CP51A_ASPFU
ID CP51A_ASPFU Reviewed; 515 AA.
AC Q4WNT5;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2005, sequence version 1.
DT 03-AUG-2022, entry version 131.
DE RecName: Full=Sterol 14-alpha demethylase cyp51A {ECO:0000303|PubMed:11427550};
DE EC=1.14.14.154 {ECO:0000269|PubMed:18191972, ECO:0000269|PubMed:26459890, ECO:0000269|PubMed:29439966, ECO:0000269|PubMed:9184358};
DE AltName: Full=Cytochrome P450 monooxygenase 51A {ECO:0000303|PubMed:11427550};
DE AltName: Full=Ergosterol biosynthesis protein 11A {ECO:0000303|PubMed:16622700};
GN Name=cyp51A {ECO:0000303|PubMed:11427550};
GN Synonyms=erg11A {ECO:0000303|PubMed:16622700}; ORFNames=AFUA_4G06890;
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, CATALYTIC ACTIVITY, PATHWAY, AND ACTIVITY REGULATION.
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.
RX PubMed=11427550; DOI=10.1128/jcm.39.7.2431-2438.2001;
RA Mellado E., Diaz-Guerra T.M., Cuenca-Estrella M., Rodriguez-Tudela J.L.;
RT "Identification of two different 14-alpha sterol demethylase-related genes
RT (cyp51A and cyp51B) in Aspergillus fumigatus and other Aspergillus
RT species.";
RL J. Clin. Microbiol. 39:2431-2438(2001).
RN [4]
RP FUNCTION, AND MUTAGENESIS OF GLY-54.
RX PubMed=12543662; DOI=10.1128/aac.47.2.577-581.2003;
RA Mann P.A., Parmegiani R.M., Wei S.Q., Mendrick C.A., Li X., Loebenberg D.,
RA DiDomenico B., Hare R.S., Walker S.S., McNicholas P.M.;
RT "Mutations in Aspergillus fumigatus resulting in reduced susceptibility to
RT posaconazole appear to be restricted to a single amino acid in the
RT cytochrome P450 14alpha-demethylase.";
RL Antimicrob. Agents Chemother. 47:577-581(2003).
RN [5]
RP FUNCTION, AND MUTAGENESIS OF GLY-54.
RX PubMed=12604551; DOI=10.1128/aac.47.3.1120-1124.2003;
RA Diaz-Guerra T.M., Mellado E., Cuenca-Estrella M., Rodriguez-Tudela J.L.;
RT "A point mutation in the 14alpha-sterol demethylase gene cyp51A contributes
RT to itraconazole resistance in Aspergillus fumigatus.";
RL Antimicrob. Agents Chemother. 47:1120-1124(2003).
RN [6]
RP FUNCTION, AND MUTAGENESIS OF GLY-54.
RX PubMed=12709346; DOI=10.1128/aac.47.5.1719-1726.2003;
RA Nascimento A.M., Goldman G.H., Park S., Marras S.A., Delmas G., Oza U.,
RA Lolans K., Dudley M.N., Mann P.A., Perlin D.S.;
RT "Multiple resistance mechanisms among Aspergillus fumigatus mutants with
RT high-level resistance to itraconazole.";
RL Antimicrob. Agents Chemother. 47:1719-1726(2003).
RN [7]
RP FUNCTION, AND MUTAGENESIS OF MET-220.
RX PubMed=15215142; DOI=10.1128/aac.48.7.2747-2750.2004;
RA Mellado E., Garcia-Effron G., Alcazar-Fuoli L., Cuenca-Estrella M.,
RA Rodriguez-Tudela J.L.;
RT "Substitutions at methionine 220 in the 14alpha-sterol demethylase (Cyp51A)
RT of Aspergillus fumigatus are responsible for resistance in vitro to azole
RT antifungal drugs.";
RL Antimicrob. Agents Chemother. 48:2747-2750(2004).
RN [8]
RP FUNCTION, ACTIVITY REGULATION, INHIBITOR-BINDING, AND 3D-MODELING.
RX PubMed=15142553; DOI=10.1016/j.bmc.2004.03.034;
RA Gollapudy R., Ajmani S., Kulkarni S.A.;
RT "Modeling and interactions of Aspergillus fumigatus lanosterol 14-alpha
RT demethylase 'A' with azole antifungals.";
RL Bioorg. Med. Chem. 12:2937-2950(2004).
RN [9]
RP FUNCTION, AND ACTIVITY REGULATION.
RX PubMed=15855543; DOI=10.1128/aac.49.5.2119-2121.2005;
RA Garcia-Effron G., Mellado E., Gomez-Lopez A., Alcazar-Fuoli L.,
RA Cuenca-Estrella M., Rodriguez-Tudela J.L.;
RT "Differences in interactions between azole drugs related to modifications
RT in the 14-alpha sterol demethylase gene (cyp51A) of Aspergillus
RT fumigatus.";
RL Antimicrob. Agents Chemother. 49:2119-2121(2005).
