HMDH1_YEAST
ID HMDH1_YEAST Reviewed; 1054 AA.
AC P12683; D6W0K8;
DT 01-OCT-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1989, sequence version 1.
DT 03-AUG-2022, entry version 214.
DE RecName: Full=3-hydroxy-3-methylglutaryl-coenzyme A reductase 1 {ECO:0000303|PubMed:3526336};
DE Short=HMG-CoA reductase 1 {ECO:0000303|PubMed:3526336};
DE EC=1.1.1.34 {ECO:0000269|PubMed:3526336};
GN Name=HMG1 {ECO:0000303|PubMed:3526336}; OrderedLocusNames=YML075C;
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], FUNCTION, DISRUPTION PHENOTYPE, AND
RP PATHWAY.
RX PubMed=3065625; DOI=10.1128/mcb.8.9.3797-3808.1988;
RA Basson M.E., Thorsness M., Finer-Moore J., Stroud R.M., Rine J.;
RT "Structural and functional conservation between yeast and human 3-hydroxy-
RT 3-methylglutaryl coenzyme A reductases, the rate-limiting enzyme of sterol
RT biosynthesis.";
RL Mol. Cell. Biol. 8:3797-3808(1988).
RN [2]
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 [3]
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 [4]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 776-965, FUNCTION, CATALYTIC ACTIVITY,
RP DISRUPTION PHENOTYPE, AND PATHWAY.
RX PubMed=3526336; DOI=10.1073/pnas.83.15.5563;
RA Basson M.E., Thorsness M., Rine J.;
RT "Saccharomyces cerevisiae contains two functional genes encoding 3-hydroxy-
RT 3-methylglutaryl-coenzyme A reductase.";
RL Proc. Natl. Acad. Sci. U.S.A. 83:5563-5567(1986).
RN [5]
RP SUBCELLULAR LOCATION.
RX PubMed=8744950; DOI=10.1091/mbc.7.5.769;
RA Koning A.J., Roberts C.J., Wright R.L.;
RT "Different subcellular localization of Saccharomyces cerevisiae HMG-CoA
RT reductase isozymes at elevated levels corresponds to distinct endoplasmic
RT reticulum membrane proliferations.";
RL Mol. Biol. Cell 7:769-789(1996).
RN [6]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RX PubMed=14562095; DOI=10.1038/nature02026;
RA Huh W.-K., Falvo J.V., Gerke L.C., Carroll A.S., Howson R.W.,
RA Weissman J.S., O'Shea E.K.;
RT "Global analysis of protein localization in budding yeast.";
RL Nature 425:686-691(2003).
RN [7]
RP PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT THR-552, AND IDENTIFICATION BY
RP MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC STRAIN=ADR376;
RX PubMed=17330950; DOI=10.1021/pr060559j;
RA Li X., Gerber S.A., Rudner A.D., Beausoleil S.A., Haas W., Villen J.,
RA Elias J.E., Gygi S.P.;
RT "Large-scale phosphorylation analysis of alpha-factor-arrested
RT Saccharomyces cerevisiae.";
RL J. Proteome Res. 6:1190-1197(2007).
RN [8]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=19779198; DOI=10.1126/science.1172867;
RA Holt L.J., Tuch B.B., Villen J., Johnson A.D., Gygi S.P., Morgan D.O.;
RT "Global analysis of Cdk1 substrate phosphorylation sites provides insights
RT into evolution.";
RL Science 325:1682-1686(2009).
RN [9]
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: HMG-CoA reductase; part of the first module of ergosterol
CC biosynthesis pathway constitutes by the early steps of the pathway,
CC conserved across all eukaryotes, and which results in the formation of
CC mevalonate from acetyl-coenzyme A (acetyl-CoA) (PubMed:3065625,
CC PubMed:3526336). HMG1 and HMG2 catalyze the reduction of
CC hydroxymethylglutaryl-CoA (HMG-CoA) to mevalonate that is the rate-
CC limiting step within the first mosule (PubMed:3526336). The first
CC module starts with the action of the cytosolic acetyl-CoA
CC acetyltransferase ERG10 that catalyzes the formation of acetoacetyl-
CC CoA. The hydroxymethylglutaryl-CoA synthase ERG13 then condenses
CC acetyl-CoA with acetoacetyl-CoA to form HMG-CoA. The rate-limiting step
CC of the early module is the reduction to mevalonate by the 3-hydroxy-3-
CC methylglutaryl-coenzyme A (HMG-CoA) reductases HMG1 and HMG2 which are
CC derived from a single ancestral HMGR gene by gene duplication
CC (PubMed:32679672). {ECO:0000269|PubMed:3065625,
CC ECO:0000269|PubMed:3526336, ECO:0000303|PubMed:32679672}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=(R)-mevalonate + CoA + 2 NADP(+) = (3S)-hydroxy-3-
CC methylglutaryl-CoA + 2 H(+) + 2 NADPH; Xref=Rhea:RHEA:15989,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:36464, ChEBI:CHEBI:43074,
CC ChEBI:CHEBI:57287, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349; EC=1.1.1.34;
CC Evidence={ECO:0000255|PROSITE-ProRule:PRU10003,
CC ECO:0000269|PubMed:3526336};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:15991;
CC Evidence={ECO:0000269|PubMed:3526336};
CC -!- PATHWAY: Metabolic intermediate biosynthesis; (R)-mevalonate
CC biosynthesis; (R)-mevalonate from acetyl-CoA: step 3/3.
