ERG1_CANAL
ID ERG1_CANAL Reviewed; 496 AA.
AC Q92206; A0A1D8PEC8; Q59QB2;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-FEB-1997, sequence version 1.
DT 03-AUG-2022, entry version 136.
DE RecName: Full=Squalene epoxidase ERG1 {ECO:0000303|PubMed:9161422};
DE Short=SE {ECO:0000303|PubMed:9161422};
DE EC=1.14.14.17 {ECO:0000269|PubMed:3877503, ECO:0000269|PubMed:6378256, ECO:0000269|PubMed:9161422};
DE AltName: Full=Ergosterol biosynthesis protein 1 {ECO:0000303|PubMed:9161422};
DE AltName: Full=Squalene monooxygenase ERG1 {ECO:0000305};
GN Name=ERG1 {ECO:0000303|Ref.1}; OrderedLocusNames=CAALFM_C108590CA;
GN ORFNames=CaO19.406, CaO19.8036;
OS Candida albicans (strain SC5314 / ATCC MYA-2876) (Yeast).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC Saccharomycetales; Debaryomycetaceae; Candida/Lodderomyces clade; Candida.
OX NCBI_TaxID=237561;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 10259 / CBS 5796 / DSM 5817 / JCM 2078 / NBRC 1060;
RA Ishii N., Yamamoto M., Arisawa M., Aoki Y.;
RL Submitted (NOV-1996) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY, AND
RP PATHWAY.
RC STRAIN=SFI-0124;
RX PubMed=9161422; DOI=10.1016/s0378-1119(96)00844-x;
RA Favre B., Ryder N.S.;
RT "Cloning and expression of squalene epoxidase from the pathogenic yeast
RT Candida albicans.";
RL Gene 189:119-126(1997).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=15123810; DOI=10.1073/pnas.0401648101;
RA Jones T., Federspiel N.A., Chibana H., Dungan J., Kalman S., Magee B.B.,
RA Newport G., Thorstenson Y.R., Agabian N., Magee P.T., Davis R.W.,
RA Scherer S.;
RT "The diploid genome sequence of Candida albicans.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:7329-7334(2004).
RN [4]
RP GENOME REANNOTATION.
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=17419877; DOI=10.1186/gb-2007-8-4-r52;
RA van het Hoog M., Rast T.J., Martchenko M., Grindle S., Dignard D.,
RA Hogues H., Cuomo C., Berriman M., Scherer S., Magee B.B., Whiteway M.,
RA Chibana H., Nantel A., Magee P.T.;
RT "Assembly of the Candida albicans genome into sixteen supercontigs aligned
RT on the eight chromosomes.";
RL Genome Biol. 8:RESEARCH52.1-RESEARCH52.12(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND GENOME REANNOTATION.
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=24025428; DOI=10.1186/gb-2013-14-9-r97;
RA Muzzey D., Schwartz K., Weissman J.S., Sherlock G.;
RT "Assembly of a phased diploid Candida albicans genome facilitates allele-
RT specific measurements and provides a simple model for repeat and indel
RT structure.";
RL Genome Biol. 14:RESEARCH97.1-RESEARCH97.14(2013).
RN [6]
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP REGULATION, AND PATHWAY.
RX PubMed=6378256; DOI=10.1016/0005-2760(84)90013-4;
RA Ryder N.S., Dupont M.C.;
RT "Properties of a particulate squalene epoxidase from Candida albicans.";
RL Biochim. Biophys. Acta 794:466-471(1984).
RN [7]
RP CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=3877503; DOI=10.1042/bj2300765;
RA Ryder N.S., Dupont M.C.;
RT "Inhibition of squalene epoxidase by allylamine antimycotic compounds. A
RT comparative study of the fungal and mammalian enzymes.";
RL Biochem. J. 230:765-770(1985).
RN [8]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=15845783; DOI=10.1093/jac/dki112;
RA Pasrija R., Krishnamurthy S., Prasad T., Ernst J.F., Prasad R.;
RT "Squalene epoxidase encoded by ERG1 affects morphogenesis and drug
RT susceptibilities of Candida albicans.";
RL J. Antimicrob. Chemother. 55:905-913(2005).
