ERG4_YEAST
ID ERG4_YEAST Reviewed; 473 AA.
AC P25340; D6VUC5; E9P929;
DT 01-MAY-1992, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-1996, sequence version 2.
DT 03-AUG-2022, entry version 173.
DE RecName: Full=Delta(24(24(1)))-sterol reductase ERG4 {ECO:0000303|PubMed:8125337};
DE EC=1.3.1.71 {ECO:0000269|PubMed:10722850};
DE AltName: Full=C-24(28) sterol reductase ERG4 {ECO:0000303|PubMed:8125337};
DE AltName: Full=Ergosterol biosynthetic protein 4 {ECO:0000303|PubMed:8125337};
DE AltName: Full=Sterol Delta(24(28))-reductase ERG4 {ECO:0000303|PubMed:8125337};
GN Name=ERG4 {ECO:0000303|PubMed:8125337}; OrderedLocusNames=YGL012W;
GN ORFNames=YGL022;
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].
RC STRAIN=ATCC 46191 / IL125-2B;
RX PubMed=1882555; DOI=10.1002/yea.320070313;
RA Chen W., Capieaux E., Balzi E., Goffeau A.;
RT "The YGL022 gene encodes a putative transport protein.";
RL Yeast 7:305-308(1991).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=ATCC 46191 / IL125-2B;
RX PubMed=1882553; DOI=10.1002/yea.320070311;
RA Chen W., Balzi E., Capieaux E., Choder M., Goffeau A.;
RT "The DNA sequencing of the 17 kb HindIII fragment spanning the LEU1 and
RT ATE1 loci on chromosome VII from Saccharomyces cerevisiae reveals the PDR6
RT gene, a new member of the genetic network controlling pleiotropic drug
RT resistance.";
RL Yeast 7:287-299(1991).
RN [3]
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 [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 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 [6]
RP FUNCTION.
RX PubMed=8125337; DOI=10.1016/0378-1119(94)90728-5;
RA Lai M.H., Bard M., Pierson C.A., Alexander J.F., Goebl M., Carter G.T.,
RA Kirsch D.R.;
RT "The identification of a gene family in the Saccharomyces cerevisiae
RT ergosterol biosynthesis pathway.";
RL Gene 140:41-49(1994).
RN [7]
RP FUNCTION, DISRUPTION PHENOTYPE, CATALYTIC ACTIVITY, SUBCELLULAR LOCATION,
RP AND PATHWAY.
RX PubMed=10722850; DOI=10.1016/s0014-5793(00)01290-4;
RA Zweytick D., Hrastnik C., Kohlwein S.D., Daum G.;
RT "Biochemical characterization and subcellular localization of the sterol C-
RT 24(28) reductase, erg4p, from the yeast saccharomyces cerevisiae.";
RL FEBS Lett. 470:83-87(2000).
RN [8]
RP FUNCTION.
RX PubMed=12882006; DOI=10.1023/a:1023572403185;
RA He X., Zhang B., Tan H.;
RT "Overexpression of a sterol C-24(28) reductase increases ergosterol
RT production in Saccharomyces cerevisiae.";
RL Biotechnol. Lett. 25:773-778(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 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 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-24(28) sterol reductase; part of the third module of
CC ergosterol biosynthesis pathway that includes the late steps of the
CC pathway (PubMed:8125337, PubMed:10722850, PubMed:12882006). ERG4
CC Catalyzes the last step of ergosterol biosynthesis by converting
CC ergosta-5,7,22,24(28)-tetraen-3beta-ol into ergosterol
CC (PubMed:10722850, PubMed:12882006). 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:10722850,
CC ECO:0000269|PubMed:12882006, ECO:0000269|PubMed:8125337,
CC ECO:0000303|PubMed:32679672}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=ergosterol + NADP(+) = ergosta-5,7,22,24(28)-tetraen-3beta-ol
CC + H(+) + NADPH; Xref=Rhea:RHEA:18501, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16933, ChEBI:CHEBI:18249, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:58349; EC=1.3.1.71;
CC Evidence={ECO:0000269|PubMed:10722850};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:18503;
CC Evidence={ECO:0000269|PubMed:10722850};
CC -!- PATHWAY: Steroid metabolism; ergosterol biosynthesis; ergosterol from
CC zymosterol: step 5/5. {ECO:0000269|PubMed:10722850}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:10722850}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Leads to pleiotropic defects such as
CC hypersensitivity to divalent cations and a number of drugs such as
CC cycloheximide, miconazole, 4-nitroquinoline, fluconazole, and sodium
CC dodecyl sulfate (PubMed:10722850). Leads also to sensitivity to the
CC Golgi-destabilizing drug brefeldin A (PubMed:10722850).
CC {ECO:0000269|PubMed:10722850}.
CC -!- MISCELLANEOUS: Present with 1640 molecules/cell in log phase SD medium.
CC {ECO:0000269|PubMed:14562106}.