CC {ECO:0000269|PubMed:3526336}.
CC -!- INTERACTION:
CC P12683; P12684: HMG2; NbExp=5; IntAct=EBI-8377, EBI-8384;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:14562095, ECO:0000269|PubMed:8744950}; Multi-pass
CC membrane protein {ECO:0000255}. Nucleus envelope
CC {ECO:0000269|PubMed:14562095}.
CC -!- DOMAIN: The sterol-sensing domain (SSD) is required for sterol pathway
CC signals to stimulate hmg2 ER-associated degradation and detects both
CC geranylgeranyl pyrophosphate and a secondary oxysterol signal.
CC {ECO:0000250|UniProtKB:P12684}.
CC -!- DISRUPTION PHENOTYPE: When both HMG1 and HMG2 are deleted, cells are
CC unable to undergo spore germination and vegetative growth.
CC {ECO:0000269|PubMed:3065625, ECO:0000269|PubMed:3526336}.
CC -!- SIMILARITY: Belongs to the HMG-CoA reductase family. {ECO:0000305}.
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DR EMBL; M22002; AAA34676.1; -; Genomic_DNA.
DR EMBL; Z46373; CAA86503.1; -; Genomic_DNA.
DR EMBL; BK006946; DAA09822.1; -; Genomic_DNA.
DR PIR; A30239; A30239.
DR RefSeq; NP_013636.1; NM_001182434.1.
DR AlphaFoldDB; P12683; -.
DR SMR; P12683; -.
DR BioGRID; 35066; 203.
DR DIP; DIP-4529N; -.
DR IntAct; P12683; 31.
DR MINT; P12683; -.
DR STRING; 4932.YML075C; -.
DR iPTMnet; P12683; -.
DR MaxQB; P12683; -.
DR PaxDb; P12683; -.
DR PRIDE; P12683; -.
DR EnsemblFungi; YML075C_mRNA; YML075C; YML075C.
DR GeneID; 854900; -.
DR KEGG; sce:YML075C; -.
DR SGD; S000004540; HMG1.
DR VEuPathDB; FungiDB:YML075C; -.
DR eggNOG; KOG2480; Eukaryota.
DR GeneTree; ENSGT00940000155305; -.
DR HOGENOM; CLU_001734_0_0_1; -.
DR InParanoid; P12683; -.
DR OMA; ILFFDCV; -.
DR BioCyc; MetaCyc:YML075C-MON; -.
DR BioCyc; YEAST:YML075C-MON; -.
DR BRENDA; 1.1.1.34; 984.
DR Reactome; R-SCE-191273; Cholesterol biosynthesis.
DR UniPathway; UPA00058; UER00103.
DR PRO; PR:P12683; -.
DR Proteomes; UP000002311; Chromosome XIII.
DR RNAct; P12683; protein.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IDA:SGD.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005635; C:nuclear envelope; IDA:SGD.
DR GO; GO:0034399; C:nuclear periphery; HDA:SGD.
DR GO; GO:0005778; C:peroxisomal membrane; IBA:GO_Central.
DR GO; GO:0004420; F:hydroxymethylglutaryl-CoA reductase (NADPH) activity; IDA:SGD.
DR GO; GO:0015936; P:coenzyme A metabolic process; IEA:InterPro.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IMP:SGD.
DR GO; GO:0019287; P:isopentenyl diphosphate biosynthetic process, mevalonate pathway; IC:SGD.
DR GO; GO:0008299; P:isoprenoid biosynthetic process; IBA:GO_Central.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR CDD; cd00643; HMG-CoA_reductase_classI; 1.
DR Gene3D; 1.10.3270.10; -; 1.
DR Gene3D; 3.30.70.420; -; 1.
DR Gene3D; 3.90.770.10; -; 1.
DR InterPro; IPR025583; HMG-CoA_N_dom.
DR InterPro; IPR002202; HMG_CoA_Rdtase.
DR InterPro; IPR023074; HMG_CoA_Rdtase_cat_sf.
DR InterPro; IPR023076; HMG_CoA_Rdtase_CS.
DR InterPro; IPR004554; HMG_CoA_Rdtase_eu_arc.
DR InterPro; IPR023282; HMG_CoA_Rdtase_N.
DR InterPro; IPR009023; HMG_CoA_Rdtase_NAD(P)-bd_sf.
DR InterPro; IPR009029; HMG_CoA_Rdtase_sub-bd_dom_sf.
DR InterPro; IPR000731; SSD.
DR PANTHER; PTHR10572; PTHR10572; 1.
DR Pfam; PF00368; HMG-CoA_red; 1.
DR Pfam; PF13323; HPIH; 1.
