ER25A_ASPFU
ID ER25A_ASPFU Reviewed; 302 AA.
AC Q4WBI8;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 90.
DE RecName: Full=Methylsterol monooxygenase erg25A {ECO:0000303|PubMed:25107308};
DE EC=1.14.18.- {ECO:0000305|PubMed:25107308};
DE AltName: Full=C-4 methylsterol oxidase erg25A {ECO:0000303|PubMed:25107308};
DE AltName: Full=Ergosterol biosynthesis protein 25A {ECO:0000303|PubMed:25107308};
DE AltName: Full=Sterol-C4-methyl oxidase erg25A {ECO:0000303|PubMed:25107308};
DE Short=SMO {ECO:0000303|PubMed:25107308};
GN Name=erg25A {ECO:0000303|PubMed:25107308}; ORFNames=AFUA_8G02440;
OS Neosartorya fumigata (strain ATCC MYA-4609 / Af293 / CBS 101355 / FGSC
OS A1100) (Aspergillus fumigatus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Fumigati.
OX NCBI_TaxID=330879;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC MYA-4609 / Af293 / CBS 101355 / FGSC A1100;
RX PubMed=16372009; DOI=10.1038/nature04332;
RA Nierman W.C., Pain A., Anderson M.J., Wortman J.R., Kim H.S., Arroyo J.,
RA Berriman M., Abe K., Archer D.B., Bermejo C., Bennett J.W., Bowyer P.,
RA Chen D., Collins M., Coulsen R., Davies R., Dyer P.S., Farman M.L.,
RA Fedorova N., Fedorova N.D., Feldblyum T.V., Fischer R., Fosker N.,
RA Fraser A., Garcia J.L., Garcia M.J., Goble A., Goldman G.H., Gomi K.,
RA Griffith-Jones S., Gwilliam R., Haas B.J., Haas H., Harris D.E.,
RA Horiuchi H., Huang J., Humphray S., Jimenez J., Keller N., Khouri H.,
RA Kitamoto K., Kobayashi T., Konzack S., Kulkarni R., Kumagai T., Lafton A.,
RA Latge J.-P., Li W., Lord A., Lu C., Majoros W.H., May G.S., Miller B.L.,
RA Mohamoud Y., Molina M., Monod M., Mouyna I., Mulligan S., Murphy L.D.,
RA O'Neil S., Paulsen I., Penalva M.A., Pertea M., Price C., Pritchard B.L.,
RA Quail M.A., Rabbinowitsch E., Rawlins N., Rajandream M.A., Reichard U.,
RA Renauld H., Robson G.D., Rodriguez de Cordoba S., Rodriguez-Pena J.M.,
RA Ronning C.M., Rutter S., Salzberg S.L., Sanchez M., Sanchez-Ferrero J.C.,
RA Saunders D., Seeger K., Squares R., Squares S., Takeuchi M., Tekaia F.,
RA Turner G., Vazquez de Aldana C.R., Weidman J., White O., Woodward J.R.,
RA Yu J.-H., Fraser C.M., Galagan J.E., Asai K., Machida M., Hall N.,
RA Barrell B.G., Denning D.W.;
RT "Genomic sequence of the pathogenic and allergenic filamentous fungus
RT Aspergillus fumigatus.";
RL Nature 438:1151-1156(2005).
RN [2]
RP IDENTIFICATION, FUNCTION, AND PATHWAY.
RX PubMed=16110826; DOI=10.1080/13693780400029114;
RA Ferreira M.E., Colombo A.L., Paulsen I., Ren Q., Wortman J., Huang J.,
RA Goldman M.H., Goldman G.H.;
RT "The ergosterol biosynthesis pathway, transporter genes, and azole
RT resistance in Aspergillus fumigatus.";
RL Med. Mycol. 43:S313-S319(2005).
RN [3]
RP FUNCTION.