CC -!- SIMILARITY: Belongs to the ERG4/ERG24 family. {ECO:0000305}.
CC -!- CAUTION: Was originally thought to be a transport protein.
CC {ECO:0000305|PubMed:1882555}.
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DR EMBL; S58126; AAD13895.1; -; Genomic_DNA.
DR EMBL; S57891; AAB19615.1; -; Genomic_DNA.
DR EMBL; Z72534; CAA96712.1; -; Genomic_DNA.
DR EMBL; AY693205; AAT93224.1; -; Genomic_DNA.
DR EMBL; BK006941; DAA08086.1; -; Genomic_DNA.
DR PIR; S64014; S64014.
DR RefSeq; NP_011503.1; NM_001180877.1.
DR AlphaFoldDB; P25340; -.
DR SMR; P25340; -.
DR BioGRID; 33234; 273.
DR DIP; DIP-7177N; -.
DR IntAct; P25340; 13.
DR MINT; P25340; -.
DR STRING; 4932.YGL012W; -.
DR iPTMnet; P25340; -.
DR MaxQB; P25340; -.
DR PaxDb; P25340; -.
DR PRIDE; P25340; -.
DR EnsemblFungi; YGL012W_mRNA; YGL012W; YGL012W.
DR GeneID; 852872; -.
DR KEGG; sce:YGL012W; -.
DR SGD; S000002980; ERG4.
DR VEuPathDB; FungiDB:YGL012W; -.
DR eggNOG; KOG1435; Eukaryota.
DR GeneTree; ENSGT00390000000417; -.
DR HOGENOM; CLU_015631_3_1_1; -.
DR InParanoid; P25340; -.
DR OMA; KQLPYFC; -.
DR BioCyc; MetaCyc:YGL012W-MON; -.
DR BioCyc; YEAST:YGL012W-MON; -.
DR UniPathway; UPA00768; UER00764.
DR PRO; PR:P25340; -.
DR Proteomes; UP000002311; Chromosome VII.
DR RNAct; P25340; protein.
DR GO; GO:0005783; C:endoplasmic reticulum; IDA:SGD.
DR GO; GO:0030176; C:integral component of endoplasmic reticulum membrane; IBA:GO_Central.
DR GO; GO:0000246; F:delta24(24-1) sterol reductase activity; IDA:SGD.
DR GO; GO:0016627; F:oxidoreductase activity, acting on the CH-CH group of donors; IBA:GO_Central.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IMP:SGD.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR InterPro; IPR001171; ERG24_DHCR-like.
DR InterPro; IPR018083; Sterol_reductase_CS.
DR Pfam; PF01222; ERG4_ERG24; 1.
DR PROSITE; PS01017; STEROL_REDUCT_1; 1.
DR PROSITE; PS01018; STEROL_REDUCT_2; 1.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Lipid biosynthesis; Lipid metabolism; Membrane;
KW NADP; Oxidoreductase; Reference proteome; Steroid biosynthesis;
KW Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..473
FT /note="Delta(24(24(1)))-sterol reductase ERG4"
FT /id="PRO_0000207491"
FT TOPO_DOM 1..39
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 40..64
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 65..101
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 102..123
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 124..138
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 139..157
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 158..174
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 175..197
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 198..232
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 233..249
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 250..326
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT TRANSMEM 327..346
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 347..414
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 415..439
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 440..473
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT REGION 1..20
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..15
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 353
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 357
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 393
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 405..406
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 445
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 449..453
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 460
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT CONFLICT 33
FT /note="P -> L (in Ref. 5; AAT93224)"
FT /evidence="ECO:0000305"
FT CONFLICT 366
FT /note="G -> V (in Ref. 1 and 2)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 473 AA; 56040 MW; B4BFF14559272DD6 CRC64;
MAKDNSEKLQ VQGEEKKSKQ PVNFLPQGKW LKPNEIEYEF GGTTGVIGML IGFPLLMYYM
WICAEFYHGK VALPKAGESW MHFIKHLYQL VLENGIPEKY DWTIFLTFWV FQIIFYYTLP
GIWTKGQPLS HLKGKQLPYF CNAMWTLYVT TTLVLVLHFT NLFRLYVIID RFGRIMTCAI
ISGFAFSIIL YLWTLFISHD YHRMTGNHLY DFFMGAPLNP RWGILDLKMF FEVRLPWFTL
YFITLGACLK QWETYGYVTP QLGVVMLAHW LYANACAKGE ELIVPTWDMA YEKFGFMLIF
WNIAGVPYTY CHCTLYLYYH DPSEYHWSTL YNVSLYVVLL CAYYFFDTAN AQKNAFRKQM
SGDKTGRKTF PFLPYQILKN PKYMVTSNGS YLLIDGWYTL ARKIHYTADW TQSLVWALSC
GFNSVFPWFF PVFFLVVLIH RAFRDQAKCK RKYGKDWDEY CKHCPYVFIP YVF