RN [10]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=15917566; DOI=10.1128/aac.49.6.2536-2538.2005;
RA Mellado E., Garcia-Effron G., Buitrago M.J., Alcazar-Fuoli L.,
RA Cuenca-Estrella M., Rodriguez-Tudela J.L.;
RT "Targeted gene disruption of the 14-alpha sterol demethylase (cyp51A) in
RT Aspergillus fumigatus and its role in azole drug susceptibility.";
RL Antimicrob. Agents Chemother. 49:2536-2538(2005).
RN [11]
RP FUNCTION, AND MUTAGENESIS OF GLY-54 AND MET-220.
RX PubMed=15563516; DOI=10.1093/jac/dkh507;
RA Chen J., Li H., Li R., Bu D., Wan Z.;
RT "Mutations in the cyp51A gene and susceptibility to itraconazole in
RT Aspergillus fumigatus serially isolated from a patient with lung
RT aspergilloma.";
RL J. Antimicrob. Chemother. 55:31-37(2005).
RN [12]
RP FUNCTION, AND MUTAGENESIS OF GLY-54.
RX PubMed=15634974; DOI=10.1128/jcm.43.1.214-222.2005;
RA Balashov S.V., Gardiner R., Park S., Perlin D.S.;
RT "Rapid, high-throughput, multiplex, real-time PCR for identification of
RT mutations in the cyp51A gene of Aspergillus fumigatus that confer
RT resistance to itraconazole.";
RL J. Clin. Microbiol. 43:214-222(2005).
RN [13]
RP FUNCTION, AND MUTAGENESIS OF GLY-54.
RX PubMed=15695702; DOI=10.1128/jcm.43.2.906-908.2005;
RA Trama J.P., Mordechai E., Adelson M.E.;
RT "Detection of Aspergillus fumigatus and a mutation that confers reduced
RT susceptibility to itraconazole and posaconazole by real-time PCR and
RT pyrosequencing.";
RL J. Clin. Microbiol. 43:906-908(2005).
RN [14]
RP IDENTIFICATION, AND FUNCTION.
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 [15]
RP INDUCTION.
RX PubMed=16622700; DOI=10.1007/s00294-006-0073-2;
RA da Silva Ferreira M.E., Malavazi I., Savoldi M., Brakhage A.A.,
RA Goldman M.H., Kim H.S., Nierman W.C., Goldman G.H.;
RT "Transcriptome analysis of Aspergillus fumigatus exposed to voriconazole.";
RL Curr. Genet. 50:32-44(2006).
RN [16]
RP FUNCTION, AND MUTAGENESIS OF LEU-98.
RX PubMed=17371828; DOI=10.1128/aac.01092-06;
RA Mellado E., Garcia-Effron G., Alcazar-Fuoli L., Melchers W.J.,
RA Verweij P.E., Cuenca-Estrella M., Rodriguez-Tudela J.L.;
RT "A new Aspergillus fumigatus resistance mechanism conferring in vitro
RT cross-resistance to azole antifungals involves a combination of cyp51A
RT alterations.";
RL Antimicrob. Agents Chemother. 51:1897-1904(2007).
RN [17]
RP INDUCTION.
RX PubMed=18721228; DOI=10.1111/j.1365-2958.2008.06376.x;
RA Schrettl M., Kim H.S., Eisendle M., Kragl C., Nierman W.C., Heinekamp T.,
RA Werner E.R., Jacobsen I., Illmer P., Yi H., Brakhage A.A., Haas H.;
RT "SreA-mediated iron regulation in Aspergillus fumigatus.";
RL Mol. Microbiol. 70:27-43(2008).
RN [18]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND DISRUPTION PHENOTYPE.
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 [19]
RP 3D-MODELING, FUNCTION, AND INHIBITOR-BINDING.
RX PubMed=21300838; DOI=10.1128/aac.01651-10;
RA Fraczek M.G., Bromley M., Bowyer P.;
RT "An improved model of the Aspergillus fumigatus CYP51A protein.";
RL Antimicrob. Agents Chemother. 55:2483-2486(2011).
RN [20]
RP FUNCTION, AND MUTAGENESIS OF LEU-98.
RX PubMed=21907818; DOI=10.1016/j.fgb.2011.08.002;
RA Snelders E., Karawajczyk A., Verhoeven R.J., Venselaar H., Schaftenaar G.,
RA Verweij P.E., Melchers W.J.;
RT "The structure-function relationship of the Aspergillus fumigatus cyp51A
RT L98H conversion by site-directed mutagenesis: the mechanism of L98H azole
RT resistance.";
RL Fungal Genet. Biol. 48:1062-1070(2011).
RN [21]
RP 3D-MODELING, FUNCTION, AND INHIBITOR-BINDING.
RX PubMed=21871783; DOI=10.1016/j.ijantimicag.2011.06.005;
RA Alcazar-Fuoli L., Cuesta I., Rodriguez-Tudela J.L., Cuenca-Estrella M.,
RA Sanglard D., Mellado E.;
RT "Three-dimensional models of 14alpha-sterol demethylase (Cyp51A) from
RT Aspergillus lentulus and Aspergillus fumigatus: an insight into differences
RT in voriconazole interaction.";
RL Int. J. Antimicrob. Agents 38:426-434(2011).
