CP51A_GIBZE
ID CP51A_GIBZE Reviewed; 507 AA.
AC I1RJR2;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 13-JUN-2012, sequence version 1.
DT 03-AUG-2022, entry version 66.
DE RecName: Full=Sterol 14-alpha demethylase CYP51A {ECO:0000303|PubMed:20955812};
DE EC=1.14.14.154 {ECO:0000305|PubMed:20955812};
DE AltName: Full=Ergosterol biosynthetic protein CYP51A {ECO:0000303|PubMed:20955812};
GN Name=CYP51A {ECO:0000303|PubMed:20955812};
GN ORFNames=FG04092, FGRAMPH1_01T14465;
OS Gibberella zeae (strain ATCC MYA-4620 / CBS 123657 / FGSC 9075 / NRRL 31084
OS / PH-1) (Wheat head blight fungus) (Fusarium graminearum).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Nectriaceae; Fusarium.
OX NCBI_TaxID=229533;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC MYA-4620 / CBS 123657 / FGSC 9075 / NRRL 31084 / PH-1;
RX PubMed=17823352; DOI=10.1126/science.1143708;
RA Cuomo C.A., Gueldener U., Xu J.-R., Trail F., Turgeon B.G., Di Pietro A.,
RA Walton J.D., Ma L.-J., Baker S.E., Rep M., Adam G., Antoniw J., Baldwin T.,
RA Calvo S.E., Chang Y.-L., DeCaprio D., Gale L.R., Gnerre S., Goswami R.S.,
RA Hammond-Kosack K., Harris L.J., Hilburn K., Kennell J.C., Kroken S.,
RA Magnuson J.K., Mannhaupt G., Mauceli E.W., Mewes H.-W., Mitterbauer R.,
RA Muehlbauer G., Muensterkoetter M., Nelson D., O'Donnell K., Ouellet T.,
RA Qi W., Quesneville H., Roncero M.I.G., Seong K.-Y., Tetko I.V., Urban M.,
RA Waalwijk C., Ward T.J., Yao J., Birren B.W., Kistler H.C.;
RT "The Fusarium graminearum genome reveals a link between localized
RT polymorphism and pathogen specialization.";
RL Science 317:1400-1402(2007).
RN [2]
RP GENOME REANNOTATION.
RC STRAIN=ATCC MYA-4620 / CBS 123657 / FGSC 9075 / NRRL 31084 / PH-1;
RX PubMed=20237561; DOI=10.1038/nature08850;
RA Ma L.-J., van der Does H.C., Borkovich K.A., Coleman J.J., Daboussi M.-J.,
RA Di Pietro A., Dufresne M., Freitag M., Grabherr M., Henrissat B.,
RA Houterman P.M., Kang S., Shim W.-B., Woloshuk C., Xie X., Xu J.-R.,
RA Antoniw J., Baker S.E., Bluhm B.H., Breakspear A., Brown D.W.,
RA Butchko R.A.E., Chapman S., Coulson R., Coutinho P.M., Danchin E.G.J.,
RA Diener A., Gale L.R., Gardiner D.M., Goff S., Hammond-Kosack K.E.,
RA Hilburn K., Hua-Van A., Jonkers W., Kazan K., Kodira C.D., Koehrsen M.,
RA Kumar L., Lee Y.-H., Li L., Manners J.M., Miranda-Saavedra D.,
RA Mukherjee M., Park G., Park J., Park S.-Y., Proctor R.H., Regev A.,
RA Ruiz-Roldan M.C., Sain D., Sakthikumar S., Sykes S., Schwartz D.C.,
RA Turgeon B.G., Wapinski I., Yoder O., Young S., Zeng Q., Zhou S.,
RA Galagan J., Cuomo C.A., Kistler H.C., Rep M.;
RT "Comparative genomics reveals mobile pathogenicity chromosomes in
RT Fusarium.";
RL Nature 464:367-373(2010).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC MYA-4620 / CBS 123657 / FGSC 9075 / NRRL 31084 / PH-1;
RX PubMed=26198851; DOI=10.1186/s12864-015-1756-1;
RA King R., Urban M., Hammond-Kosack M.C.U., Hassani-Pak K.,
RA Hammond-Kosack K.E.;
RT "The completed genome sequence of the pathogenic ascomycete fungus Fusarium
RT graminearum.";
RL BMC Genomics 16:544-544(2015).
RN [4]
RP FUNCTION.
RX PubMed=20955812; DOI=10.1016/j.fgb.2010.10.004;
RA Liu X., Yu F., Schnabel G., Wu J., Wang Z., Ma Z.;
RT "Paralogous cyp51 genes in Fusarium graminearum mediate differential
RT sensitivity to sterol demethylation inhibitors.";
RL Fungal Genet. Biol. 48:113-123(2011).
RN [5]
RP INDUCTION.