CC -!- FUNCTION: Squalene epoxidase; part of the third module of ergosterol
CC biosynthesis pathway that includes the late steps of the pathway
CC (PubMed:9161422, PubMed:6378256, PubMed:3877503, PubMed:15845783). Erg1
CC catalyzes the epoxidation of squalene into 2,3-epoxysqualene
CC (PubMed:9161422, PubMed:6378256, PubMed:3877503, PubMed:15845783). The
CC third module or late pathway involves the ergosterol synthesis itself
CC through consecutive reactions that mainly occur in the endoplasmic
CC reticulum (ER) membrane. Firstly, the squalene synthase ERG9 catalyzes
CC the condensation of 2 farnesyl pyrophosphate moieties to form squalene,
CC which is the precursor of all steroids. Squalene synthase is crucial
CC for balancing the incorporation of farnesyl diphosphate (FPP) into
CC sterol and nonsterol isoprene synthesis. Secondly, the squalene
CC epoxidase ERG1 catalyzes the stereospecific oxidation of squalene to
CC (S)-2,3-epoxysqualene, which is considered to be a rate-limiting enzyme
CC in steroid biosynthesis. Then, the lanosterol synthase ERG7 catalyzes
CC the cyclization of (S)-2,3 oxidosqualene to lanosterol, a reaction that
CC forms the sterol core. In the next steps, lanosterol is transformed to
CC zymosterol through a complex process involving various demethylation,
CC reduction and desaturation reactions. The lanosterol 14-alpha-
CC demethylase ERG11 (also known as CYP51) catalyzes C14-demethylation of
CC lanosterol to produce 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol,
CC which is critical for ergosterol biosynthesis. The C-14 reductase ERG24
CC reduces the C14=C15 double bond of 4,4-dimethyl-cholesta-8,14,24-
CC trienol to produce 4,4-dimethyl-cholesta-8,24-dienol. 4,4-dimethyl-
CC cholesta-8,24-dienol is substrate of the C-4 demethylation complex
CC ERG25-ERG26-ERG27 in which ERG25 catalyzes the three-step
CC monooxygenation required for the demethylation of 4,4-dimethyl and
CC 4alpha-methylsterols, ERG26 catalyzes the oxidative decarboxylation
CC that results in a reduction of the 3-beta-hydroxy group at the C-3
CC carbon to an oxo group, and ERG27 is responsible for the reduction of
CC the keto group on the C-3. ERG28 has a role as a scaffold to help
CC anchor ERG25, ERG26 and ERG27 to the endoplasmic reticulum and ERG29
CC regulates the activity of the iron-containing C4-methylsterol oxidase
CC ERG25. Then, the sterol 24-C-methyltransferase ERG6 catalyzes the
CC methyl transfer from S-adenosyl-methionine to the C-24 of zymosterol to
CC form fecosterol. The C-8 sterol isomerase ERG2 catalyzes the reaction
CC which results in unsaturation at C-7 in the B ring of sterols and thus
CC converts fecosterol to episterol. The sterol-C5-desaturase ERG3 then
CC catalyzes the introduction of a C-5 double bond in the B ring to
CC produce 5-dehydroepisterol. The C-22 sterol desaturase ERG5 further
CC converts 5-dehydroepisterol into ergosta-5,7,22,24(28)-tetraen-3beta-ol
CC by forming the C-22(23) double bond in the sterol side chain. Finally,
CC ergosta-5,7,22,24(28)-tetraen-3beta-ol is substrate of the C-24(28)
CC sterol reductase ERG4 to produce ergosterol (Probable).
CC {ECO:0000269|PubMed:15845783, ECO:0000269|PubMed:3877503,
CC ECO:0000269|PubMed:6378256, ECO:0000269|PubMed:9161422, ECO:0000305}.
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:3877503, ECO:0000269|PubMed:6378256,
CC ECO:0000269|PubMed:9161422};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25283;
CC Evidence={ECO:0000269|PubMed:3877503, ECO:0000269|PubMed:6378256,
CC ECO:0000269|PubMed:9161422};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:Q14534};
CC -!- ACTIVITY REGULATION: Activity is completely abolished by Triton X-100,
CC deoxycholate or Cu(2+), and partially inhibited by thiol reagents,
CC rotenone and antimycin A (PubMed:6378256). The allylamine antimycotic
CC agents naftifine and SF 86-327are potent inhibitors and show apparently
CC non-competitive kinetics with respect to the substrate squalene
CC (PubMed:3877503). {ECO:0000269|PubMed:3877503,
CC ECO:0000269|PubMed:6378256}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=50 uM for squalene {ECO:0000269|PubMed:6378256};
CC -!- PATHWAY: Terpene metabolism; lanosterol biosynthesis; lanosterol from
CC farnesyl diphosphate: step 2/3. {ECO:0000269|PubMed:6378256,
CC ECO:0000269|PubMed:9161422}.
CC -!- SUBCELLULAR LOCATION: Microsome membrane
CC {ECO:0000250|UniProtKB:P32476}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P32476}. Endoplasmic reticulum membrane
CC {ECO:0000250|UniProtKB:P32476}; Multi-pass membrane protein
CC {ECO:0000250|UniProtKB:P32476}.
