and mevalonate,
FT respectively."
FT /evidence="ECO:0000269|PubMed:18302342"
FT MUTAGEN 104
FT /note="T->A: No effect on kinase activity. Approximately 4-
FT fold increase affinity for ATP. Normal affinity for
FT mevalonate."
FT /evidence="ECO:0000269|PubMed:18302342"
FT MUTAGEN 145
FT /note="S->A: Modest changes in KM for ATP. 20-fold increase
FT in KM for mevalonate. Approximately 2-fold decrease in
FT Vmax."
FT /evidence="ECO:0000269|PubMed:11278915"
FT MUTAGEN 146
FT /note="S->A: Modest changes in KM for ATP. 20-fold increase
FT in KM for mevalonate. 4000-fold decrease in Vmax."
FT /evidence="ECO:0000269|PubMed:11278915"
FT MUTAGEN 149
FT /note="Y->A: No effect on kinase activity. Approximately
FT 4- and 8-fold decrease affinities for ATP and mevalonate,
FT respectively."
FT /evidence="ECO:0000269|PubMed:18302342"
FT MUTAGEN 193
FT /note="E->Q: No change in protein stability. Decreased
FT kinase activity. Approximately 50-fold decrease in Vmax.
FT Approximately 20- and 40-fold decrease affinities for ATP
FT and mevalonate, respectively."
FT /evidence="ECO:0000269|PubMed:9325256"
FT MUTAGEN 196
FT /note="I->A: No effect on kinase activity. Approximately
FT 2- and 3-fold decrease affinities for ATP and mevalonate,
FT respectively."
FT /evidence="ECO:0000269|PubMed:18302342"
FT MUTAGEN 201
FT /note="S->A: Modest changes in KM for ATP. 100-fold
FT increase in KM for mevalonate. Approximately 2-fold
FT increase in Vmax."
FT /evidence="ECO:0000269|PubMed:11278915"
FT MUTAGEN 204
FT /note="D->A: No change in protein stability. Loss of kinase
FT activity. Normal affinities for ATP and mevalonate."
FT /evidence="ECO:0000269|PubMed:9325256"
FT MUTAGEN 204
FT /note="D->N: No change in protein stability. Loss of kinase
FT activity. Normal affinities for ATP and mevalonate."
FT /evidence="ECO:0000269|PubMed:9325256"
FT MUTAGEN 243
FT /note="T->A: Modest changes in KM for ATP. 40-fold increase
FT in KM for mevalonate. Approximately 2-fold decrease in
FT Vmax."
FT /evidence="ECO:0000269|PubMed:11278915"
FT MUTAGEN 296
FT /note="E->Q: No change in protein stability. No effect on
FT kinase activity."
FT /evidence="ECO:0000269|PubMed:9325256"
FT STRAND 4..17
FT /evidence="ECO:0007829|PDB:2R3V"
FT TURN 19..21
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 22..24
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 28..43
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 45..52
FT /evidence="ECO:0007829|PDB:2R3V"
FT TURN 54..56
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 59..63
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 64..69
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 85..95
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 103..119
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 122..125
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 129..137
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 141..143
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 145..160
FT /evidence="ECO:0007829|PDB:2R3V"
FT TURN 167..171
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 173..175
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 179..196
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 197..199
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 203..210
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 212..216
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 221..223
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 230..236
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 243..256
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 258..283
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 288..307
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 313..323
FT /evidence="ECO:0007829|PDB:2R3V"
FT TURN 324..326
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 328..331
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 336..343
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 350..361
FT /evidence="ECO:0007829|PDB:2R3V"
FT TURN 362..364
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 366..373
FT /evidence="ECO:0007829|PDB:2R3V"
FT STRAND 377..380
FT /evidence="ECO:0007829|PDB:2R3V"
FT HELIX 387..392
FT /evidence="ECO:0007829|PDB:2R3V"
SQ SEQUENCE 396 AA; 42451 MW; C8F6B629B58CD229 CRC64;
MLSEVLLVSA PGKVILHGEH AVVHGKVALA VSLNLRTFLR LQPHSNGKVD LSLPNIGIKR
AWDVARLQSL DTSFLEQGDV TTPTSEQVEK LKEVAGLPDD CAVTERLAVL AFLYLYLSIC
RKQRALPSLD IVVWSELPPG AGLGSSAAYS VCLAAALLTV CEEIPNPLKD GDCVNRWTKE
DLELINKWAF QGERMIHGNP SGVDNAVSTW GGALRYHQGK ISSLKRSPAL QILLTNTKVP
RNTRALVAGV RNRLLKFPEI VAPLLTSIDA ISLECERVLG EMGEAPAPEQ YLVLEELIDM
NQHHLNALGV GHASLDQLCQ VTRARGLHSK LTGAGGGGCG ITLLKPGLEQ PEVEATKQAL
TSCGFDCLET SIGAPGVSIH SATSLDSRVQ QALDGL
