CP51B_GIBZE
ID CP51B_GIBZE Reviewed; 526 AA.
AC I1RBR4;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 13-JUN-2012, sequence version 1.
DT 03-AUG-2022, entry version 61.
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=CYP51B {ECO:0000303|PubMed:20955812};
GN ORFNames=FG01000, FGRAMPH1_01T02507;
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).
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). CYP51B encodes the enzyme primarily
CC responsible for eburicol 14-alpha-demethylation, and plays an essential
CC role in ascospore formation (PubMed:20955812). The third module or late
CC pathway involves the ergosterol synthesis itself through consecutive
CC reactions that mainly occur in the endoplasmic reticulum (ER) membrane.
CC Firstly, the squalene synthase ERG9 catalyzes the condensation of 2
CC farnesyl pyrophosphate moieties to form squalene, which is the
CC precursor of all steroids. Squalene synthase is crucial for balancing
CC the incorporation of farnesyl diphosphate (FPP) into sterol and
CC nonsterol isoprene synthesis. Secondly, squalene is converted into
CC lanosterol by the consecutive action of the squalene epoxidase ERG1 and
CC the lanosterol synthase ERG7. Then, the delta(24)-sterol C-
CC methyltransferase ERG6 methylates lanosterol at C-24 to produce
CC eburicol. Eburicol is the substrate of the sterol 14-alpha demethylase
CC encoded by CYP51A, CYP51B and CYP51C, to yield 4,4,24-trimethyl
CC ergosta-8,14,24(28)-trienol. CYP51B encodes the enzyme primarily
CC responsible for sterol 14-alpha-demethylation, and plays an essential
CC role in ascospore formation. CYP51A encodes an additional sterol 14-
CC alpha-demethylase, induced on ergosterol depletion and responsible for
CC the intrinsic variation in azole sensitivity. The third CYP51 isoform,
CC CYP51C, does not encode a sterol 14-alpha-demethylase, but is required
CC for full virulence on host wheat ears. The C-14 reductase ERG24 then
CC reduces the C14=C15 double bond which leads to 4,4-dimethylfecosterol.
CC A sequence of further demethylations at C-4, involving the C-4
CC demethylation complex containing the C-4 methylsterol oxidases ERG25,
CC the sterol-4-alpha-carboxylate 3-dehydrogenase ERG26 and the 3-keto-
CC steroid reductase ERG27, leads to the production of fecosterol via 4-
CC methylfecosterol. ERG28 has a role as a scaffold to help anchor ERG25,
CC ERG26 and ERG27 to the endoplasmic reticulum. The C-8 sterol isomerase
CC ERG2 then catalyzes the reaction which results in unsaturation at C-7
CC in the B ring of sterols and thus converts fecosterol to episterol. The
CC sterol-C5-desaturases ERG3A and ERG3BB then catalyze the introduction
CC of a C-5 double bond in the B ring to produce 5-dehydroepisterol. The
CC C-22 sterol desaturases ERG5A and ERG5B further convert 5-
CC dehydroepisterol into ergosta-5,7,22,24(28)-tetraen-3beta-ol by forming
CC the C-22(23) double bond in the sterol side chain. Finally, ergosta-
CC 5,7,22,24(28)-tetraen-3beta-ol is substrate of the C-24(28) sterol
CC 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 increased in the absence of the C-24(28)
CC sterol reductase ERG4 (PubMed:22947191). Expression is positively
CC regulated by the FgSR transcription factor that targets gene promoters
CC containing 2 conserved CGAA repeat sequences (PubMed:30874562).
CC {ECO:0000269|PubMed:22947191, 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; and leads to the accumulation of eburicol and 2
CC additional 14-methylated sterols, 4,4,14-trimethylergosta-trienol and
CC 4,4,14-trimethylergosta-dienol (PubMed:23442154). Leads to reduced
CC ability to produce conidia (PubMed:20955812). Affects ergosterol
CC production in the presence of ebuconazole or triadimefon
CC (PubMed:20955812). 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; HG970332; CEF73055.1; -; Genomic_DNA.
DR RefSeq; XP_011316750.1; XM_011318448.1.
DR SMR; I1RBR4; -.
DR STRING; 5518.FGSG_01000P0; -.
DR GeneID; 23548459; -.
DR KEGG; fgr:FGSG_01000; -.
DR VEuPathDB; FungiDB:FGRAMPH1_01G02507; -.
DR eggNOG; KOG0684; Eukaryota.
DR HOGENOM; CLU_001570_15_0_1; -.
DR InParanoid; I1RBR4; -.
DR UniPathway; UPA00768; -.
DR PHI-base; PHI:2908; -.
DR Proteomes; UP000070720; Chromosome 1.
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..526
FT /note="Sterol 14-alpha demethylase CYP51A"
FT /id="PRO_0000454395"
FT TRANSMEM 27..47
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 123
FT /ligand="lanosterol"
FT /ligand_id="ChEBI:CHEBI:16521"
FT /evidence="ECO:0000250|UniProtKB:P10614"
FT BINDING 470
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 526 AA; 59252 MW; 3DA43F5AB3AA3A81 CRC64;
MGLLQELAGH PLAQQFQELP LGQQVGIGFA VFLVLSVVLN VLNQLLFRNP NEPPMVFHWF
PFVGSTITYG MDPPTFFREN RAKHGDVFTF ILLGKKTTVA VGPAGNDFIL NGKLKDVCAE
EIYTVLTTPV FGKDVVYDCP NAKLMEQKKF MKIALTTEAF RSYVPIISSE VRDYFKRSPD
FKGKSGIADI PKKMAEITIF TASHALQGSA IRSKFDESLA ALYHDLDMGF TPINFMLHWA
PLPWNRKRDH AQRTVAKIYM DTIKERRAKG NNESEHDMMK HLMNSTYKNG IRVPDHEVAH
MMIALLMAGQ HSSSSTSSWI MLRLAQYPHI MEELYQEQVK NLGADLPPLT YEDLAKLPLN
QAIVKETLRL HAPIHSIMRA VKSPMPVPGT KYVIPTSHTL LAAPGVSATD SAFFPNPDEW
DPHRWEADSP NFPRMASKGE DEEKIDYGYG LVSKGSASPY LPFGAGRHRC IGEHFANAQL
QTIVAEVVRE FKFRNVDGGH TLIDTDYASL FSRPLEPANI HWERRQ
