ID   ERG12_YEAST             Reviewed;         443 AA.
AC   P07277; D6W033;
DT   01-APR-1988, integrated into UniProtKB/Swiss-Prot.
DT   01-APR-1988, sequence version 1.
DT   24-JAN-2024, entry version 196.
DE   RecName: Full=Mevalonate kinase {ECO:0000303|PubMed:1645230};
DE            Short=MK {ECO:0000303|PubMed:1645230};
DE            Short=MvK {ECO:0000303|PubMed:1645230};
DE            EC=2.7.1.36 {ECO:0000269|PubMed:1645230};
DE   AltName: Full=Ergosterol biosynthesis protein 12 {ECO:0000303|PubMed:1645230};
DE   AltName: Full=Regulation of autonomous replication protein 1 {ECO:0000303|PubMed:3323847};
GN   Name=ERG12 {ECO:0000303|PubMed:1645230};
GN   Synonyms=RAR1 {ECO:0000303|PubMed:3323847}; OrderedLocusNames=YMR208W;
GN   ORFNames=YM8261.02;
OS   Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC   Saccharomycetales; Saccharomycetaceae; Saccharomyces.
OX   NCBI_TaxID=559292;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=3323847; DOI=10.1007/bf00327205;
RA   Kearsey S.E., Edwards J.;
RT   "Mutations that increase the mitotic stability of minichromosomes in yeast:
RT   characterization of RAR1.";
RL   Mol. Gen. Genet. 210:509-517(1987).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY,
RP   BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, AND PATHWAY.
RX   PubMed=1645230; DOI=10.1007/bf00362081;
RA   Oulmouden A., Karst F.;
RT   "Nucleotide sequence of the ERG12 gene of Saccharomyces cerevisiae encoding
RT   mevalonate kinase.";
RL   Curr. Genet. 19:9-14(1991).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=9169872;
RA   Bowman S., Churcher C.M., Badcock K., Brown D., Chillingworth T.,
RA   Connor R., Dedman K., Devlin K., Gentles S., Hamlin N., Hunt S., Jagels K.,
RA   Lye G., Moule S., Odell C., Pearson D., Rajandream M.A., Rice P.,
RA   Skelton J., Walsh S.V., Whitehead S., Barrell B.G.;
RT   "The nucleotide sequence of Saccharomyces cerevisiae chromosome XIII.";
RL   Nature 387:90-93(1997).
RN   [4]
RP   GENOME REANNOTATION.
RC   STRAIN=ATCC 204508 / S288c;
RX   PubMed=24374639; DOI=10.1534/g3.113.008995;
RA   Engel S.R., Dietrich F.S., Fisk D.G., Binkley G., Balakrishnan R.,
RA   Costanzo M.C., Dwight S.S., Hitz B.C., Karra K., Nash R.S., Weng S.,
RA   Wong E.D., Lloyd P., Skrzypek M.S., Miyasato S.R., Simison M., Cherry J.M.;
RT   "The reference genome sequence of Saccharomyces cerevisiae: Then and now.";
RL   G3 (Bethesda) 4:389-398(2014).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-246.
RC   STRAIN=SP1;
RA   Saito A., Kazuta Y., Kondo H., Tanabe T.;
RL   Submitted (OCT-1995) to the EMBL/GenBank/DDBJ databases.
RN   [6]
RP   LEVEL OF PROTEIN EXPRESSION [LARGE SCALE ANALYSIS].
RX   PubMed=14562106; DOI=10.1038/nature02046;
RA   Ghaemmaghami S., Huh W.-K., Bower K., Howson R.W., Belle A., Dephoure N.,
RA   O'Shea E.K., Weissman J.S.;
RT   "Global analysis of protein expression in yeast.";
RL   Nature 425:737-741(2003).
RN   [7]
RP   REVIEW ON ERGOSTEROL BIOSYNTHESIS.
RX   PubMed=32679672; DOI=10.3390/genes11070795;
RA   Jorda T., Puig S.;
RT   "Regulation of ergosterol biosynthesis in Saccharomyces cerevisiae.";
RL   Genes (Basel) 11:0-0(2020).