CC -!- DISRUPTION PHENOTYPE: Impairs ergosterol production and leads to
CC increased susceptibility to terbinafine (PubMed:15845783). Leads also
CC to susceptibility to polyenes, nystatin and amphotericin B
CC (PubMed:15845783). Impairs the localization of the membrane-bound
CC transporter CDR1 (PubMed:15845783). Reduces the formation of hyphae
CC (PubMed:15845783). {ECO:0000269|PubMed:15845783}.
CC -!- SIMILARITY: Belongs to the squalene monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; D88252; BAA13565.1; -; Genomic_DNA.
DR EMBL; U69674; AAC49715.1; -; Genomic_DNA.
DR EMBL; CP017623; AOW26497.1; -; Genomic_DNA.
DR RefSeq; XP_711894.1; XM_706801.1.
DR AlphaFoldDB; Q92206; -.
DR SMR; Q92206; -.
DR BioGRID; 1229551; 1.
DR STRING; 237561.Q92206; -.
DR ChEMBL; CHEMBL1897; -.
DR DrugBank; DB00857; Terbinafine.
DR DrugBank; DB00525; Tolnaftate.
DR DrugCentral; Q92206; -.
DR PRIDE; Q92206; -.
DR GeneID; 3646509; -.
DR KEGG; cal:CAALFM_C108590CA; -.
DR CGD; CAL0000179458; ERG1.
DR VEuPathDB; FungiDB:C1_08590C_A; -.
DR eggNOG; KOG1298; Eukaryota.
DR HOGENOM; CLU_026390_0_0_1; -.
DR InParanoid; Q92206; -.
DR OMA; KSKFWGL; -.
DR OrthoDB; 583514at2759; -.
DR UniPathway; UPA00767; UER00752.
DR PRO; PR:Q92206; -.
DR Proteomes; UP000000559; Chromosome 1.
DR GO; GO:0005783; C:endoplasmic reticulum; IBA:GO_Central.
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:0005886; C:plasma membrane; IDA:CGD.
DR GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR GO; GO:0004506; F:squalene monooxygenase activity; IDA:CGD.
DR GO; GO:0036187; P:cell growth mode switching, budding to filamentous; IMP:CGD.
DR GO; GO:0009267; P:cellular response to starvation; IMP:CGD.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IMP:CGD.
DR GO; GO:0030447; P:filamentous growth; IMP:CGD.
DR GO; GO:0036180; P:filamentous growth of a population of unicellular organisms in response to biotic stimulus; IMP:CGD.
DR GO; GO:0036171; P:filamentous growth of a population of unicellular organisms in response to chemical stimulus; IMP:CGD.
DR GO; GO:0036170; P:filamentous growth of a population of unicellular organisms in response to starvation; IMP:CGD.
DR GO; GO:0051668; P:localization within membrane; IMP:CGD.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR Gene3D; 3.50.50.60; -; 2.
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 Endoplasmic reticulum; FAD; Flavoprotein; Membrane; Microsome;
KW Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..496
FT /note="Squalene epoxidase ERG1"
FT /id="PRO_0000209848"
FT TRANSMEM 4..24
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 431..451
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 466..486
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 15..16
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 35..36
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 43
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 148
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 164
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 332
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT BINDING 345
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
FT SITE 77
FT /note="Important for enzyme activity"
FT /evidence="ECO:0000250|UniProtKB:Q14534"
SQ SEQUENCE 496 AA; 55298 MW; C844CE43A679B920 CRC64;
MSSVKYDAII IGAGVIGPTI ATAFARQGRK VLIVERDWSK PDRIVGELMQ PAGIKALREL
GMIKAINNIR AVDCTGYYIK YYDETITIPY PLKKDACITN PVKPVPDAVD GVNDKLDSDS
TLNVDDWDFD ERVRGAAFHH GDFLMNLRQI CRDEPNVTAV EATVTKILRD PSDPNTVIGV
QTKQPSGTVD YHAKLTISCD GIYSKFRKEL SPTNVPTIGS YFIGLYLKNA ELPAKGKGHV
LLGGHAPALI YSVSPTETRV LCVYVSSKPP SAANDAVYKY LRDNILPAIP KETVPAFKEA
LEERKFRIMP NQYLSAMKQG SENHKGFILL GDSLNMRHPL TGGGMTVGLN DSVLLAKLLH
PKFVEDFDDH QLIAKRLKTF HRKRKNLDAV INTLSISLYS LFAADKKPLR ILRNGCFKYF
QRGGECVNGP IGLLSGMLPF PMLLFNHFFS VAFYSVYLNF IERGLLGFPL ALFEAFEVLF
TAIVIFTPYL WNEIVR
