ERG1_YEAST
ID ERG1_YEAST Reviewed; 496 AA.
AC P32476; D6VUW0;
DT 01-OCT-1993, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 2.
DT 03-AUG-2022, entry version 198.
DE RecName: Full=Squalene epoxidase ERG1 {ECO:0000303|PubMed:1743514};
DE Short=SE {ECO:0000303|PubMed:8358382};
DE EC=1.14.14.17 {ECO:0000269|PubMed:1743514, ECO:0000269|PubMed:8358382, ECO:0000269|PubMed:9450962};
DE AltName: Full=Ergosterol biosynthetic protein 1 {ECO:0000303|PubMed:1743514};
DE AltName: Full=Squalene monooxygenase ERG1 {ECO:0000305};
GN Name=ERG1 {ECO:0000303|PubMed:1743514}; OrderedLocusNames=YGR175C;
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, AND
RP PATHWAY.
RC STRAIN=A2-M8;
RX PubMed=1743514; DOI=10.1016/0378-1119(91)90310-8;
RA Jandrositz A., Turnowsky F., Hoegenauer G.;
RT "The gene encoding squalene epoxidase from Saccharomyces cerevisiae:
RT cloning and characterization.";
RL Gene 107:155-160(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 204508 / S288c;
RX PubMed=9169869;
RA Tettelin H., Agostoni-Carbone M.L., Albermann K., Albers M., Arroyo J.,
RA Backes U., Barreiros T., Bertani I., Bjourson A.J., Brueckner M.,
RA Bruschi C.V., Carignani G., Castagnoli L., Cerdan E., Clemente M.L.,
RA Coblenz A., Coglievina M., Coissac E., Defoor E., Del Bino S., Delius H.,
RA Delneri D., de Wergifosse P., Dujon B., Durand P., Entian K.-D., Eraso P.,
RA Escribano V., Fabiani L., Fartmann B., Feroli F., Feuermann M.,
RA Frontali L., Garcia-Gonzalez M., Garcia-Saez M.I., Goffeau A.,
RA Guerreiro P., Hani J., Hansen M., Hebling U., Hernandez K., Heumann K.,
RA Hilger F., Hofmann B., Indge K.J., James C.M., Klima R., Koetter P.,
RA Kramer B., Kramer W., Lauquin G., Leuther H., Louis E.J., Maillier E.,
RA Marconi A., Martegani E., Mazon M.J., Mazzoni C., McReynolds A.D.K.,
RA Melchioretto P., Mewes H.-W., Minenkova O., Mueller-Auer S., Nawrocki A.,
RA Netter P., Neu R., Nombela C., Oliver S.G., Panzeri L., Paoluzi S.,
RA Plevani P., Portetelle D., Portillo F., Potier S., Purnelle B., Rieger M.,
RA Riles L., Rinaldi T., Robben J., Rodrigues-Pousada C.,
RA Rodriguez-Belmonte E., Rodriguez-Torres A.M., Rose M., Ruzzi M.,
RA Saliola M., Sanchez-Perez M., Schaefer B., Schaefer M., Scharfe M.,
RA Schmidheini T., Schreer A., Skala J., Souciet J.-L., Steensma H.Y.,
RA Talla E., Thierry A., Vandenbol M., van der Aart Q.J.M., Van Dyck L.,
RA Vanoni M., Verhasselt P., Voet M., Volckaert G., Wambutt R., Watson M.D.,
RA Weber N., Wedler E., Wedler H., Wipfli P., Wolf K., Wright L.F.,
RA Zaccaria P., Zimmermann M., Zollner A., Kleine K.;
RT "The nucleotide sequence of Saccharomyces cerevisiae chromosome VII.";
RL Nature 387:81-84(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 FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND PATHWAY.
RX PubMed=8358382; DOI=10.1248/bpb.16.349;
RA Satoh T., Horie M., Watanabe H., Tsuchiya Y., Kamei T.;
RT "Enzymatic properties of squalene epoxidase from Saccharomyces
RT cerevisiae.";
RL Biol. Pharm. Bull. 16:349-352(1993).
RN [5]
RP PARTIAL PROTEIN SEQUENCE, FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND
RP SUBCELLULAR LOCATION.
RX PubMed=9450962; DOI=10.1091/mbc.9.2.375;
RA Leber R., Landl K., Zinser E., Ahorn H., Spoek A., Kohlwein S.D.,
RA Turnowsky F., Daum G.;
RT "Dual localization of squalene epoxidase, Erg1p, in yeast reflects a
RT relationship between the endoplasmic reticulum and lipid particles.";
RL Mol. Biol. Cell 9:375-386(1998).