CC   -!- FUNCTION: Mevalonate kinase; part of the second module of ergosterol
CC       biosynthesis pathway that includes the middle steps of the pathway
CC       (PubMed:1645230). ERG12 converts mevalonate into 5-phosphomevalonate
CC       (PubMed:1645230). The second module is carried out in the vacuole and
CC       involves the formation of farnesyl diphosphate, which is also an
CC       important intermediate in the biosynthesis of ubiquinone, dolichol,
CC       heme and prenylated proteins. Activity by the mevalonate kinase ERG12
CC       first converts mevalonate into 5-phosphomevalonate. 5-phosphomevalonate
CC       is then further converted to 5-diphosphomevalonate by the
CC       phosphomevalonate kinase ERG8. The diphosphomevalonate decarboxylase
CC       MVD1/ERG19 then produces isopentenyl diphosphate. The isopentenyl-
CC       diphosphate delta-isomerase IDI1 then catalyzes the 1,3-allylic
CC       rearrangement of the homoallylic substrate isopentenyl (IPP) to its
CC       highly electrophilic allylic isomer, dimethylallyl diphosphate (DMAPP).
CC       Finally the farnesyl diphosphate synthase ERG20 catalyzes the
CC       sequential condensation of isopentenyl pyrophosphate with dimethylallyl
CC       pyrophosphate, and then with the resultant geranylpyrophosphate to the
CC       ultimate product farnesyl pyrophosphate (PubMed:32679672).
CC       {ECO:0000269|PubMed:1645230, ECO:0000303|PubMed:32679672}.
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:1645230};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:17066;
CC         Evidence={ECO:0000269|PubMed:1645230};
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 by binding competitively at the ATP-binding
CC       site. {ECO:0000269|PubMed:1645230}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=0.13 mM for mevalonate {ECO:0000269|PubMed:1645230};
CC         Vmax=27 nmol/min/mg enzyme {ECO:0000269|PubMed:1645230};
CC   -!- PATHWAY: Isoprenoid biosynthesis; isopentenyl diphosphate biosynthesis
CC       via mevalonate pathway; isopentenyl diphosphate from (R)-mevalonate:
CC       step 1/3. {ECO:0000269|PubMed:1645230}.
CC   -!- SUBUNIT: Homodimer. {ECO:0000250|UniProtKB:P17256}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000305|PubMed:1645230}.
CC   -!- MISCELLANEOUS: Present with 3300 molecules/cell in log phase SD medium.
CC       {ECO:0000269|PubMed:14562106}.
CC   -!- SIMILARITY: Belongs to the GHMP kinase family. Mevalonate kinase
CC       subfamily. {ECO:0000305}.
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DR   EMBL; X06114; CAA29487.1; -; Genomic_DNA.
DR   EMBL; X55875; CAA39359.1; -; Genomic_DNA.
DR   EMBL; Z49809; CAA89923.1; -; Genomic_DNA.
DR   EMBL; D78165; BAA24409.1; -; Genomic_DNA.
DR   EMBL; BK006946; DAA10107.1; -; Genomic_DNA.
DR   PIR; S05875; BVBYR1.
DR   RefSeq; NP_013935.1; NM_001182715.1.
DR   AlphaFoldDB; P07277; -.
DR   SMR; P07277; -.
DR   BioGRID; 35386; 99.
DR   IntAct; P07277; 3.
DR   STRING; 4932.YMR208W; -.
DR   iPTMnet; P07277; -.
DR   MaxQB; P07277; -.
DR   PaxDb; 4932-YMR208W; -.
DR   PeptideAtlas; P07277; -.
DR   EnsemblFungi; YMR208W_mRNA; YMR208W; YMR208W.
DR   GeneID; 855248; -.
DR   KEGG; sce:YMR208W; -.
DR   AGR; SGD:S000004821; -.
DR   SGD; S000004821; ERG12.
DR   VEuPathDB; FungiDB:YMR208W; -.
DR   eggNOG; KOG1511; Eukaryota.
DR   GeneTree; ENSGT00950000183187; -.
DR   HOGENOM; CLU_017814_0_1_1; -.
