ERG25_YEAST
ID ERG25_YEAST Reviewed; 309 AA.
AC P53045; D6VUJ5; E9P8T3; Q45U26;
DT 01-OCT-1996, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 1.
DT 03-AUG-2022, entry version 179.
DE RecName: Full=C-4 methylsterol oxidase ERG25 {ECO:0000303|PubMed:8552601};
DE EC=1.14.18.- {ECO:0000269|PubMed:12880870, ECO:0000269|PubMed:8552601};
DE AltName: Full=Ergosterol biosynthetic protein 25 {ECO:0000303|PubMed:8552601};
DE AltName: Full=Sterol-C4-methyl oxidase ERG25 {ECO:0000303|PubMed:8552601};
DE Short=SMO {ECO:0000303|PubMed:8552601};
GN Name=ERG25 {ECO:0000303|PubMed:8552601}; Synonyms=FET6;
GN OrderedLocusNames=YGR060W;
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, DOMAIN,
RP AND PATHWAY.
RX PubMed=8552601; DOI=10.1073/pnas.93.1.186;
RA Bard M., Bruner D.A., Pierson C.A., Lees N.D., Biermann B., Frye L.,
RA Koegel C., Barbuch R.;
RT "Cloning and characterization of ERG25, the Saccharomyces cerevisiae gene
RT encoding C-4 sterol methyl oxidase.";
RL Proc. Natl. Acad. Sci. U.S.A. 93:186-190(1996).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, COFACTOR, AND SUBCELLULAR
RP LOCATION.
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 [3]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=SK1;
RX PubMed=16273108; DOI=10.1038/ng1674;
RA Deutschbauer A.M., Davis R.W.;
RT "Quantitative trait loci mapped to single-nucleotide resolution in yeast.";
RL Nat. Genet. 37:1333-1340(2005).
RN [4]
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 [5]
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 [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 204508 / S288c;
RX PubMed=17322287; DOI=10.1101/gr.6037607;
RA Hu Y., Rolfs A., Bhullar B., Murthy T.V.S., Zhu C., Berger M.F.,
RA Camargo A.A., Kelley F., McCarron S., Jepson D., Richardson A., Raphael J.,
RA Moreira D., Taycher E., Zuo D., Mohr S., Kane M.F., Williamson J.,
RA Simpson A.J.G., Bulyk M.L., Harlow E., Marsischky G., Kolodner R.D.,
RA LaBaer J.;
RT "Approaching a complete repository of sequence-verified protein-encoding
RT clones for Saccharomyces cerevisiae.";
RL Genome Res. 17:536-543(2007).
RN [7]
RP FUNCTION, SUBUNIT, INTERACTION WITH ERG27 AND ERG28, AND SUBCELLULAR
RP LOCATION.
RX PubMed=12119386; DOI=10.1073/pnas.112202799;
RA Mo C., Valachovic M., Randall S.K., Nickels J.T., Bard M.;
RT "Protein-protein interactions among C-4 demethylation enzymes involved in
RT yeast sterol biosynthesis.";
RL Proc. Natl. Acad. Sci. U.S.A. 99:9739-9744(2002).
RN [8]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=12880870; DOI=10.1016/s1388-1981(03)00093-3;
RA Darnet S., Rahier A.;
RT "Enzymological properties of sterol-C4-methyl-oxidase of yeast sterol
RT biosynthesis.";
RL Biochim. Biophys. Acta 1633:106-117(2003).
RN [9]
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 [10]
RP UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-96, AND IDENTIFICATION BY MASS
RP 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 [11]
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 [12]
RP SUBCELLULAR LOCATION.
RX PubMed=15716577; DOI=10.1074/mcp.m400123-mcp200;
RA Natter K., Leitner P., Faschinger A., Wolinski H., McCraith S., Fields S.,
RA Kohlwein S.D.;
RT "The spatial organization of lipid synthesis in the yeast Saccharomyces
RT cerevisiae derived from large scale green fluorescent protein tagging and
RT high resolution microscopy.";
RL Mol. Cell. Proteomics 4:662-672(2005).