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 UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-311, AND IDENTIFICATION BY
RP MASS SPECTROMETRY.
RC STRAIN=SUB592;
RX PubMed=12872131; DOI=10.1038/nbt849;
RA Peng J., Schwartz D., Elias J.E., Thoreen C.C., Cheng D., Marsischky G.,
RA Roelofs J., Finley D., Gygi S.P.;
RT "A proteomics approach to understanding protein ubiquitination.";
RL Nat. Biotechnol. 21:921-926(2003).
RN [8]
RP UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-284, AND IDENTIFICATION BY
RP MASS SPECTROMETRY.
RX PubMed=14557538; DOI=10.1073/pnas.2135500100;
RA Hitchcock A.L., Auld K., Gygi S.P., Silver P.A.;
RT "A subset of membrane-associated proteins is ubiquitinated in response to
RT mutations in the endoplasmic reticulum degradation machinery.";
RL Proc. Natl. Acad. Sci. U.S.A. 100:12735-12740(2003).
RN [9]
RP FUNCTION, AND INTERACTION WITH ERG28.
RX PubMed=15995173; DOI=10.1194/jlr.m500153-jlr200;
RA Mo C., Bard M.;
RT "Erg28p is a key protein in the yeast sterol biosynthetic enzyme complex.";
RL J. Lipid Res. 46:1991-1998(2005).
RN [10]
RP TOPOLOGY [LARGE SCALE ANALYSIS].
RC STRAIN=ATCC 208353 / W303-1A;
RX PubMed=16847258; DOI=10.1073/pnas.0604075103;
RA Kim H., Melen K., Oesterberg M., von Heijne G.;
RT "A global topology map of the Saccharomyces cerevisiae membrane proteome.";
RL Proc. Natl. Acad. Sci. U.S.A. 103:11142-11147(2006).
RN [11]
RP UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-289 AND LYS-311, AND
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX PubMed=22106047; DOI=10.1002/pmic.201100166;
RA Starita L.M., Lo R.S., Eng J.K., von Haller P.D., Fields S.;
RT "Sites of ubiquitin attachment in Saccharomyces cerevisiae.";
RL Proteomics 12:236-240(2012).
RN [12]
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 epoxidase; part of the third module of ergosterol
CC biosynthesis pathway that includes the late steps of the pathway
CC (PubMed:1743514, PubMed:8358382, PubMed:9450962). ERG1 catalyzes the
CC epoxidation of squalene into 2,3-epoxysqualene (PubMed:1743514,
CC PubMed:8358382, PubMed:9450962). 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:1743514,
CC ECO:0000269|PubMed:8358382, ECO:0000269|PubMed:9450962,
CC ECO:0000303|PubMed:32679672}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=O2 + reduced [NADPH--hemoprotein reductase] + squalene = (S)-
CC 2,3-epoxysqualene + H(+) + H2O + oxidized [NADPH--hemoprotein
CC reductase]; Xref=Rhea:RHEA:25282, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:15440, ChEBI:CHEBI:15441, ChEBI:CHEBI:57618,
CC ChEBI:CHEBI:58210; EC=1.14.14.17;
CC Evidence={ECO:0000269|PubMed:1743514, ECO:0000269|PubMed:8358382,
CC ECO:0000269|PubMed:9450962};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:Q14534};
CC -!- ACTIVITY REGULATION: Inhibited by the allylamine antimycotic drugs.
CC {ECO:0000305}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=13.5 uM for squalene {ECO:0000269|PubMed:8358382};
CC pH dependence:
CC Optimum pH is 7.5. {ECO:0000269|PubMed:8358382};
CC -!- PATHWAY: Terpene metabolism; lanosterol biosynthesis; lanosterol from
CC farnesyl diphosphate: step 2/3. {ECO:0000269|PubMed:1743514,
CC ECO:0000269|PubMed:8358382, ECO:0000269|PubMed:9450962}.
CC -!- SUBUNIT: Interacts with ERG28. {ECO:0000269|PubMed:15995173}.
CC -!- SUBCELLULAR LOCATION: Microsome membrane {ECO:0000269|PubMed:9450962};
CC Multi-pass membrane protein {ECO:0000305}. Endoplasmic reticulum
CC membrane {ECO:0000269|PubMed:9450962}; Multi-pass membrane protein
CC {ECO:0000305}. Lipid droplet {ECO:0000269|PubMed:9450962}.
CC -!- MISCELLANEOUS: Present with 65400 molecules/cell in log phase SD
CC medium. {ECO:0000269|PubMed:14562106}.
