ERG25_CANAL
ID ERG25_CANAL Reviewed; 308 AA.
AC O59933; A0A1D8PS80; Q59V08;
DT 15-JUL-1999, integrated into UniProtKB/Swiss-Prot.
DT 01-AUG-1998, sequence version 1.
DT 25-MAY-2022, entry version 126.
DE RecName: Full=C-4 methylsterol oxidase {ECO:0000303|PubMed:10783002};
DE EC=1.14.18.9 {ECO:0000269|PubMed:10783002};
DE AltName: Full=Ergosterol biosynthesis protein 25 {ECO:0000303|PubMed:10783002};
DE AltName: Full=Sterol-C4-methyl oxidase {ECO:0000303|PubMed:10783002};
DE Short=SMO {ECO:0000303|PubMed:10783002};
GN Name=ERG25 {ECO:0000303|PubMed:10783002};
GN OrderedLocusNames=CAALFM_CR02370WA; ORFNames=CaO19.11216, CaO19.3732;
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], FUNCTION, DISRUPTION PHENOTYPE,
RP MUTAGENESIS OF ASN-247, DOMAIN, AND PATHWAY.
RC STRAIN=CAI-8;
RX PubMed=10783002; DOI=10.1007/s11745-000-0521-2;
RA Kennedy M.A., Johnson T.A., Lees N.D., Barbuch R., Eckstein J.A., Bard M.;
RT "Cloning and sequencing of the Candida albicans C-4 sterol methyl oxidase
RT gene (ERG25) and expression of an ERG25 conditional lethal mutation in
RT Saccharomyces cerevisiae.";
RL Lipids 35:257-262(2000).
RN [2]
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 [3]
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 [4]
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 [5]
RP INDUCTION.
RX PubMed=14653518; DOI=10.1080/1369378031000137233;
RA Song J.L., Lyons C.N., Holleman S., Oliver B.G., White T.C.;
RT "Antifungal activity of fluconazole in combination with lovastatin and
RT their effects on gene expression in the ergosterol and prenylation pathways
RT in Candida albicans.";
RL Med. Mycol. 41:417-425(2003).
RN [6]
RP INDUCTION.
RX PubMed=15273122; DOI=10.1128/aac.48.8.3064-3079.2004;
RA Karababa M., Coste A.T., Rognon B., Bille J., Sanglard D.;
RT "Comparison of gene expression profiles of Candida albicans azole-resistant
RT clinical isolates and laboratory strains exposed to drugs inducing
RT multidrug transporters.";
RL Antimicrob. Agents Chemother. 48:3064-3079(2004).
RN [7]
RP INDUCTION.
RX PubMed=15075282; DOI=10.1128/ec.3.2.536-545.2004;
RA Garcia-Sanchez S., Aubert S., Iraqui I., Janbon G., Ghigo J.M.,
RA d'Enfert C.;
RT "Candida albicans biofilms: a developmental state associated with specific
RT and stable gene expression patterns.";
RL Eukaryot. Cell 3:536-545(2004).
RN [8]
RP INDUCTION.
RX PubMed=15473366; DOI=10.1080/13693780410001712016;
RA Pierson C.A., Eckstein J., Barbuch R., Bard M.;
RT "Ergosterol gene expression in wild-type and ergosterol-deficient mutants
RT of Candida albicans.";
RL Med. Mycol. 42:385-389(2004).
RN [9]
RP INDUCTION.
RX PubMed=15820985; DOI=10.1093/jac/dki088;
RA Copping V.M.S., Barelle C.J., Hube B., Gow N.A.R., Brown A.J.P., Odds F.C.;
RT "Exposure of Candida albicans to antifungal agents affects expression of
RT SAP2 and SAP9 secreted proteinase genes.";
RL J. Antimicrob. Chemother. 55:645-654(2005).
RN [10]
RP INDUCTION.
RX PubMed=22265407; DOI=10.1016/j.cell.2011.10.048;
RA Nobile C.J., Fox E.P., Nett J.E., Sorrells T.R., Mitrovich Q.M.,
RA Hernday A.D., Tuch B.B., Andes D.R., Johnson A.D.;
RT "A recently evolved transcriptional network controls biofilm development in
RT Candida albicans.";
RL Cell 148:126-138(2012).
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:10783002). ERG25 is a catalytic component of the C-4
CC demethylation complex that catalyzes the conversion of 4,4-
CC dimethylfecosterol into fecosterol via 4-methylfecosterol
CC (PubMed:10783002). Catalyzes the three-step monooxygenation required
CC for the demethylation of 4,4-dimethyl and 4alpha-methylsterols
CC (PubMed:10783002). The third module or late pathway involves the
CC ergosterol synthesis itself through consecutive reactions that mainly
CC occur in the endoplasmic reticulum (ER) membrane. Firstly, the squalene
CC synthase ERG9 catalyzes the condensation of 2 farnesyl pyrophosphate
CC moieties to form squalene, which is the precursor of all steroids.