DR   InParanoid; P07277; -.
DR   OMA; VIIFGEH; -.
DR   OrthoDB; 5472812at2759; -.
DR   BioCyc; MetaCyc:YMR208W-MONOMER; -.
DR   BioCyc; YEAST:YMR208W-MONOMER; -.
DR   Reactome; R-SCE-191273; Cholesterol biosynthesis.
DR   UniPathway; UPA00057; UER00098.
DR   BioGRID-ORCS; 855248; 6 hits in 10 CRISPR screens.
DR   ChiTaRS; ERG12; yeast.
DR   PRO; PR:P07277; -.
DR   Proteomes; UP000002311; Chromosome XIII.
DR   RNAct; P07277; Protein.
DR   GO; GO:0005737; C:cytoplasm; HDA:SGD.
DR   GO; GO:0005829; C:cytosol; HDA:SGD.
DR   GO; GO:0005634; C:nucleus; HDA:SGD.
DR   GO; GO:0005524; F:ATP binding; ISS:UniProtKB.
DR   GO; GO:0000287; F:magnesium ion binding; ISS:UniProtKB.
DR   GO; GO:0004496; F:mevalonate kinase activity; IDA:SGD.
DR   GO; GO:0006696; P:ergosterol biosynthetic process; IDA:UniProt.
DR   GO; GO:0010142; P:farnesyl diphosphate biosynthetic process, mevalonate pathway; IMP:SGD.
DR   GO; GO:0019287; P:isopentenyl diphosphate biosynthetic process, mevalonate pathway; IMP:SGD.
DR   GO; GO:0016310; P:phosphorylation; IEA:UniProtKB-KW.
DR   Gene3D; 3.30.230.10; -; 1.
DR   Gene3D; 3.30.70.890; GHMP kinase, C-terminal domain; 1.
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; 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   ATP-binding; Cytoplasm; Kinase; Lipid biosynthesis; Lipid metabolism;
KW   Magnesium; Metal-binding; Nucleotide-binding; Reference proteome;
KW   Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW   Sterol metabolism; Transferase.
FT   CHAIN           1..443
FT                   /note="Mevalonate kinase"
FT                   /id="PRO_0000156662"
FT   ACT_SITE        202
FT                   /note="Proton acceptor"
FT                   /evidence="ECO:0000250|UniProtKB:Q03426"
FT   BINDING         12
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:P17256"
FT   BINDING         138
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:P17256"
FT   BINDING         143..149
FT                   /ligand="ATP"
FT                   /ligand_id="ChEBI:CHEBI:30616"
FT                   /evidence="ECO:0000250|UniProtKB:P17256"
FT   BINDING         149
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000250|UniProtKB:P17256"
FT   BINDING         191
FT                   /ligand="Mg(2+)"
FT                   /ligand_id="ChEBI:CHEBI:18420"
FT                   /evidence="ECO:0000250|UniProtKB:P17256"
SQ   SEQUENCE   443 AA;  48460 MW;  8B24052A72C97280 CRC64;
     MSLPFLTSAP GKVIIFGEHS AVYNKPAVAA SVSALRTYLL ISESSAPDTI ELDFPDISFN
     HKWSINDFNA ITEDQVNSQK LAKAQQATDG LSQELVSLLD PLLAQLSESF HYHAAFCFLY
     MFVCLCPHAK NIKFSLKSTL PIGAGLGSSA SISVSLALAM AYLGGLIGSN DLEKLSENDK
     HIVNQWAFIG EKCIHGTPSG IDNAVATYGN ALLFEKDSHN GTINTNNFKF LDDFPAIPMI
     LTYTRIPRST KDLVARVRVL VTEKFPEVMK PILDAMGECA LQGLEIMTKL SKCKGTDDEA
     VETNNELYEQ LLELIRINHG LLVSIGVSHP GLELIKNLSD DLRIGSTKLT GAGGGGCSLT
     LLRRDITQEQ IDSFKKKLQD DFSYETFETD LGGTGCCLLS AKNLNKDLKI KSLVFQLFEN
     KTTTKQQIDD LLLPGNTNLP WTS
//