ERG4A_ASPFU
ID ERG4A_ASPFU Reviewed; 471 AA.
AC Q4WW43;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 67.
DE RecName: Full=Delta(24(24(1)))-sterol reductase erg4A {ECO:0000303|PubMed:27986720};
DE EC=1.3.1.71 {ECO:0000305|PubMed:16110826};
DE AltName: Full=C-24(28) sterol reductase erg4A {ECO:0000303|PubMed:27986720};
DE AltName: Full=Ergosterol biosynthesis protein 4A {ECO:0000303|PubMed:16110826};
DE AltName: Full=Sterol Delta(24(28))-reductase erg4A {ECO:0000303|PubMed:27986720};
GN Name=erg4A {ECO:0000303|PubMed:27986720}; ORFNames=AFUA_5G14350;
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, DISRUPTION PHENOTYPE, SUBCELLULAR LOCATION, INDUCTION,
RP BIOTECHNOLOGY, AND PATHWAY.
RX PubMed=27986720; DOI=10.1128/aem.02924-16;
RA Long N., Xu X., Zeng Q., Sang H., Lu L.;
RT "Erg4A and Erg4B are required for conidiation and azole resistance via
RT regulation of ergosterol biosynthesis in Aspergillus fumigatus.";
RL Appl. Environ. Microbiol. 83:0-0(2017).
CC -!- FUNCTION: Delta(24(24(1)))-sterol reductase; part of the third module
CC of ergosterol biosynthesis pathway that includes the late steps of the
CC pathway (PubMed:27986720). Catalyzes the last step of ergosterol
CC biosynthesis by converting ergosta-5,7,22,24(28)-tetraen-3beta-ol into
CC ergosterol (PubMed:27986720). 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, 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:27986720, ECO:0000305|PubMed:16110826,
CC ECO:0000305|PubMed:18191972}.
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:0000305|PubMed:27986720};
CC PhysiologicalDirection=right-to-left; Xref=Rhea:RHEA:18503;
CC Evidence={ECO:0000305|PubMed:27986720};
CC -!- PATHWAY: Steroid metabolism; ergosterol biosynthesis.
CC {ECO:0000305|PubMed:16110826}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC {ECO:0000269|PubMed:27986720}; Multi-pass membrane protein
CC {ECO:0000255}.
CC -!- INDUCTION: Expression is induced in the absence of erg4A.
CC {ECO:0000269|PubMed:27986720}.
CC -!- DISRUPTION PHENOTYPE: Deletion of both erg4A and erg4B results in
CC fluffy colonies with severely impaired conidiation and increased
CC susceptibility to antifungal azoles itraconazole and voriconazole, but
CC does not affect virulence (PubMed:27986720). The double deletion leads
CC also to the loss of ergosterol production and accumulation of the
CC ergosta-5,7,22,24(28)-tetraenol precursor (PubMed:27986720).
CC {ECO:0000269|PubMed:27986720}.
CC -!- BIOTECHNOLOGY: Inhibition of erg4A and erg4B might be an effective
CC approach for alleviating A.fumigatus infection.
CC {ECO:0000269|PubMed:27986720}.
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 ERG4/ERG24 family. {ECO:0000305}.
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DR EMBL; AAHF01000003; EAL91183.1; -; Genomic_DNA.
DR RefSeq; XP_753221.1; XM_748128.1.
DR STRING; 746128.CADAFUBP00006063; -.
DR EnsemblFungi; EAL91183; EAL91183; AFUA_5G14350.
DR GeneID; 3511014; -.
DR KEGG; afm:AFUA_5G14350; -.
DR VEuPathDB; FungiDB:Afu5g14350; -.
DR eggNOG; KOG1435; Eukaryota.
DR HOGENOM; CLU_015631_3_1_1; -.
DR InParanoid; Q4WW43; -.
DR OMA; TVMIIHR; -.
DR OrthoDB; 532774at2759; -.
DR UniPathway; UPA00768; -.
DR Proteomes; UP000002530; Chromosome 5.
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.
PE 1: Evidence at protein level;
KW Endoplasmic reticulum; Glycoprotein; Lipid biosynthesis; Lipid metabolism;
KW Membrane; NADP; Oxidoreductase; Reference proteome; Steroid biosynthesis;
KW Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transmembrane;
KW Transmembrane helix.
FT CHAIN 1..471
FT /note="Delta(24(24(1)))-sterol reductase erg4A"
FT /id="PRO_0000454120"
FT TRANSMEM 33..53
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 89..109
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 130..150
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 159..179
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 216..236
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 244..264
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 282..302
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 313..333
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 397..417
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 340
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 344
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 380
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 392..393
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 432
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 436..440
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 447
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT CARBOHYD 15
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 471 AA; 54516 MW; 560D4AA6F7DFA752 CRC64;
MKSKMAAKDQ KRLDNASSSD TKIEFEFGGA PGVTLIMIGF PLLMYYMYIG AVLYDGLLPT
PEDGQSWADF LSHLVSLAYT HAYPTRKAWT IYWTFLILEG AGYLYLPGVY GKGKRLPHLG
GKQLPYYCSA VSSWYLTIAA ALILHFTGVL KLYTLIDEFG PLMSVAICSG IFVSIVAYIS
ALVRGVEHRM TGSHVYDFFM GAELNPRLFG WLDFKMFFEV RIPWFILFLL TLGTALKQLE
EYGLVAGEVL FLLMAHFLYA NACAKGEELI ITSWDMYYEK WGFMLIFWNL AGVPMSYCHC
TLYLAYHDPS TYHWNPWVLA VWAVAYLFMY WVWDTCNSQK NYFRAQERGV TVDRKTFPQL
PWKYIENPQS IPTKTGDSIL CSGWFGMARK VHYTCDVFFA ISWGLITGFN SPFPWFYPCF
FTVMIIHRAR RDINRCRERY GEAWMEYERR VPYLFIPVSF ADLPHKDKLT D