RX PubMed=18191972; DOI=10.1016/j.steroids.2007.11.005;
RA Alcazar-Fuoli L., Mellado E., Garcia-Effron G., Lopez J.F., Grimalt J.O.,
RA Cuenca-Estrella J.M., Rodriguez-Tudela J.L.;
RT "Ergosterol biosynthesis pathway in Aspergillus fumigatus.";
RL Steroids 73:339-347(2008).
RN [4]
RP FUNCTION, DOMAIN, DISRUPTION PHENOTYPE, INDUCTION, AND PATHWAY.
RX PubMed=25107308; DOI=10.1099/mic.0.080440-0;
RA Blosser S.J., Merriman B., Grahl N., Chung D., Cramer R.A.;
RT "Two C4-sterol methyl oxidases (Erg25) catalyse ergosterol intermediate
RT demethylation and impact environmental stress adaptation in Aspergillus
RT fumigatus.";
RL Microbiology 160:2492-2506(2014).
CC -!- FUNCTION: Sterol-C4-methyl oxidase; part of the third module of
CC ergosterol biosynthesis pathway that includes the late steps of the
CC pathway (PubMed:25107308). Erg25A 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:25107308). 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, squalene is converted into lanosterol by the
CC consecutive action of the squalene epoxidase erg1 and the lanosterol
CC synthase erg7. Then, the delta(24)-sterol C-methyltransferase erg6
CC methylates lanosterol at C-24 to produce eburicol. Eburicol is the
CC substrate of the sterol 14-alpha demethylase encoded by cyp51A and
CC cyp51B, to yield 4,4,24-trimethyl ergosta-8,14,24(28)-trienol. The C-14
CC reductase erg24 then reduces the C14=C15 double bond which leads to
CC 4,4-dimethylfecosterol. A sequence of further demethylations at C-4,
CC involving the C-4 demethylation complex containing the C-4 methylsterol
CC oxidases erg25A or erg25B, the sterol-4-alpha-carboxylate 3-
CC dehydrogenase erg26 and the 3-keto-steroid reductase erg27, leads to
CC the production of fecosterol via 4-methylfecosterol. The C-8 sterol
CC isomerase erg2 then catalyzes the reaction which results in
CC unsaturation at C-7 in the B ring of sterols and thus converts
CC fecosterol to episterol. The sterol-C5-desaturase erg3B then catalyzes
CC the introduction of a C-5 double bond in the B ring to produce 5-
CC dehydroepisterol. The 2 other sterol-C5-desaturases, erg3A and erg3C,
CC seem to be less important in ergosterol biosynthesis. The C-22 sterol
CC desaturase erg5 further converts 5-dehydroepisterol into ergosta-
CC 5,7,22,24(28)-tetraen-3beta-ol by forming the C-22(23) double bond in
CC the sterol side chain. Finally, ergosta-5,7,22,24(28)-tetraen-3beta-ol
CC is substrate of the C-24(28) sterol reductases erg4A and erg4B to
CC produce ergosterol. Possible alternative sterol biosynthetic pathways
CC might exist from fecosterol to ergosterol, depending on the activities
CC of the erg3 isoforms (PubMed:16110826, PubMed:18191972) (Probable).
CC {ECO:0000269|PubMed:25107308, ECO:0000305|PubMed:16110826,
CC ECO:0000305|PubMed:18191972}.
CC -!- COFACTOR:
CC Name=Fe cation; Xref=ChEBI:CHEBI:24875;
CC Evidence={ECO:0000250|UniProtKB:P53045};
CC -!- PATHWAY: Steroid metabolism; ergosterol biosynthesis.
CC {ECO:0000269|PubMed:25107308}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000305};
CC Multi-pass membrane protein {ECO:0000255}.
CC -!- INDUCTION: Expression is controled by the transcriptional regulator
CC srbA. {ECO:0000269|PubMed:25107308}.
CC -!- DOMAIN: The histidine box domains may contain the active site and/or be
CC involved in metal ion binding. {ECO:0000305|PubMed:25107308}.
