ID KIME_RAT Reviewed; 395 AA.
AC P17256;
DT 01-AUG-1990, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1990, sequence version 1.
DT 24-JAN-2024, entry version 169.
DE RecName: Full=Mevalonate kinase {ECO:0000305};
DE Short=MK;
DE EC=2.7.1.36 {ECO:0000269|PubMed:14680942};
GN Name=Mvk {ECO:0000312|RGD:621295};
OS Rattus norvegicus (Rat).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Rattus.
OX NCBI_TaxID=10116;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], AND PROTEIN SEQUENCE OF 1-20.
RC STRAIN=Sprague-Dawley; TISSUE=Liver;
RX PubMed=2158094; DOI=10.1073/pnas.87.8.2872;
RA Tanaka R.D., Lee L.Y., Schafer B.L., Kratunis V.J., Mohler W.A.,
RA Robinson G.W., Mosley S.T.;
RT "Molecular cloning of mevalonate kinase and regulation of its mRNA levels
RT in rat liver.";
RL Proc. Natl. Acad. Sci. U.S.A. 87:2872-2876(1990).
RN [2]
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 [3]
RP SUBCELLULAR LOCATION.
RX PubMed=1312092; DOI=10.1016/s0021-9258(18)42802-5;
RA Stamellos K.D., Shackelford J.E., Tanaka R.D., Krisans S.K.;
RT "Mevalonate kinase is localized in rat liver peroxisomes.";
RL J. Biol. Chem. 267:5560-5568(1992).
RN [4]
RP CATALYTIC ACTIVITY, FUNCTION, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP MUTAGENESIS OF HIS-20.
RX PubMed=14680942; DOI=10.1016/s1046-5928(03)00221-3;
RA Chu X., Li D.;
RT "Expression, purification, and characterization of His20 mutants of rat
RT mevalonate kinase.";
RL Protein Expr. Purif. 32:75-82(2003).
RN [5] {ECO:0007744|PDB:1KVK}
RP X-RAY CRYSTALLOGRAPHY (2.4 ANGSTROMS) IN COMPLEX WITH ATP AND MAGNESIUM,
RP SUBUNIT, AND COFACTOR.
RX PubMed=11877411; DOI=10.1074/jbc.m200912200;
RA Fu Z., Wang M., Potter D., Miziorko H.M., Kim J.-J.;
RT "The structure of a binary complex between a mammalian mevalonate kinase
RT and ATP: insights into the reaction mechanism and human inherited
RT disease.";
RL J. Biol. Chem. 277:18134-18142(2002).
RN [6] {ECO:0007744|PDB:2R42}
RP X-RAY CRYSTALLOGRAPHY (2.40 ANGSTROMS) IN COMPLEX WITH THE INHIBITOR
RP FARNESYL DIPHOSPHATE ANALOG.
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).
CC -!- FUNCTION: Catalyzes the phosphorylation of mevalonate to mevalonate 5-
CC phosphate, a key step in isoprenoid and cholesterol biosynthesis.
CC {ECO:0000250|UniProtKB:Q03426}.
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:14680942};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:11877411};
CC -!- ACTIVITY REGULATION: Farnesyl pyrophosphate and geranyl pyrophosphate
CC inhibit mevalonate kinase activity by binding competitively at the ATP-
CC binding sites. {ECO:0000250|UniProtKB:Q03426}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=34.6 uM for (R,S)-mevalonate {ECO:0000269|PubMed:14680942};
CC KM=953 uM for ATP {ECO:0000269|PubMed:14680942};
CC Vmax=38.7 umol/min/mg enzyme with (R,S)-mevalonate as substrate
CC {ECO:0000269|PubMed:14680942};
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:11877411}.
CC -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:14730012}.
CC Peroxisome {ECO:0000269|PubMed:1312092}.
CC -!- MISCELLANEOUS: The authors of PubMed:14730012 identify two forms of Mvk
CC in rat liver, one form localizes to the cytosol and the other form to
CC the peroxisome, whereas according to the authors of PubMed:14730012 the
CC protein is found only in the cytoplasm with no evidence for its
CC peroxisomal localization.