RN [13]
RP UBIQUITINATION [LARGE SCALE ANALYSIS] AT LYS-96, AND IDENTIFICATION BY MASS
RP 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 [14]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=29773647; DOI=10.1074/jbc.ra118.001781;
RA Ward D.M., Chen O.S., Li L., Kaplan J., Bhuiyan S.A., Natarajan S.K.,
RA Bard M., Cox J.E.;
RT "Altered sterol metabolism in budding yeast affects mitochondrial iron-
RT sulfur (Fe-S) cluster synthesis.";
RL J. Biol. Chem. 293:10782-10795(2018).
RN [15]
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: C-4 methylsterol oxidase; part of the third module of
CC ergosterol biosynthesis pathway that includes the late steps of the
CC pathway (PubMed:8552601, PubMed:12880870, PubMed:29773647). ERG25 is a
CC catalytic component of the C-4 demethylation complex that catalyzes the
CC three-step monooxygenation required for the demethylation of 4,4-
CC dimethyl and 4alpha-methylsterols (PubMed:8552601, PubMed:12880870).
CC The third module or late pathway involves the ergosterol synthesis
CC itself through consecutive reactions that mainly occur in the
CC endoplasmic reticulum (ER) membrane. Firstly, the squalene synthase
CC ERG9 catalyzes the condensation of 2 farnesyl pyrophosphate moieties to
CC form squalene, which is the precursor of all steroids. Squalene
CC synthase is crucial for balancing the incorporation of farnesyl
CC diphosphate (FPP) into sterol and nonsterol isoprene synthesis.
CC Secondly, the squalene epoxidase ERG1 catalyzes the stereospecific
CC oxidation of squalene to (S)-2,3-epoxysqualene, which is considered to
CC be a rate-limiting enzyme in steroid biosynthesis. Then, the lanosterol
CC synthase ERG7 catalyzes the cyclization of (S)-2,3 oxidosqualene to
CC lanosterol, a reaction that forms the sterol core. In the next steps,
CC lanosterol is transformed to zymosterol through a complex process
CC involving various demethylation, reduction and desaturation reactions.
CC The lanosterol 14-alpha-demethylase ERG11 (also known as CYP51)
CC catalyzes C14-demethylation of lanosterol to produce 4,4'-dimethyl
CC cholesta-8,14,24-triene-3-beta-ol, which is critical for ergosterol
CC biosynthesis. The C-14 reductase ERG24 reduces the C14=C15 double bond
CC of 4,4-dimethyl-cholesta-8,14,24-trienol to produce 4,4-dimethyl-
CC cholesta-8,24-dienol. 4,4-dimethyl-cholesta-8,24-dienol is substrate of
CC the C-4 demethylation complex ERG25-ERG26-ERG27 in which ERG25
CC catalyzes the three-step monooxygenation required for the demethylation
CC of 4,4-dimethyl and 4alpha-methylsterols, ERG26 catalyzes the oxidative
CC decarboxylation that results in a reduction of the 3-beta-hydroxy group
CC at the C-3 carbon to an oxo group, and ERG27 is responsible for the
CC reduction of the keto group on the C-3. ERG28 has a role as a scaffold
CC to help anchor ERG25, ERG26 and ERG27 to the endoplasmic reticulum and
CC ERG29 regulates the activity of the iron-containing C4-methylsterol
CC oxidase ERG25. Then, the sterol 24-C-methyltransferase ERG6 catalyzes
CC the methyl transfer from S-adenosyl-methionine to the C-24 of
CC zymosterol to form fecosterol. The C-8 sterol isomerase ERG2 catalyzes
CC the reaction which results in unsaturation at C-7 in the B ring of
CC sterols and thus converts fecosterol to episterol. The sterol-C5-
CC desaturase ERG3 then catalyzes the introduction of a C-5 double bond in
CC the B ring to produce 5-dehydroepisterol. The C-22 sterol desaturase
