ERG9_YEAST
ID ERG9_YEAST Reviewed; 444 AA.
AC P29704; D3DLD8;
DT 01-APR-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1995, sequence version 2.
DT 03-AUG-2022, entry version 189.
DE RecName: Full=Squalene synthase ERG9 {ECO:0000303|PubMed:1807826};
DE Short=SQS {ECO:0000303|PubMed:1807826};
DE Short=SS {ECO:0000303|PubMed:1807826};
DE EC=2.5.1.21 {ECO:0000269|PubMed:1807826, ECO:0000269|PubMed:8323279};
DE AltName: Full=Ergosterol biosynthetic protein 9 {ECO:0000303|PubMed:1807826};
DE AltName: Full=FPP:FPP farnesyltransferase ERG9 {ECO:0000305};
DE AltName: Full=Farnesyl-diphosphate farnesyltransferase ERG9 {ECO:0000305};
GN Name=ERG9 {ECO:0000303|PubMed:1807826}; OrderedLocusNames=YHR190W;
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, CATALYTIC ACTIVITY,
RP SUBCELLULAR LOCATION, AND PATHWAY.
RX PubMed=1807826; DOI=10.1007/bf00317063;
RA Fegueur M., Richard L., Charles A.D., Karst F.;
RT "Isolation and primary structure of the ERG9 gene of Saccharomyces
RT cerevisiae encoding squalene synthetase.";
RL Curr. Genet. 20:365-372(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], IDENTIFICATION, FUNCTION, DISRUPTION
RP PHENOTYPE, AND PATHWAY.
RX PubMed=2068081; DOI=10.1073/pnas.88.14.6038;
RA Jennings S.M., Tsay Y.H., Fisch T.M., Robinson G.W.;
RT "Molecular cloning and characterization of the yeast gene for squalene
RT synthetase.";
RL Proc. Natl. Acad. Sci. U.S.A. 88:6038-6042(1991).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 204508 / S288c;
RX PubMed=8091229; DOI=10.1126/science.8091229;
RA Johnston M., Andrews S., Brinkman R., Cooper J., Ding H., Dover J., Du Z.,
RA Favello A., Fulton L., Gattung S., Geisel C., Kirsten J., Kucaba T.,
RA Hillier L.W., Jier M., Johnston L., Langston Y., Latreille P., Louis E.J.,
RA Macri C., Mardis E., Menezes S., Mouser L., Nhan M., Rifkin L., Riles L.,
RA St Peter H., Trevaskis E., Vaughan K., Vignati D., Wilcox L., Wohldman P.,
RA Waterston R., Wilson R., Vaudin M.;
RT "Complete nucleotide sequence of Saccharomyces cerevisiae chromosome
RT VIII.";
RL Science 265:2077-2082(1994).
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 FUNCTION, CATALYTIC ACTIVITY, COFACTOR, AND PATHWAY.
RX PubMed=8323279; DOI=10.1006/abbi.1993.1331;
RA Zhang D., Jennings S.M., Robinson G.W., Poulter C.D.;
RT "Yeast squalene synthase: expression, purification, and characterization of
RT soluble recombinant enzyme.";
RL Arch. Biochem. Biophys. 304:133-143(1993).
RN [6]
RP FUNCTION.
RX PubMed=8663358; DOI=10.1074/jbc.271.28.16927;
RA Li L., Kaplan J.;
RT "Characterization of yeast methyl sterol oxidase (ERG25) and identification
RT of a human homologue.";
RL J. Biol. Chem. 271:16927-16933(1996).
RN [7]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=9742963; DOI=10.1016/s0014-5793(98)01019-9;
RA Grabowska D., Karst F., Szkopinska A.;
RT "Effect of squalene synthase gene disruption on synthesis of polyprenols in
RT Saccharomyces cerevisiae.";
RL FEBS Lett. 434:406-408(1998).
RN [8]
RP INDUCTION.
RX PubMed=10209263; DOI=10.1016/s0167-4781(99)00035-4;
RA Kennedy M.A., Barbuch R., Bard M.;
RT "Transcriptional regulation of the squalene synthase gene (ERG9) in the
RT yeast Saccharomyces cerevisiae.";
RL Biochim. Biophys. Acta 1445:110-122(1999).