CC Squalene synthase is crucial for balancing the incorporation of
CC 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:0000269|PubMed:10783002, ECO:0000305}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=4,4-dimethyl-5alpha-cholest-7-en-3beta-ol + 6 Fe(II)-
CC [cytochrome b5] + 5 H(+) + 3 O2 = 4alpha-carboxy-4beta-methyl-5alpha-
CC cholest-7-ene-3beta-ol + 6 Fe(III)-[cytochrome b5] + 4 H2O;
CC Xref=Rhea:RHEA:55220, Rhea:RHEA-COMP:10438, Rhea:RHEA-COMP:10439,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:16455, ChEBI:CHEBI:29033, ChEBI:CHEBI:29034,
CC ChEBI:CHEBI:58387; EC=1.14.18.9;
CC Evidence={ECO:0000305|PubMed:10783002};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:55221;
CC Evidence={ECO:0000305|PubMed:10783002};
CC -!- COFACTOR:
CC Name=Fe cation; Xref=ChEBI:CHEBI:24875;
CC Evidence={ECO:0000250|UniProtKB:P53045};
CC -!- PATHWAY: Steroid biosynthesis; zymosterol biosynthesis; zymosterol from
CC lanosterol: step 3/6. {ECO:0000269|PubMed:10783002}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000305};
CC Single-pass membrane protein {ECO:0000255}.
CC -!- INDUCTION: Expression is induced by fluconazole and in azole-resistant
CC strains (PubMed:15273122, PubMed:15820985). Expression is induced
CC during biofilm formation (PubMed:15075282). Expression is up-regulated
CC when ERG6, CYP51/ERG11 or ERG24 are deleted (PubMed:15473366).
CC {ECO:0000269|PubMed:15075282, ECO:0000269|PubMed:15273122,
CC ECO:0000269|PubMed:15473366, ECO:0000269|PubMed:15820985}.
CC -!- DOMAIN: The histidine box domains may contain the active site and/or be
CC involved in metal ion binding. {ECO:0000305|PubMed:10783002}.
CC -!- DISRUPTION PHENOTYPE: Essential gene; conditional lethal mutations
CC decrease the production of ergosterol and accumulate 4,4-
CC dimethylzymosterol. {ECO:0000269|PubMed:10783002}.
CC -!- SIMILARITY: Belongs to the sterol desaturase family. {ECO:0000305}.
CC ---------------------------------------------------------------------------
CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms
CC Distributed under the Creative Commons Attribution (CC BY 4.0) License
CC ---------------------------------------------------------------------------
DR EMBL; AF051914; AAC06014.1; -; Genomic_DNA.
DR EMBL; CP017630; AOW30984.1; -; Genomic_DNA.
DR RefSeq; XP_713420.1; XM_708327.2.
DR AlphaFoldDB; O59933; -.
DR STRING; 237561.O59933; -.
DR GeneID; 3644933; -.
DR KEGG; cal:CAALFM_CR02370WA; -.
DR CGD; CAL0000179313; ERG25.
DR VEuPathDB; FungiDB:CR_02370W_A; -.
DR eggNOG; KOG0873; Eukaryota.
DR HOGENOM; CLU_047036_5_0_1; -.
DR InParanoid; O59933; -.
DR OMA; IVHEFIY; -.
DR OrthoDB; 1493916at2759; -.
DR UniPathway; UPA00770; UER00756.
DR PRO; PR:O59933; -.
DR Proteomes; UP000000559; Chromosome R.
DR GO; GO:0005783; C:endoplasmic reticulum; ISS:CGD.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IBA:GO_Central.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0016020; C:membrane; IBA:GO_Central.
DR GO; GO:0000254; F:C-4 methylsterol oxidase activity; ISS:CGD.
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; ISS:CGD.
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; Lipid biosynthesis; Lipid metabolism;
KW Membrane; NAD; Oxidoreductase; Reference proteome; Steroid biosynthesis;
KW Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..308
FT /note="C-4 methylsterol oxidase"
FT /id="PRO_0000117037"
FT TRANSMEM 56..76
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 145..282
FT /note="Fatty acid hydroxylase"
FT /evidence="ECO:0000255"
FT MOTIF 160..164
FT /note="Histidine box-1"
FT /evidence="ECO:0000305|PubMed:10783002"
FT MOTIF 173..177
FT /note="Histidine box-2"
FT /evidence="ECO:0000305|PubMed:10783002"
FT MOTIF 257..263
FT /note="Histidine box-3"
FT /evidence="ECO:0000305|PubMed:10783002"
FT MUTAGEN 247
FT /note="N->D: Leads to temperature-sensitive (ts)
FT conditional lethality."
FT /evidence="ECO:0000269|PubMed:10783002"
SQ SEQUENCE 308 AA; 36561 MW; 45D7D7AE4081BC15 CRC64;
MSSISNVYHD YSSFSNATTF SQVYQNFNQL DNLNVFEKLW GSYYYYMAND LFATGLLFFL
THEIFYFGRC LPWAIIDRIP YFRKWKIQDE KIPSDKEQWE CLKSVLTSHF LVEAFPIWFF
HPLCQKIGIS YQVPFPKITD MLIQWAVFFV LEDTWHYWFH RGLHYGVFYK YIHKQHHRYA
APFGLAAEYA HPVEVALLGL GTVGIPIVWC LITGNLHLFT VSIWIILRLF QAVDAHSGYE
FPWSLHNFLP FWAGADHHDE HHHYFIGGYS SSFRWWDFIL DTEAGPKAKK GREDKVKQNV
EKLQKKNL