CC -!- SIMILARITY: Belongs to the squalene monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; M64994; AAA34592.1; -; Genomic_DNA.
DR EMBL; Z72960; CAA97201.1; -; Genomic_DNA.
DR EMBL; BK006941; DAA08271.1; -; Genomic_DNA.
DR PIR; S64489; S64489.
DR RefSeq; NP_011691.1; NM_001181304.1.
DR AlphaFoldDB; P32476; -.
DR SMR; P32476; -.
DR BioGRID; 33428; 76.
DR DIP; DIP-6325N; -.
DR IntAct; P32476; 17.
DR MINT; P32476; -.
DR STRING; 4932.YGR175C; -.
DR ChEMBL; CHEMBL1888; -.
DR iPTMnet; P32476; -.
DR MaxQB; P32476; -.
DR PaxDb; P32476; -.
DR PRIDE; P32476; -.
DR TopDownProteomics; P32476; -.
DR EnsemblFungi; YGR175C_mRNA; YGR175C; YGR175C.
DR GeneID; 853086; -.
DR KEGG; sce:YGR175C; -.
DR SGD; S000003407; ERG1.
DR VEuPathDB; FungiDB:YGR175C; -.
DR eggNOG; KOG1298; Eukaryota.
DR GeneTree; ENSGT00390000011759; -.
DR HOGENOM; CLU_026390_0_0_1; -.
DR InParanoid; P32476; -.
DR OMA; KSKFWGL; -.
DR BioCyc; MetaCyc:YGR175C-MON; -.
DR BioCyc; YEAST:YGR175C-MON; -.
DR Reactome; R-SCE-191273; Cholesterol biosynthesis.
DR UniPathway; UPA00767; UER00752.
DR PRO; PR:P32476; -.
DR Proteomes; UP000002311; Chromosome VII.
DR RNAct; P32476; protein.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:SGD.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0005811; C:lipid droplet; IDA:SGD.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR GO; GO:0004506; F:squalene monooxygenase activity; IDA:SGD.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IMP:SGD.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR Gene3D; 3.50.50.60; -; 1.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR InterPro; IPR013698; Squalene_epoxidase.
DR InterPro; IPR040125; Squalene_monox.
DR PANTHER; PTHR10835; PTHR10835; 1.
DR Pfam; PF08491; SE; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW Direct protein sequencing; Endoplasmic reticulum; FAD; Flavoprotein;
KW Isopeptide bond; Lipid biosynthesis; Lipid droplet; Lipid metabolism;
KW Membrane; Microsome; Oxidoreductase; Reference proteome;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..496
FT /note="Squalene epoxidase ERG1"
FT /id="PRO_0000209851"
FT TOPO_DOM 1..16
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 17..37
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 38..474
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 475..495
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 496
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT BINDING 28..29
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 48..49
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 56
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 158
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 335
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 348
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT SITE 90
FT /note="Important for enzyme activity"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT CROSSLNK 284
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0000269|PubMed:14557538"
FT CROSSLNK 289
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0007744|PubMed:22106047"
FT CROSSLNK 311
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0007744|PubMed:22106047"
FT VARIANT 251
FT /note="L -> F (in strain: A2-M8; confers resistance to the
FT allylamine antifungal terbinafine)"
SQ SEQUENCE 496 AA; 55126 MW; BBEFD766634855E8 CRC64;
MSAVNVAPEL INADNTITYD AIVIGAGVIG PCVATGLARK GKKVLIVERD WAMPDRIVGE
LMQPGGVRAL RSLGMIQSIN NIEAYPVTGY TVFFNGEQVD IPYPYKADIP KVEKLKDLVK
DGNDKVLEDS TIHIKDYEDD ERERGVAFVH GRFLNNLRNI TAQEPNVTRV QGNCIEILKD
EKNEVVGAKV DIDGRGKVEF KAHLTFICDG IFSRFRKELH PDHVPTVGSS FVGMSLFNAK
NPAPMHGHVI LGSDHMPILV YQISPEETRI LCAYNSPKVP ADIKSWMIKD VQPFIPKSLR
PSFDEAVSQG KFRAMPNSYL PARQNDVTGM CVIGDALNMR HPLTGGGMTV GLHDVVLLIK
KIGDLDFSDR EKVLDELLDY HFERKSYDSV INVLSVALYS LFAADSDNLK ALQKGCFKYF
QRGGDCVNKP VEFLSGVLPK PLQLTRVFFA VAFYTIYLNM EERGFLGLPM ALLEGIMILI
TAIRVFTPFL FGELIG