RN [9]
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 [10]
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 [11]
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: Squalene synthase; part of the third module of ergosterol
CC biosynthesis pathway that includes the late steps of the pathway
CC (PubMed:1807826, PubMed:2068081, PubMed:8323279, PubMed:9742963). ERG9
CC produces squalene from 2 farnesyl pyrophosphate moieties
CC (PubMed:1807826, PubMed:8323279). The third module or late pathway
CC involves the ergosterol synthesis itself through consecutive reactions
CC that mainly occur in the endoplasmic reticulum (ER) membrane. Firstly,
CC the squalene synthase ERG9 catalyzes the condensation of 2 farnesyl
CC pyrophosphate moieties to form squalene, which is the precursor of all
CC steroids. Squalene synthase is crucial for balancing the incorporation
CC of farnesyl diphosphate (FPP) into sterol and nonsterol isoprene
CC synthesis. Secondly, the squalene epoxidase ERG1 catalyzes the
CC stereospecific oxidation of squalene to (S)-2,3-epoxysqualene, which is
CC considered to be a rate-limiting enzyme in steroid biosynthesis. Then,
CC the lanosterol synthase ERG7 catalyzes the cyclization of (S)-2,3
CC oxidosqualene to lanosterol, a reaction that forms the sterol core. In
CC the next steps, lanosterol is transformed to zymosterol through a
CC complex process involving various demethylation, reduction and
CC desaturation reactions. The lanosterol 14-alpha-demethylase ERG11 (also
CC known as CYP51) catalyzes C14-demethylation of lanosterol to produce
CC 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol, which is critical for
CC ergosterol biosynthesis. The C-14 reductase ERG24 reduces the C14=C15
CC double bond of 4,4-dimethyl-cholesta-8,14,24-trienol to produce 4,4-
CC dimethyl-cholesta-8,24-dienol. 4,4-dimethyl-cholesta-8,24-dienol is
CC substrate of the C-4 demethylation complex ERG25-ERG26-ERG27 in which
CC ERG25 catalyzes the three-step monooxygenation required for the
CC demethylation of 4,4-dimethyl and 4alpha-methylsterols, ERG26 catalyzes
CC the oxidative decarboxylation that results in a reduction of the 3-
CC beta-hydroxy group at the C-3 carbon to an oxo group, and ERG27 is
CC responsible for the reduction of the keto group on the C-3. ERG28 has a
CC role as a scaffold to help anchor ERG25, ERG26 and ERG27 to the
CC endoplasmic reticulum and ERG29 regulates the activity of the iron-
CC containing C4-methylsterol oxidase ERG25. Then, the sterol 24-C-
CC methyltransferase ERG6 catalyzes the methyl transfer from S-adenosyl-
CC methionine to the C-24 of zymosterol to form fecosterol. The C-8 sterol
CC isomerase ERG2 catalyzes the reaction which results in unsaturation at
CC C-7 in the B ring of sterols and thus converts fecosterol to episterol.
CC The sterol-C5-desaturase ERG3 then catalyzes the introduction of a C-5
CC double bond in the B ring to produce 5-dehydroepisterol. The C-22
CC sterol desaturase ERG5 further converts 5-dehydroepisterol into
CC ergosta-5,7,22,24(28)-tetraen-3beta-ol by forming the C-22(23) double
CC bond in the sterol side chain. Finally, ergosta-5,7,22,24(28)-tetraen-
CC 3beta-ol is substrate of the C-24(28) sterol reductase ERG4 to produce
CC ergosterol (PubMed:32679672). {ECO:0000269|PubMed:1807826,
CC ECO:0000269|PubMed:2068081, ECO:0000269|PubMed:8323279,
CC ECO:0000269|PubMed:9742963, ECO:0000303|PubMed:32679672}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 (2E,6E)-farnesyl diphosphate + H(+) + NADPH = 2 diphosphate