DR Pfam; PF12349; Sterol-sensing; 1.
DR PRINTS; PR00071; HMGCOARDTASE.
DR SUPFAM; SSF55035; SSF55035; 1.
DR SUPFAM; SSF56542; SSF56542; 1.
DR TIGRFAMs; TIGR00533; HMG_CoA_R_NADP; 1.
DR PROSITE; PS00066; HMG_COA_REDUCTASE_1; 1.
DR PROSITE; PS00318; HMG_COA_REDUCTASE_2; 1.
DR PROSITE; PS01192; HMG_COA_REDUCTASE_3; 1.
DR PROSITE; PS50065; HMG_COA_REDUCTASE_4; 1.
DR PROSITE; PS50156; SSD; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Glycoprotein; Lipid biosynthesis; Lipid metabolism;
KW Membrane; NADP; Nucleus; Oxidoreductase; Phosphoprotein;
KW Reference proteome; Steroid biosynthesis; Steroid metabolism;
KW Sterol biosynthesis; Sterol metabolism; Transmembrane; Transmembrane helix.
FT CHAIN 1..1054
FT /note="3-hydroxy-3-methylglutaryl-coenzyme A reductase 1"
FT /id="PRO_0000114456"
FT TOPO_DOM 1..28
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT TRANSMEM 29..49
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 50..187
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT TRANSMEM 188..208
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 209..217
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT TRANSMEM 218..238
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 239..246
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT TRANSMEM 247..267
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 268..309
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT TRANSMEM 310..330
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 331..336
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT TRANSMEM 337..357
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 358..400
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT TRANSMEM 401..421
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 422..498
FT /note="Lumenal"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT TRANSMEM 499..519
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 520..1054
FT /note="Cytoplasmic"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT DOMAIN 189..357
FT /note="SSD"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00199"
FT REGION 567..591
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 567..582
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 714
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 848
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 924
FT /note="Charge relay system"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT ACT_SITE 1020
FT /note="Proton donor"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10003"
FT BINDING 720..726
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 781..783
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 808..816
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 877..879
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 1019..1020
FT /ligand="CoA"
FT /ligand_id="ChEBI:CHEBI:57287"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT BINDING 1024..1025
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:P04035"
FT MOD_RES 552
FT /note="Phosphothreonine"
FT /evidence="ECO:0007744|PubMed:17330950"
FT CARBOHYD 115
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 181
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 452
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
FT CARBOHYD 490
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255"
SQ SEQUENCE 1054 AA; 115626 MW; 2B624944FB7B2DD0 CRC64;
MPPLFKGLKQ MAKPIAYVSR FSAKRPIHII LFSLIISAFA YLSVIQYYFN GWQLDSNSVF
ETAPNKDSNT LFQECSHYYR DSSLDGWVSI TAHEASELPA PHHYYLLNLN FNSPNETDSI
PELANTVFEK DNTKYILQED LSVSKEISST DGTKWRLRSD RKSLFDVKTL AYSLYDVFSE
NVTQADPFDV LIMVTAYLMM FYTIFGLFND MRKTGSNFWL SASTVVNSAS SLFLALYVTQ
CILGKEVSAL TLFEGLPFIV VVVGFKHKIK IAQYALEKFE RVGLSKRITT DEIVFESVSE
EGGRLIQDHL LCIFAFIGCS MYAHQLKTLT NFCILSAFIL IFELILTPTF YSAILALRLE
MNVIHRSTII KQTLEEDGVV PSTARIISKA EKKSVSSFLN LSVVVIIMKL SVILLFVFIN
FYNFGANWVN DAFNSLYFDK ERVSLPDFIT SNASENFKEQ AIVSVTPLLY YKPIKSYQRI
EDMVLLLLRN VSVAIRDRFV SKLVLSALVC SAVINVYLLN AARIHTSYTA DQLVKTEVTK
KSFTAPVQKA STPVLTNKTV ISGSKVKSLS SAQSSSSGPS SSSEEDDSRD IESLDKKIRP
LEELEALLSS GNTKQLKNKE VAALVIHGKL PLYALEKKLG DTTRAVAVRR KALSILAEAP
VLASDRLPYK NYDYDRVFGA CCENVIGYMP LPVGVIGPLV IDGTSYHIPM ATTEGCLVAS
AMRGCKAINA GGGATTVLTK DGMTRGPVVR FPTLKRSGAC KIWLDSEEGQ NAIKKAFNST
SRFARLQHIQ TCLAGDLLFM RFRTTTGDAM GMNMISKGVE YSLKQMVEEY GWEDMEVVSV
SGNYCTDKKP AAINWIEGRG KSVVAEATIP GDVVRKVLKS DVSALVELNI AKNLVGSAMA
GSVGGFNAHA ANLVTAVFLA LGQDPAQNVE SSNCITLMKE VDGDLRISVS MPSIEVGTIG
GGTVLEPQGA MLDLLGVRGP HATAPGTNAR QLARIVACAV LAGELSLCAA LAAGHLVQSH
MTHNRKPAEP TKPNNLDATD INRLKDGSVT CIKS
