ERG4B_ASPFU
ID ERG4B_ASPFU Reviewed; 571 AA.
AC Q4WJ59;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 17-APR-2007, sequence version 2.
DT 03-AUG-2022, entry version 71.
DE RecName: Full=Delta(24(24(1)))-sterol reductase erg4B {ECO:0000303|PubMed:27986720};
DE EC=1.3.1.71 {ECO:0000305|PubMed:16110826};
DE AltName: Full=C-24(28) sterol reductase erg4B {ECO:0000303|PubMed:27986720};
DE AltName: Full=Ergosterol biosynthesis protein 4B {ECO:0000303|PubMed:16110826};
DE AltName: Full=Sterol Delta(24(28))-reductase erg4V {ECO:0000303|PubMed:27986720};
GN Name=erg4B {ECO:0000303|PubMed:16110826}; ORFNames=AFUA_1G07140;
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 FUNCTION.
RX PubMed=9184358; DOI=10.1093/jac/39.5.597;
RA Venkateswarlu K., Kelly S.L.;
RT "Stereoselective interaction of SCH 39304, a triazole, with sterol 14alpha-
RT demethylase of Aspergillus fumigatus.";
RL J. Antimicrob. Chemother. 39:597-601(1997).
RN [3]
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 [4]
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 [5]
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; AAHF01000007; EAL88423.2; -; Genomic_DNA.
DR RefSeq; XP_750461.2; XM_745368.2.
DR STRING; 330879.Q4WJ59; -.
DR EnsemblFungi; EAL88423; EAL88423; AFUA_1G07140.
DR GeneID; 3507720; -.
DR KEGG; afm:AFUA_1G07140; -.
DR HOGENOM; CLU_015631_3_0_1; -.
DR InParanoid; Q4WJ59; -.
DR OMA; KQLPYFC; -.
DR OrthoDB; 532774at2759; -.
DR UniPathway; UPA00768; -.
DR Proteomes; UP000002530; Chromosome 1.
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 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..571
FT /note="Delta(24(24(1)))-sterol reductase erg4B"
FT /id="PRO_0000454121"
FT TRANSMEM 140..160
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 197..217
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 238..258
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 267..287
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 324..344
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 348..368
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 390..410
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 425..445
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 513..533
FT /note="Helical"
FT /evidence="ECO:0000255"
FT REGION 1..116
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 45..78
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 80..110
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 448
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 452
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 488
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 500..501
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 540
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 544..548
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT BINDING 555
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:G4SW86"
FT CARBOHYD 107
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 571 AA; 65267 MW; FD984400E9A3E54B CRC64;
MTVTRSQTGK TPKKLERPGY VETPGRRVTR SRVVVASETS ADDVSDSATE IRGRSKSTTR
RRQVKTEEAS EGEEKGRANG HINGNTNGHT NGHTNGHTNG HTNGHTNGST KKPRVIDGWV
EGSDPKIDYS GEFEFGGSWG VLSMMIGFPL LMYYMWIGAV YYDGKFPRPS EGQSMSEFLA
HMGHLVCEGA YPSLRAWIIY WVFFIFEALC YVLLPGVTVM GRALPHLGGK QLPYYCSGVW
SFYTSIALAG VLHFTGIFKL YTIIDEFGPL LSVAIISGFL VSFVAYFSAL ARGAQHRMTG
YHIYDFFMGA ELNPRMFGIL DFKMFFEVRL PWFILFFISL GAAARQYEVY GYVSGEVGFL
LMAHFLYANA CCKGEECIVS TWDMYYEKWG FMLIFWNLAG VPLSYCHCTI YLASHDPATY
RWNRVFLVFL YAAYLFVYWV WDTTNSQKNR FRQQERGTMV SRKTFPQLPW QTLKNPKTIT
AADGSKILVD GWYGKARKIH YTCDLYFALN WGLITGFSSP FPWFYPIFFA CMITHRALRD
IQRCRNKYGE AWVEYERQVP YLFIPVSYSS S