CC + NADP(+) + squalene; Xref=Rhea:RHEA:32295, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15440, ChEBI:CHEBI:33019, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349, ChEBI:CHEBI:175763; EC=2.5.1.21;
CC Evidence={ECO:0000269|PubMed:1807826, ECO:0000269|PubMed:8323279};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32296;
CC Evidence={ECO:0000269|PubMed:1807826, ECO:0000269|PubMed:8323279};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=2 (2E,6E)-farnesyl diphosphate + H(+) + NADH = 2 diphosphate +
CC NAD(+) + squalene; Xref=Rhea:RHEA:32299, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15440, ChEBI:CHEBI:33019, ChEBI:CHEBI:57540,
CC ChEBI:CHEBI:57945, ChEBI:CHEBI:175763; EC=2.5.1.21;
CC Evidence={ECO:0000269|PubMed:1807826, ECO:0000269|PubMed:8323279};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:32300;
CC Evidence={ECO:0000269|PubMed:1807826, ECO:0000269|PubMed:8323279};
CC -!- COFACTOR:
CC Name=Mg(2+); Xref=ChEBI:CHEBI:18420;
CC Evidence={ECO:0000269|PubMed:8323279};
CC -!- PATHWAY: Terpene metabolism; lanosterol biosynthesis; lanosterol from
CC farnesyl diphosphate: step 1/3. {ECO:0000269|PubMed:1807826,
CC ECO:0000269|PubMed:2068081, ECO:0000269|PubMed:8323279}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:14562095, ECO:0000269|PubMed:1807826}; Single-pass
CC membrane protein {ECO:0000255}. Microsome {ECO:0000305|PubMed:2068081}.
CC -!- INDUCTION: Expression is increased in mutants with phenotypes
CC consistent with known sterol biosynthetic mutations (ERG3, ERG7, ERG24)
CC (PubMed:10209263). The sterol inhibitors zaragozic acid and
CC ketoconazole, which target squalene synthase and the C-14 sterol
CC demethylase respectively, also cause an increase in expression
CC (PubMed:10209263). Heme mutants increase ERG9 expression while
CC anaerobic conditions decrease expression (PubMed:10209263).
CC Additionally, the heme activator protein transcription factors HAP1 and
CC HAP2/3/4, the yeast activator protein transcription factor yAP-1, and
CC the phospholipid transcription factor complex INO2/4 regulate ERG9
CC expression (PubMed:10209263). {ECO:0000269|PubMed:10209263}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of ergosterol and leads to
CC a 6-fold increase in the synthesis of polyprenols.
CC {ECO:0000269|PubMed:2068081, ECO:0000269|PubMed:9742963}.
CC -!- MISCELLANEOUS: Present with 10800 molecules/cell in log phase SD
CC medium. {ECO:0000269|PubMed:14562106}.
CC -!- SIMILARITY: Belongs to the phytoene/squalene synthase family.
CC {ECO:0000305}.
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DR EMBL; M63979; AAA34597.1; -; Genomic_DNA.
DR EMBL; X59959; CAA42583.1; -; Genomic_DNA.
DR EMBL; U00030; AAB68360.1; -; Genomic_DNA.
DR EMBL; BK006934; DAA06882.1; -; Genomic_DNA.
DR PIR; S46682; S46682.
DR RefSeq; NP_012060.1; NM_001179321.1.
DR AlphaFoldDB; P29704; -.
DR SMR; P29704; -.
DR BioGRID; 36624; 356.
DR DIP; DIP-4576N; -.
DR IntAct; P29704; 9.
DR MINT; P29704; -.
DR STRING; 4932.YHR190W; -.
DR ChEMBL; CHEMBL3271930; -.
DR iPTMnet; P29704; -.
DR MaxQB; P29704; -.
DR PaxDb; P29704; -.
DR PRIDE; P29704; -.
DR EnsemblFungi; YHR190W_mRNA; YHR190W; YHR190W.
DR GeneID; 856597; -.
DR KEGG; sce:YHR190W; -.
DR SGD; S000001233; ERG9.
DR VEuPathDB; FungiDB:YHR190W; -.
DR eggNOG; KOG1459; Eukaryota.
DR GeneTree; ENSGT00390000016034; -.
DR HOGENOM; CLU_031981_2_1_1; -.
DR InParanoid; P29704; -.
DR OMA; RFWPKEI; -.
DR BioCyc; MetaCyc:YHR190W-MON; -.
DR BioCyc; YEAST:YHR190W-MON; -.
DR Reactome; R-SCE-191273; Cholesterol biosynthesis.
DR UniPathway; UPA00767; UER00751.
