CP51C_GIBZE
ID CP51C_GIBZE Reviewed; 517 AA.
AC I1S2M5; A0A098E4S1;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 13-JUN-2012, sequence version 1.
DT 03-AUG-2022, entry version 64.
DE RecName: Full=Sterol 14-alpha demethylase CYP51C {ECO:0000303|PubMed:20955812};
DE EC=1.14.14.154 {ECO:0000305|PubMed:20955812};
DE AltName: Full=Ergosterol biosynthetic protein CYP51C {ECO:0000303|PubMed:20955812};
GN Name=CYP51C {ECO:0000303|PubMed:20955812};
GN ORFNames=FG11024, FGRAMPH1_01T21047;
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, AND DISRUPTION PHENOTYPE.
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, 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).
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). CYP51C, does not seem to encode an active
CC sterol 14-alpha-demethylase, but is required for full virulence on host
CC wheat ears (PubMed:20955812). 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, CYP51B
CC and CYP51C, to yield 4,4,24-trimethyl ergosta-8,14,24(28)-trienol.
CC CYP51B encodes the enzyme primarily responsible for sterol 14-alpha-
CC demethylation, and plays an essential role in ascospore formation.
CC CYP51A encodes an additional sterol 14-alpha-demethylase, induced on
CC ergosterol depletion and responsible for the intrinsic variation in
CC azole sensitivity. The third CYP51 isoform, CYP51C, does not encode a
CC sterol 14-alpha-demethylase, but is required for full virulence on host
CC wheat ears. The C-14 reductase ERG24 then reduces the C14=C15 double
CC bond which leads to 4,4-dimethylfecosterol. A sequence of further
CC demethylations at C-4, involving the C-4 demethylation complex
CC containing the C-4 methylsterol oxidases ERG25, the sterol-4-alpha-
CC carboxylate 3-dehydrogenase ERG26 and the 3-keto-steroid reductase
CC ERG27, leads to the production of fecosterol via 4-methylfecosterol.
CC ERG28 has a role as a scaffold to help anchor ERG25, ERG26 and ERG27 to
CC the endoplasmic reticulum. The C-8 sterol isomerase ERG2 then catalyzes
CC the reaction which results in unsaturation at C-7 in the B ring of
CC sterols and thus converts fecosterol to episterol. The sterol-C5-
CC desaturases ERG3A and ERG3BB then catalyze the introduction of a C-5
CC double bond in the B ring to produce 5-dehydroepisterol. The C-22
CC sterol desaturases ERG5A and ERG5B further convert 5-dehydroepisterol
CC into ergosta-5,7,22,24(28)-tetraen-3beta-ol by forming the C-22(23)
CC double bond in the sterol side chain. Finally, ergosta-5,7,22,24(28)-
CC tetraen-3beta-ol is substrate of the C-24(28) sterol reductase ERG4 to
CC produce ergosterol (Probable). {ECO:0000269|PubMed:20955812,
CC 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 increased in the absence of the C-24(28)
CC sterol reductase ERG4. {ECO:0000269|PubMed:22947191}.
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 increased sensitivity to
CC tebuconazole, diniconazole, difenoconazole, flutriafol and prochloraz,
CC but not to triadimefon and propiconazole (PubMed:20955812). Affects
CC ergosterol production in the presence of ebuconazole or triadimefon
CC (PubMed:20955812). Reduces virulence on host wheat ears
CC (PubMed:23442154). Host-induced gene silencing of the 3 genes encoding
CC sterol C14-alpha-demethylase leads to strong resistance of host to
CC Fusarium species (PubMed:24218613). {ECO:0000269|PubMed:20955812,
CC ECO:0000269|PubMed:23442154, 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; HG970334; CEF88203.1; -; Genomic_DNA.
DR RefSeq; XP_011325340.1; XM_011327038.1.
DR SMR; I1S2M5; -.
DR STRING; 5518.FGSG_11024P0; -.
DR GeneID; 23557895; -.
DR KEGG; fgr:FGSG_11024; -.
DR VEuPathDB; FungiDB:FGRAMPH1_01G21047; -.
DR eggNOG; KOG0684; Eukaryota.
DR HOGENOM; CLU_001570_15_0_1; -.
DR InParanoid; I1S2M5; -.
DR UniPathway; UPA00768; -.
DR PHI-base; PHI:2909; -.
DR Proteomes; UP000070720; Chromosome 3.
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; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..517
FT /note="Sterol 14-alpha demethylase CYP51C"
FT /id="PRO_0000454357"
FT TRANSMEM 10..30
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 115
FT /ligand="lanosterol"
FT /ligand_id="ChEBI:CHEBI:16521"
FT /evidence="ECO:0000250|UniProtKB:P10614"
FT BINDING 300
FT /ligand="itraconazole"
FT /ligand_id="ChEBI:CHEBI:6076"
FT /evidence="ECO:0000250|UniProtKB:P10614"
FT BINDING 458
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 517 AA; 58636 MW; 1187F1E067040323 CRC64;
MESLYETLRT LPLSVSIPLT TSIIIILSIV TNVVKQLWFP NPHRPPVVFH IFPFIGSTVQ
YGIDPYAFFF DCRDKYGDCF TFILLGKSTT VFLGPKGNDF ILNGKHADLN AEDVYGKLTT
PVFGEEVVYD CSNARFMDQK RLLKLGLTTD SLRCYIPKFV KEVEDYVKNS PYFKGDTGIV
NITEVMAEIT IYTASGSLLG NEVRSMFDST FATLYRHLDD GFQPINFVMP GLPLPQNFRR
NHARKVMEKL FSDIISKRRE TGNQGDETDM IWMLMNAQYK DGEPLPDHHA ARMLIAILMG
GQHNTAVSGA WLLLNLAHKP HLVQELYEEQ TQVLGSPQEP LTWENLQKLT LNGQVIKETL
RLHSPIHSIL RQVKSPMRVP GTEWVVPPSH TLLSSPGTMA RSEEFFPRPS EWDPHRWDKI
EPLVKTAEDG QTVDYGFGVM SKSVSSPYLP FGAGRHRCVG ENYAYAQLGA IVATFIRLVH
IEQPDPKAPL PAPDYSSMFS RPMNPAEIRW RRRETVE