CC -!- DISRUPTION PHENOTYPE: Leads to the accumulation of 4-methyl fecosterol
CC and 4,4-dimethyl fecosterol (PubMed:25107308). Displays a dmoderate
CC susceptibility to hypoxia and the endoplasmic reticulum stress-inducing
CC agent DTT, but does not affect virulence in murine or insect models of
CC invasive aspergillosis (PubMed:25107308).
CC {ECO:0000269|PubMed:25107308}.
CC -!- MISCELLANEOUS: In Aspergillus, the biosynthesis pathway of the sterol
CC precursors leading to the prevalent sterol ergosterol differs from
CC yeast. The ring system of lanosterol in S.cerevisiae is firstly
CC demethylised in three enzymatic steps leading to the intermediate
CC zymosterol and secondly a methyl group is added to zymosterol by the
CC sterol 24-C-methyltransferase to form fecosterol. In Aspergillus,
CC lanosterol is firstly transmethylated by the sterol 24-C-
CC methyltransferase leading to the intermediate eburicol and secondly
CC demethylated in three steps to form fecosterol.
CC {ECO:0000305|PubMed:18191972}.
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; AAHF01000014; EAL84924.1; -; Genomic_DNA.
DR RefSeq; XP_746962.1; XM_741869.1.
DR STRING; 746128.CADAFUBP00008191; -.
DR EnsemblFungi; EAL84924; EAL84924; AFUA_8G02440.
DR GeneID; 3504393; -.
DR KEGG; afm:AFUA_8G02440; -.
DR VEuPathDB; FungiDB:Afu8g02440; -.
DR eggNOG; KOG0873; Eukaryota.
DR HOGENOM; CLU_047036_5_0_1; -.
DR InParanoid; Q4WBI8; -.
DR OMA; YGGVAHH; -.
DR OrthoDB; 1493916at2759; -.
DR UniPathway; UPA00768; -.
DR Proteomes; UP000002530; Chromosome 8.
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; IBA:GO_Central.
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; IBA:GO_Central.
DR GO; GO:0016126; P:sterol biosynthetic process; IBA:GO_Central.
DR InterPro; IPR006694; Fatty_acid_hydroxylase.
DR Pfam; PF04116; FA_hydroxylase; 1.
PE 2: Evidence at transcript level;
KW Endoplasmic reticulum; Glycoprotein; Lipid biosynthesis; Lipid metabolism;
KW Membrane; Oxidoreductase; Reference proteome; Steroid biosynthesis;
KW Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..302
FT /note="Methylsterol monooxygenase erg25A"
FT /id="PRO_0000454127"
FT TRANSMEM 47..67
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 105..125
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 132..152
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 193..213
FT /note="Helical"
FT /evidence="ECO:0000255"
FT DOMAIN 147..283
FT /note="Fatty acid hydroxylase"
FT /evidence="ECO:0000255"
FT MOTIF 161..165
FT /note="Histidine box-1"
FT /evidence="ECO:0000305|PubMed:25107308"
FT MOTIF 174..178
FT /note="Histidine box-2"
FT /evidence="ECO:0000305|PubMed:25107308"
FT MOTIF 258..264
FT /note="Histidine box-3"
FT /evidence="ECO:0000305|PubMed:25107308"
FT CARBOHYD 5
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 269
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 302 AA; 35109 MW; A8E79C643666FE14 CRC64;
MDSLNSSYPQ SAMATYSDLL DLAAQQQPHL SGLERLWWAH YAYWDNNIVA TATGIITFLA
HEIIYFSRCL PWIIADSLPS IFLKYKIQDQ KPPPSAAEQW ACTKYILLIH FVVELPLIVL
FHPMMELCGL SFTIPFPDLR TLTAQIIIFF LLEDTYHYWL HRAMHWGPLY RSIHRIHHQY
AAPFGLTAEY ASPWETLLLG LGTIGPPLLL ALMDCNVHLV TVLAWVTLRQ FQAIDSHSGY
DFPWSLRRIL PFWGGADWHD DHHRYFWGNY SSSFRHWDVL MGTVAGPEAR EKRRAEREKR
QA