DR PRO; PR:P29704; -.
DR Proteomes; UP000002311; Chromosome VIII.
DR RNAct; P29704; protein.
DR GO; GO:0005783; C:endoplasmic reticulum; HDA:SGD.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IDA:SGD.
DR GO; GO:0005741; C:mitochondrial outer membrane; HDA:SGD.
DR GO; GO:0005739; C:mitochondrion; HDA:SGD.
DR GO; GO:0004310; F:farnesyl-diphosphate farnesyltransferase activity; IDA:SGD.
DR GO; GO:0051996; F:squalene synthase activity; IDA:SGD.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IMP:SGD.
DR GO; GO:0045338; P:farnesyl diphosphate metabolic process; IBA:GO_Central.
DR GO; GO:0008299; P:isoprenoid biosynthetic process; IEA:UniProtKB-KW.
DR CDD; cd00683; Trans_IPPS_HH; 1.
DR Gene3D; 1.10.600.10; -; 1.
DR InterPro; IPR008949; Isoprenoid_synthase_dom_sf.
DR InterPro; IPR002060; Squ/phyt_synthse.
DR InterPro; IPR006449; Squal_synth-like.
DR InterPro; IPR019845; Squalene/phytoene_synthase_CS.
DR InterPro; IPR044844; Trans_IPPS_euk-type.
DR InterPro; IPR033904; Trans_IPPS_HH.
DR PANTHER; PTHR11626; PTHR11626; 1.
DR Pfam; PF00494; SQS_PSY; 1.
DR SFLD; SFLDG01018; Squalene/Phytoene_Synthase_Lik; 1.
DR SUPFAM; SSF48576; SSF48576; 1.
DR TIGRFAMs; TIGR01559; squal_synth; 1.
DR PROSITE; PS01044; SQUALEN_PHYTOEN_SYN_1; 1.
DR PROSITE; PS01045; SQUALEN_PHYTOEN_SYN_2; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Isoprene biosynthesis; Lipid biosynthesis;
KW Lipid metabolism; Magnesium; Membrane; Microsome; Multifunctional enzyme;
KW NADP; Reference proteome; Steroid biosynthesis; Steroid metabolism;
KW Sterol biosynthesis; Sterol metabolism; Transferase; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..444
FT /note="Squalene synthase ERG9"
FT /id="PRO_0000067454"
FT TRANSMEM 421..441
FT /note="Helical"
FT /evidence="ECO:0000255"
FT CONFLICT 48
FT /note="L -> F (in Ref. 1; CAA42583)"
FT /evidence="ECO:0000305"
FT CONFLICT 286
FT /note="G -> S (in Ref. 2; AAA34597)"
FT /evidence="ECO:0000305"
FT CONFLICT 320
FT /note="N -> D (in Ref. 1; CAA42583)"
FT /evidence="ECO:0000305"
FT CONFLICT 330
FT /note="Y -> C (in Ref. 1; CAA42583)"
FT /evidence="ECO:0000305"
FT CONFLICT 429
FT /note="L -> S (in Ref. 1; CAA42583)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 444 AA; 51720 MW; 3DA00295B8DFDB16 CRC64;
MGKLLQLALH PVEMKAALKL KFCRTPLFSI YDQSTSPYLL HCFELLNLTS RSFAAVIREL
HPELRNCVTL FYLILRALDT IEDDMSIEHD LKIDLLRHFH EKLLLTKWSF DGNAPDVKDR
AVLTDFESIL IEFHKLKPEY QEVIKEITEK MGNGMADYIL DENYNLNGLQ TVHDYDVYCH
YVAGLVGDGL TRLIVIAKFA NESLYSNEQL YESMGLFLQK TNIIRDYNED LVDGRSFWPK
EIWSQYAPQL KDFMKPENEQ LGLDCINHLV LNALSHVIDV LTYLAGIHEQ STFQFCAIPQ
VMAIATLALV FNNREVLHGN VKIRKGTTCY LILKSRTLRG CVEIFDYYLR DIKSKLAVQD
PNFLKLNIQI SKIEQFMEEM YQDKLPPNVK PNETPIFLKV KERSRYDDEL VPTQQEEEYK
FNMVLSIILS VLLGFYYIYT LHRA