RX PubMed=22947191; DOI=10.1111/j.1364-3703.2012.00829.x;
RA Liu X., Jiang J., Yin Y., Ma Z.;
RT "Involvement of FgERG4 in ergosterol biosynthesis, vegetative
RT differentiation and virulence in Fusarium graminearum.";
RL Mol. Plant Pathol. 14:71-83(2013).
RN [6]
RP FUNCTION, DISRUPTION PHENOTYPE, INDUCTION, AND PATHWAY.
RX PubMed=23442154; DOI=10.1111/nph.12193;
RA Fan J., Urban M., Parker J.E., Brewer H.C., Kelly S.L.,
RA Hammond-Kosack K.E., Fraaije B.A., Liu X., Cools H.J.;
RT "Characterization of the sterol 14alpha-demethylases of Fusarium
RT graminearum identifies a novel genus-specific CYP51 function.";
RL New Phytol. 198:821-835(2013).
RN [7]
RP DISRUPTION PHENOTYPE.
RX PubMed=24218613; DOI=10.1073/pnas.1306373110;
RA Koch A., Kumar N., Weber L., Keller H., Imani J., Kogel K.H.;
RT "Host-induced gene silencing of cytochrome P450 lanosterol C14alpha-
RT demethylase-encoding genes confers strong resistance to Fusarium species.";
RL Proc. Natl. Acad. Sci. U.S.A. 110:19324-19329(2013).
RN [8]
RP INDUCTION.
RX PubMed=30874562; DOI=10.1038/s41467-019-09145-6;
RA Liu Z., Jian Y., Chen Y., Kistler H.C., He P., Ma Z., Yin Y.;
RT "A phosphorylated transcription factor regulates sterol biosynthesis in
RT Fusarium graminearum.";
RL Nat. Commun. 10:1228-1228(2019).
CC -!- FUNCTION: Sterol 14-alpha demethylase; part of the third module of
CC ergosterol biosynthesis pathway that includes the late steps of the
CC pathway (PubMed:20955812). CYP51A encodes an minor sterol 14-alpha-
CC demethylase induced on ergosterol depletion and responsible for the
CC intrinsic variation in azole sensitivity (PubMed:20955812). The third
CC module or late pathway involves the ergosterol synthesis itself through
CC consecutive reactions that mainly occur in the endoplasmic reticulum
CC (ER) membrane. Firstly, the squalene synthase ERG9 catalyzes the
CC condensation of 2 farnesyl pyrophosphate moieties to form squalene,
CC which is the precursor of all steroids. Squalene synthase is crucial
CC for balancing the incorporation of farnesyl diphosphate (FPP) into
CC sterol and nonsterol isoprene synthesis. Secondly, squalene is
CC converted into lanosterol by the consecutive action of the squalene
CC epoxidase ERG1 and the lanosterol synthase ERG7. Then, the delta(24)-
CC sterol C-methyltransferase ERG6 methylates lanosterol at C-24 to
CC produce eburicol. Eburicol is the substrate of the sterol 14-alpha
CC demethylase encoded by CYP51A, CYP51B and CYP51C, to yield 4,4,24-
CC trimethyl ergosta-8,14,24(28)-trienol. CYP51B encodes the enzyme
CC primarily responsible for sterol 14-alpha-demethylation, and plays an
CC essential role in ascospore formation. CYP51A encodes an additional
CC sterol 14-alpha-demethylase, induced on ergosterol depletion and
CC responsible for the intrinsic variation in azole sensitivity. The third
CC CYP51 isoform, CYP51C, does not encode a sterol 14-alpha-demethylase,
CC but is required for full virulence on host wheat ears. 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 ERG25, the sterol-4-alpha-carboxylate 3-dehydrogenase ERG26
CC and the 3-keto-steroid reductase ERG27, leads to the production of
CC fecosterol via 4-methylfecosterol. ERG28 has a role as a scaffold to
CC help anchor ERG25, ERG26 and ERG27 to the endoplasmic reticulum. The C-
CC 8 sterol 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-desaturases ERG3A and ERG3BB
CC then catalyze the introduction of a C-5 double bond in the B ring to
CC produce 5-dehydroepisterol. The C-22 sterol desaturases ERG5A and ERG5B
CC further convert 5-dehydroepisterol into ergosta-5,7,22,24(28)-tetraen-
CC 3beta-ol by forming the C-22(23) double bond in the sterol side chain.
CC Finally, ergosta-5,7,22,24(28)-tetraen-3beta-ol is substrate of the C-
CC 24(28) sterol reductase ERG4 to produce ergosterol (Probable).
CC {ECO:0000269|PubMed:20955812, ECO:0000305|PubMed:23442154}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=a 14alpha-methyl steroid + 3 O2 + 3 reduced [NADPH--
CC hemoprotein reductase] = a Delta(14) steroid + formate + 4 H(+) + 4
CC H2O + 3 oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:54028, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:15740, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC ChEBI:CHEBI:138029, ChEBI:CHEBI:138031; EC=1.14.14.154;
CC Evidence={ECO:0000305|PubMed:23442154};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54029;
CC Evidence={ECO:0000305|PubMed:23442154};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P10614};
CC -!- PATHWAY: Steroid metabolism; ergosterol biosynthesis.