CC ERG5 further converts 5-dehydroepisterol into ergosta-5,7,22,24(28)-
CC tetraen-3beta-ol by forming the C-22(23) double bond in the sterol side
CC chain. Finally, ergosta-5,7,22,24(28)-tetraen-3beta-ol is substrate of
CC the C-24(28) sterol reductase ERG4 to produce ergosterol
CC (PubMed:32679672). {ECO:0000269|PubMed:12880870,
CC ECO:0000269|PubMed:29773647, ECO:0000269|PubMed:8552601,
CC ECO:0000303|PubMed:32679672}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4,4-dimethyl-5alpha-cholesta-8,24-dien-3beta-ol + 6 Fe(II)-
CC [cytochrome b5] + 5 H(+) + 3 O2 = 4beta-methylzymosterol-4alpha-
CC carboxylate + 6 Fe(III)-[cytochrome b5] + 4 H2O;
CC Xref=Rhea:RHEA:55244, Rhea:RHEA-COMP:10438, Rhea:RHEA-COMP:10439,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:18364, ChEBI:CHEBI:29033, ChEBI:CHEBI:29034,
CC ChEBI:CHEBI:64925; Evidence={ECO:0000269|PubMed:12880870,
CC ECO:0000269|PubMed:8552601};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55245;
CC Evidence={ECO:0000269|PubMed:12880870, ECO:0000269|PubMed:8552601};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4alpha-methylzymosterol + 6 Fe(II)-[cytochrome b5] + 5 H(+) +
CC 3 O2 = 4alpha-carboxyzymosterol + 6 Fe(III)-[cytochrome b5] + 4 H2O;
CC Xref=Rhea:RHEA:47056, Rhea:RHEA-COMP:10438, Rhea:RHEA-COMP:10439,
CC ChEBI:CHEBI:1949, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:29033, ChEBI:CHEBI:29034,
CC ChEBI:CHEBI:143575; Evidence={ECO:0000269|PubMed:12880870};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47057;
CC Evidence={ECO:0000269|PubMed:12880870};
CC -!- COFACTOR:
CC Name=Fe cation; Xref=ChEBI:CHEBI:24875;
CC Evidence={ECO:0000269|PubMed:8663358};
CC -!- PATHWAY: Steroid biosynthesis; zymosterol biosynthesis; zymosterol from
CC lanosterol: step 3/6. {ECO:0000269|PubMed:12880870,
CC ECO:0000269|PubMed:8552601}.
CC -!- PATHWAY: Steroid metabolism; ergosterol biosynthesis.
CC {ECO:0000269|PubMed:12880870, ECO:0000269|PubMed:8552601}.
CC -!- SUBUNIT: Heterotetramer of ERG25, ERG26, ERG27 and ERG28. ERG28 acts as
CC a scaffold to tether ERG27 and other 4,4-demethylation-related enzymes,
CC forming a demethylation enzyme complex, in the endoplasmic reticulum.
CC Interacts with ERG27 and ERG28. {ECO:0000269|PubMed:12119386,
CC ECO:0000269|PubMed:15995173}.
CC -!- INTERACTION:
CC P53045; P10614: ERG11; NbExp=3; IntAct=EBI-6506, EBI-5127;
CC P53045; Q12452: ERG27; NbExp=4; IntAct=EBI-6506, EBI-38132;
CC P53045; P40030: ERG28; NbExp=3; IntAct=EBI-6506, EBI-22518;
CC P53045; P32353: ERG3; NbExp=3; IntAct=EBI-6506, EBI-6554;
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000305|PubMed:12119386, ECO:0000305|PubMed:15716577,
CC ECO:0000305|PubMed:8663358}; Single-pass membrane protein
CC {ECO:0000305|PubMed:12119386, ECO:0000305|PubMed:15716577,
CC ECO:0000305|PubMed:8663358}.
CC -!- DOMAIN: The histidine box domains may contain the active site and/or be
CC involved in metal ion binding. {ECO:0000305|PubMed:8552601}.
CC -!- DISRUPTION PHENOTYPE: Affects mitochondrial activities and leads to an
CC increase in intermediate sterols and a corresponding decrease in
CC zymosterol and ergosterol production. {ECO:0000269|PubMed:29773647}.
CC -!- MISCELLANEOUS: Present with 77100 molecules/cell in log phase SD
CC medium. {ECO:0000269|PubMed:14562106}.
CC -!- SIMILARITY: Belongs to the sterol desaturase family. {ECO:0000305}.
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DR EMBL; U31885; AAC49139.1; -; Genomic_DNA.
