ERG4_CANAL
ID ERG4_CANAL Reviewed; 469 AA.
AC A0A1D8PJ25;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 18-JAN-2017, sequence version 1.
DT 03-AUG-2022, entry version 24.
DE RecName: Full=Delta(24(24(1)))-sterol reductase {ECO:0000250|UniProtKB:P25340};
DE EC=1.3.1.71 {ECO:0000250|UniProtKB:P25340};
DE AltName: Full=C-24(28) sterol reductase {ECO:0000250|UniProtKB:P25340};
DE AltName: Full=Ergosterol biosynthetic protein 4 {ECO:0000250|UniProtKB:P25340};
DE AltName: Full=Sterol Delta(24(28))-reductase {ECO:0000250|UniProtKB:P25340};
GN Name=ERG4 {ECO:0000250|UniProtKB:P25340}; OrderedLocusNames=orf19.5379;
GN ORFNames=CAALFM_C300760WA;
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 [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 [2]
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 [3]
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 [4]
RP INDUCTION.
RX PubMed=15917516; DOI=10.1128/aac.49.6.2226-2236.2005;
RA Liu T.T., Lee R.E., Barker K.S., Lee R.E., Wei L., Homayouni R.,
RA Rogers P.D.;
RT "Genome-wide expression profiling of the response to azole, polyene,
RT echinocandin, and pyrimidine antifungal agents in Candida albicans.";
RL Antimicrob. Agents Chemother. 49:2226-2236(2005).
RN [5]
RP INDUCTION.
RX PubMed=19527170; DOI=10.1086/599838;
RA Nett J.E., Lepak A.J., Marchillo K., Andes D.R.;
RT "Time course global gene expression analysis of an in vivo Candida
RT biofilm.";
RL J. Infect. Dis. 200:307-313(2009).
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 (By similarity). Catalyzes the last step of ergosterol
CC biosynthesis by converting ergosta-5,7,22,24(28)-tetraen-3beta-ol into
CC ergosterol (By similarity). The third module or late pathway involves
CC the ergosterol synthesis itself through consecutive reactions that
CC mainly occur in the endoplasmic reticulum (ER) membrane. Firstly, the
CC 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 (Probable). {ECO:0000250|UniProtKB:P25340, ECO:0000305}.
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:0000250|UniProtKB:P25340};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:18503;
CC Evidence={ECO:0000250|UniProtKB:P25340};
CC -!- PATHWAY: Steroid metabolism; ergosterol biosynthesis; ergosterol from
CC zymosterol: step 5/5. {ECO:0000250|UniProtKB:P25340}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000305};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- INDUCTION: Expression is induced by fluconazole and repressed by
CC caspofungin (PubMed:15917516). Expression is also repressed during
CC biofilm formation (PubMed:19527170). {ECO:0000269|PubMed:15917516,
CC ECO:0000269|PubMed:19527170}.
CC -!- SIMILARITY: Belongs to the ERG4/ERG24 family. {ECO:0000305}.
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DR EMBL; CP017625; AOW28125.1; -; Genomic_DNA.
DR RefSeq; XP_717756.2; XM_712663.2.
DR AlphaFoldDB; A0A1D8PJ25; -.
DR SMR; A0A1D8PJ25; -.
DR STRING; 237561.A0A1D8PJ25; -.
DR GeneID; 3640511; -.
DR KEGG; cal:CAALFM_C300760WA; -.
DR CGD; CAL0000199354; ERG4.
DR VEuPathDB; FungiDB:C3_00760W_A; -.
DR eggNOG; KOG1435; Eukaryota.
DR OrthoDB; 532774at2759; -.
DR UniPathway; UPA00768; UER00764.
DR Proteomes; UP000000559; Chromosome 3.
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; IBA:GO_Central.
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; IBA:GO_Central.
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 2: Evidence at transcript 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..469
FT /note="Delta(24(24(1)))-sterol reductase"
FT /id="PRO_0000454173"
FT TRANSMEM 36..56
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 97..117
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 138..158
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 174..194
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 225..245
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 290..310
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 322..342
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 415..435
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REGION 1..20
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 1..17
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 349
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 353
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 389
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 401..402
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 441
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 445..449
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 456
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
SQ SEQUENCE 469 AA; 54837 MW; 2AB107BBA8548778 CRC64;
MAASDTQSTS DETTPLVGSD ESRYIPKDQI EYEFGGPIGA LGMMIGFPLL MWYMWISAQF
YNGQFALPSE GQSWKDFIID DLFSKWVEYG IPSFGNWAFF TGFILIQALF YVTLPGVWTK
GQPLTHLNNK QLPYFCNAIW SFYTSIVLSL VLHFTGVLPV YYMLDNVGGI MTTAIFYGIS
LSIILYLICI FVTGDYHRMT GNHIYDMFMG APLNPRIGKY LDLKMFFEVR IPWFILFFLS
FGLCFKQYET YGYVTPQACF MLYAHWLYAN ACAKGEELIV PTWDMAYEKF GFMLLFWNIA
GVPFSYCQCI LYIAYQEPEV YQWSIGYNVF LFVLITIAYY FFDTGNRQKN SFRRSVAGNS
QLRKTFPYLP YSDLVNPKYI KCANGSLLLT DGWYVYARKM HYTADYIQTL TWALMCGFGS
PFPWFFPIFF FIVLVHRGYR DQRKCAKKYG KDWDRYLEAC PYMFIPYVW