CC {ECO:0000305|PubMed:23442154}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000305};
CC Single-pass membrane protein {ECO:0000255}.
CC -!- INDUCTION: Expression is induced by azole antifungals such as
CC prochloraz, tebuconazole or epoxiconazole (PubMed:23442154). Expression
CC is increased in the absence of the C-24(28) sterol reductase ERG4
CC (PubMed:22947191). Expression is positively regulated by the FgSR
CC transcription factor that targets gene promoters containing 2 conserved
CC CGAA repeat sequences (PubMed:30874562). {ECO:0000269|PubMed:22947191,
CC ECO:0000269|PubMed:23442154, ECO:0000269|PubMed:30874562}.
CC -!- DISRUPTION PHENOTYPE: Decreases the amounts of 4,4-dimethylergosta-
CC 8,14,24(28)-trienol, the product of the Fusarium sterol 14-alpha
CC demethylases (PubMed:23442154). Leads to reduced ability to produce
CC conidia (PubMed:20955812). Results in high sensitivity to triadimefon
CC and antifungal azoles such as propiconazole (PubMed:20955812,
CC PubMed:23442154). Affects ergosterol production in the presence of
CC ebuconazole or triadimefon (PubMed:20955812). Host-induced gene
CC silencing of the 3 genes encoding sterol C14-alpha-demethylase leads to
CC strong resistance of host to Fusarium species (PubMed:24218613).
CC {ECO:0000269|PubMed:20955812, ECO:0000269|PubMed:23442154,
CC ECO:0000269|PubMed:24218613}.
CC -!- MISCELLANEOUS: In Fusarium, the biosynthesis pathway of the sterol
CC precursors leading to the prevalent sterol ergosterol differs from
CC yeast. The ringsystem 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 Fusarium,
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:0000269|PubMed:23442154}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; HG970333; CEF79036.1; -; Genomic_DNA.
DR RefSeq; XP_011321548.1; XM_011323246.1.
DR SMR; I1RJR2; -.
DR STRING; 5518.FGSG_04092P0; -.
DR GeneID; 23551358; -.
DR KEGG; fgr:FGSG_04092; -.
DR VEuPathDB; FungiDB:FGRAMPH1_01G14465; -.
DR eggNOG; KOG0684; Eukaryota.
DR HOGENOM; CLU_001570_15_0_1; -.
DR InParanoid; I1RJR2; -.
DR UniPathway; UPA00768; -.
DR Proteomes; UP000070720; Chromosome 2.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR GO; GO:0016126; P:sterol biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00465; EP450IV.
DR PRINTS; PR00385; P450.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 2: Evidence at transcript level;
KW Endoplasmic reticulum; Heme; Iron; Lipid biosynthesis; Lipid metabolism;
KW Membrane; Metal-binding; Monooxygenase; Oxidoreductase; Reference proteome;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Transmembrane; Transmembrane helix.
FT CHAIN 1..507
FT /note="Sterol 14-alpha demethylase CYP51A"
FT /id="PRO_0000454355"
FT TRANSMEM 7..29
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 105
FT /ligand="lanosterol"
FT /ligand_id="ChEBI:CHEBI:16521"
FT /evidence="ECO:0000250|UniProtKB:P10614"
FT BINDING 449
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P10614"
SQ SEQUENCE 507 AA; 57533 MW; 95BFA218CC9D18FE CRC64;
MFHLLIYPLW VLVALFAVII ANLLYQQLPR RPDEPPLVFH WFPFFGNAVA YGLDPCGFFE
KCREKHGDVF TFILFGRKIV ACLGVDGNDF VLNSRLQDAN AEEVYGPLTI PVFGSDVVYD
CPNSKLMEQK KFVKFGLTQK ALESHVQLIE REVLDYVETD PSFSGRTSTI DVPKAMAEIT
IFTASRSLQG EEVRRKLTAE FAALYHDLDL GFRPVNFLFP WLPLPHNRKR DAAHIKMREV
YMDIINDRRK GGIRTEDGTD MIANLMGCTY KNGQPVPDKE IAHMMITLLM AGQHSSSSAS
SWIVLHLASS PDITEELYQE QLVNLSVNGA LPPLQYSDLD KLPLLQNVVK ETLRVHSSIH
SILRKVKRPM QVPNSPYTIT TDKVIMASPT VTAMSEEYFE NAKTWNPHRW DNRAKEEVDT
EDVIDYGYGA VSKGTKSPYL PFGAGRHRCI GEKFAYVNLG VIVATLVRNF RLSTIDGRPG
VPETDYTSLF SRPAQPAFIR WERRKKI