DR EMBL; DQ115391; AAZ22473.1; -; Genomic_DNA.
DR EMBL; Z72845; CAA97062.1; -; Genomic_DNA.
DR EMBL; AY557827; AAS56153.1; -; Genomic_DNA.
DR EMBL; BK006941; DAA08156.1; -; Genomic_DNA.
DR PIR; S64354; S64354.
DR RefSeq; NP_011574.3; NM_001181189.3.
DR AlphaFoldDB; P53045; -.
DR BioGRID; 33305; 315.
DR DIP; DIP-2799N; -.
DR IntAct; P53045; 60.
DR MINT; P53045; -.
DR STRING; 4932.YGR060W; -.
DR iPTMnet; P53045; -.
DR MaxQB; P53045; -.
DR PaxDb; P53045; -.
DR PRIDE; P53045; -.
DR EnsemblFungi; YGR060W_mRNA; YGR060W; YGR060W.
DR GeneID; 852951; -.
DR KEGG; sce:YGR060W; -.
DR SGD; S000003292; ERG25.
DR VEuPathDB; FungiDB:YGR060W; -.
DR eggNOG; KOG0873; Eukaryota.
DR GeneTree; ENSGT00940000158012; -.
DR HOGENOM; CLU_047036_5_0_1; -.
DR InParanoid; P53045; -.
DR OMA; IVHEFIY; -.
DR BioCyc; MetaCyc:YGR060W-MON; -.
DR BioCyc; YEAST:YGR060W-MON; -.
DR Reactome; R-SCE-191273; Cholesterol biosynthesis.
DR Reactome; R-SCE-192105; Synthesis of bile acids and bile salts.
DR UniPathway; UPA00768; -.
DR UniPathway; UPA00770; UER00756.
DR PRO; PR:P53045; -.
DR Proteomes; UP000002311; Chromosome VII.
DR RNAct; P53045; 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:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0005886; C:plasma membrane; IDA:SGD.
DR GO; GO:0000254; F:C-4 methylsterol oxidase activity; IDA:SGD.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IDA:SGD.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR InterPro; IPR006694; Fatty_acid_hydroxylase.
DR Pfam; PF04116; FA_hydroxylase; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Iron; Isopeptide bond; Lipid biosynthesis;
KW Lipid metabolism; Membrane; NAD; Oxidoreductase; Reference proteome;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Transmembrane; Transmembrane helix; Ubl conjugation.
FT CHAIN 1..309
FT /note="C-4 methylsterol oxidase ERG25"
FT /id="PRO_0000117039"
FT TRANSMEM 56..76
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 147..282
FT /note="Fatty acid hydroxylase"
FT /evidence="ECO:0000255"
FT REGION 287..309
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOTIF 160..164
FT /note="Histidine box-1"
FT /evidence="ECO:0000305|PubMed:8552601"
FT MOTIF 173..177
FT /note="Histidine box-2"
FT /evidence="ECO:0000305|PubMed:8552601"
FT MOTIF 257..263
FT /note="Histidine box-3"
FT /evidence="ECO:0000305|PubMed:8552601"
FT CROSSLNK 96
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in ubiquitin)"
FT /evidence="ECO:0007744|PubMed:22106047"
FT CONFLICT 302
FT /note="N -> K (in Ref. 6; AAS56153)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 309 AA; 36479 MW; E0422C416DD17794 CRC64;
MSAVFNNATL SGLVQASTYS QTLQNVAHYQ PQLNFMEKYW AAWYSYMNND VLATGLMFFL
LHEFMYFFRC LPWFIIDQIP YFRRWKLQPT KIPSAKEQLY CLKSVLLSHF LVEAIPIWTF
HPMCEKLGIT VEVPFPSLKT MALEIGLFFV LEDTWHYWAH RLFHYGVFYK YIHKQHHRYA
APFGLSAEYA HPAETLSLGF GTVGMPILYV MYTGKLHLFT LCVWITLRLF QAVDSHSGYD
FPWSLNKIMP FWAGAEHHDL HHHYFIGNYA SSFRWWDYCL DTESGPEAKA SREERMKKRA
ENNAQKKTN