CC -!- SIMILARITY: Belongs to the GHMP kinase family. Mevalonate kinase
CC subfamily. {ECO:0000305}.
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DR EMBL; M29472; AAA41588.1; -; mRNA.
DR PIR; A35629; A35629.
DR RefSeq; NP_112325.1; NM_031063.1.
DR PDB; 1KVK; X-ray; 2.40 A; A=1-395.
DR PDB; 2R42; X-ray; 2.40 A; A=1-395.
DR PDBsum; 1KVK; -.
DR PDBsum; 2R42; -.
DR AlphaFoldDB; P17256; -.
DR SMR; P17256; -.
DR BioGRID; 249600; 5.
DR STRING; 10116.ENSRNOP00000064795; -.
DR ChEMBL; CHEMBL4274; -.
DR GuidetoPHARMACOLOGY; 640; -.
DR MoonProt; P17256; -.
DR iPTMnet; P17256; -.
DR PhosphoSitePlus; P17256; -.
DR PaxDb; 10116-ENSRNOP00000064795; -.
DR GeneID; 81727; -.
DR KEGG; rno:81727; -.
DR AGR; RGD:621295; -.
DR CTD; 4598; -.
DR RGD; 621295; Mvk.
DR eggNOG; KOG1511; Eukaryota.
DR InParanoid; P17256; -.
DR OrthoDB; 5472812at2759; -.
DR PhylomeDB; P17256; -.
DR BRENDA; 2.7.1.36; 5301.
DR Reactome; R-RNO-191273; Cholesterol biosynthesis.
DR SABIO-RK; P17256; -.
DR UniPathway; UPA00057; UER00098.
DR EvolutionaryTrace; P17256; -.
DR PRO; PR:P17256; -.
DR Proteomes; UP000002494; Unplaced.
DR GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR GO; GO:0005829; C:cytosol; IBA:GO_Central.
DR GO; GO:0005777; C:peroxisome; IDA:UniProtKB.
DR GO; GO:0005524; F:ATP binding; IDA:RGD.
DR GO; GO:0042802; F:identical protein binding; IDA:UniProtKB.
DR GO; GO:0000287; F:magnesium ion binding; IDA:UniProtKB.
DR GO; GO:0004496; F:mevalonate kinase activity; IDA:RGD.
DR GO; GO:0003729; F:mRNA binding; IDA:RGD.
DR GO; GO:1990825; F:sequence-specific mRNA binding; IDA:CAFA.
DR GO; GO:0006695; P:cholesterol biosynthetic process; ISO:RGD.
DR GO; GO:0019287; P:isopentenyl diphosphate biosynthetic process, mevalonate pathway; IDA:RGD.
DR GO; GO:0008299; P:isoprenoid biosynthetic process; IDA:RGD.
DR GO; GO:0006720; P:isoprenoid metabolic process; TAS:RGD.
DR GO; GO:0050728; P:negative regulation of inflammatory response; ISO:RGD.
DR GO; GO:0017148; P:negative regulation of translation; IDA:RGD.
DR GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR GO; GO:0045540; P:regulation of cholesterol biosynthetic process; NAS:RGD.
DR GO; GO:0016125; P:sterol metabolic process; TAS:RGD.
DR Gene3D; 3.30.230.10; -; 1.
DR Gene3D; 3.30.70.890; GHMP kinase, C-terminal domain; 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_Su5_D2-typ_SF.
DR InterPro; IPR014721; Ribsml_uS5_D2-typ_fold_subgr.
DR NCBIfam; TIGR00549; mevalon_kin; 1.
DR PANTHER; PTHR43290; MEVALONATE KINASE; 1.
DR PANTHER; PTHR43290:SF2; MEVALONATE KINASE; 1.
DR Pfam; PF08544; GHMP_kinases_C; 1.
DR Pfam; PF00288; GHMP_kinases_N; 1.
DR PRINTS; PR00959; MEVGALKINASE.
DR SUPFAM; SSF55060; GHMP Kinase, C-terminal domain; 1.
DR SUPFAM; SSF54211; Ribosomal protein S5 domain 2-like; 1.
DR PROSITE; PS00627; GHMP_KINASES_ATP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; ATP-binding; Cholesterol biosynthesis;
KW Cholesterol metabolism; Cytoplasm; Direct protein sequencing; 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..395
FT /note="Mevalonate kinase"
FT /id="PRO_0000156659"
FT ACT_SITE 146
FT /note="Proton donor"
FT /evidence="ECO:0000250|UniProtKB:Q03426"
FT ACT_SITE 204
FT /note="Proton acceptor"
FT /evidence="ECO:0000250|UniProtKB:Q03426"
FT BINDING 13
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:11877411,
FT ECO:0007744|PDB:1KVK"
FT BINDING 55
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:11877411,
FT ECO:0007744|PDB:1KVK"
FT BINDING 104
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:11877411,
FT ECO:0007744|PDB:1KVK"
FT BINDING 108
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:11877411,
FT ECO:0007744|PDB:1KVK"
FT BINDING 135
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:11877411,
FT ECO:0007744|PDB:1KVK"
FT BINDING 140..146
FT /ligand="ATP"
FT /ligand_id="ChEBI:CHEBI:30616"
FT /evidence="ECO:0000269|PubMed:11877411,
FT ECO:0007744|PDB:1KVK, ECO:0007744|PDB:2R42"
FT BINDING 146
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:11877411,
FT ECO:0007744|PDB:1KVK"
FT BINDING 193
FT /ligand="Mg(2+)"
FT /ligand_id="ChEBI:CHEBI:18420"
FT /evidence="ECO:0000269|PubMed:11877411,
FT ECO:0007744|PDB:1KVK"
FT MUTAGEN 20
FT /note="H->K: Induce significant secondary structural
FT change."
FT /evidence="ECO:0000269|PubMed:14680942"
FT MUTAGEN 20
FT /note="H->L,Y: Approximately 5-fold decrease in Vmax for
FT (R,S)-mevalonate. Approximately 3-fold increase in KM for
FT (R,S)-mevalonate."
FT /evidence="ECO:0000269|PubMed:14680942"
FT STRAND 6..17
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 21..24
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 28..43
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 45..53
FT /evidence="ECO:0007829|PDB:1KVK"
FT TURN 54..57
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 58..63
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 64..68
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 90..95
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 106..120
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 123..125
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 129..137
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 141..143
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 145..160
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 167..170
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 173..175
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 179..197
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 203..210
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 212..219
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 221..223
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 230..236
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 243..256
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 258..282
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 288..308
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 313..324
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 328..331
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 336..344
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 350..362
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 366..373
FT /evidence="ECO:0007829|PDB:1KVK"
FT STRAND 377..380
FT /evidence="ECO:0007829|PDB:1KVK"
FT TURN 382..384
FT /evidence="ECO:0007829|PDB:1KVK"
FT HELIX 387..393
FT /evidence="ECO:0007829|PDB:1KVK"
SQ SEQUENCE 395 AA; 41988 MW; 803D1F44E3C525FC CRC64;
MLSEVLLVSA PGKVILHGEH AVVHGKVALA VALNLRTFLV LRPQSNGKVS LNLPNVGIKQ
VWDVATLQLL DTGFLEQGDV PAPTLEQLEK LKKVAGLPRD CVGNEGLSLL AFLYLYLAIC
RKQRTLPSLD IMVWSELPPG AGLGSSAAYS VCVAAALLTA CEEVTNPLKD RGSIGSWPEE
DLKSINKWAY EGERVIHGNP SGVDNSVSTW GGALRYQQGK MSSLKRLPAL QILLTNTKVP
RSTKALVAGV RSRLIKFPEI MAPLLTSIDA ISLECERVLG EMAAAPVPEQ YLVLEELMDM
NQHHLNALGV GHASLDQLCQ VTAAHGLHSK LTGAGGGGCG ITLLKPGLER AKVEAAKQAL
TGCGFDCWET SIGAPGVSMH SATSIEDPVR QALGL
//