RN [22]
RP INDUCTION.
RX PubMed=22144905; DOI=10.1371/journal.pgen.1002374;
RA Blatzer M., Barker B.M., Willger S.D., Beckmann N., Blosser S.J.,
RA Cornish E.J., Mazurie A., Grahl N., Haas H., Cramer R.A.;
RT "SREBP coordinates iron and ergosterol homeostasis to mediate triazole drug
RT and hypoxia responses in the human fungal pathogen Aspergillus fumigatus.";
RL PLoS Genet. 7:E1002374-E1002374(2011).
RN [23]
RP INDUCTION.
RX PubMed=22006005; DOI=10.1128/aac.05027-11;
RA Blosser S.J., Cramer R.A.;
RT "SREBP-dependent triazole susceptibility in Aspergillus fumigatus is
RT mediated through direct transcriptional regulation of erg11A (cyp51A).";
RL Antimicrob. Agents Chemother. 56:248-257(2012).
RN [24]
RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=26459890; DOI=10.1128/aac.01806-15;
RA Warrilow A.G., Parker J.E., Price C.L., Nes W.D., Kelly S.L., Kelly D.E.;
RT "In Vitro biochemical study of CYP51-mediated azole resistance in
RT Aspergillus fumigatus.";
RL Antimicrob. Agents Chemother. 59:7771-7778(2015).
RN [25]
RP FUNCTION, CATALYTIC ACTIVITY, AND ACTIVITY REGULATION.
RX PubMed=29439966; DOI=10.1128/aac.01941-17;
RA Colley T., Sehra G., Chowdhary A., Alanio A., Kelly S.L., Kizawa Y.,
RA Armstrong-James D., Fisher M.C., Warrilow A.G.S., Parker J.E., Kelly D.E.,
RA Kimura G., Nishimoto Y., Sunose M., Onions S., Crepin D., Lagasse F.,
RA Crittall M., Shannon J., McConville M., King-Underwood J., Naylor A.,
RA Bretagne S., Murray J., Ito K., Strong P., Rapeport G.;
RT "In vitro and in vivo efficacy of a novel and long-acting fungicidal azole,
RT PC1244, on Aspergillus fumigatus infection.";
RL Antimicrob. Agents Chemother. 62:0-0(2018).
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:15215142, PubMed:18191972, PubMed:26459890,
CC PubMed:29439966, PubMed:9184358). Demethylates eburicol to yield
CC 4,4,24-trimethyl ergosta-8,14,24(28)-trienol (PubMed:15215142,
CC PubMed:18191972, PubMed:26459890, PubMed:29439966, PubMed:9184358). The
CC third module or late pathway involves the ergosterol synthesis itself
CC through consecutive reactions that mainly occur in the endoplasmic
CC reticulum (ER) membrane. Firstly, the squalene synthase erg9 catalyzes
CC the 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 and cyp51B, to yield 4,4,24-trimethyl
CC ergosta-8,14,24(28)-trienol. The C-14 reductase erg24 then reduces the
CC C14=C15 double bond which leads to 4,4-dimethylfecosterol. A sequence
CC of further demethylations at C-4, involving the C-4 demethylation
CC complex containing the C-4 methylsterol oxidases erg25A or erg25B, the
CC sterol-4-alpha-carboxylate 3-dehydrogenase erg26 and the 3-keto-steroid
CC reductase erg27, leads to the production of fecosterol via 4-
CC methylfecosterol. The C-8 sterol isomerase erg2 then catalyzes the
CC reaction which results in unsaturation at C-7 in the B ring of sterols
CC and thus converts fecosterol to episterol. The sterol-C5-desaturase
CC erg3B then catalyzes the introduction of a C-5 double bond in the B
CC ring to produce 5-dehydroepisterol. The 2 other sterol-C5-desaturases,
CC erg3A and erg3C, seem to be less important in ergosterol biosynthesis.
CC The C-22 sterol desaturase erg5 further converts 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 reductases erg4A
CC and erg4B to produce ergosterol. Possible alternative sterol
CC biosynthetic pathways might exist from fecosterol to ergosterol,
CC depending on the activities of the erg3 isoforms (PubMed:16110826,
CC PubMed:18191972) (Probable). {ECO:0000269|PubMed:15215142,
CC ECO:0000269|PubMed:18191972, ECO:0000269|PubMed:26459890,
CC ECO:0000269|PubMed:29439966, ECO:0000269|PubMed:9184358,
CC ECO:0000305|PubMed:16110826, ECO:0000305|PubMed:18191972}.
CC -!- FUNCTION: As a target of azole drugs, plays a crucial role in azole
CC susceptibility. {ECO:0000269|PubMed:12543662,
CC ECO:0000269|PubMed:12604551, ECO:0000269|PubMed:12709346,
CC ECO:0000269|PubMed:15142553, ECO:0000269|PubMed:15215142,
CC ECO:0000269|PubMed:15563516, ECO:0000269|PubMed:15634974,
CC ECO:0000269|PubMed:15695702, ECO:0000269|PubMed:15855543,
CC ECO:0000269|PubMed:15917566, ECO:0000269|PubMed:17371828,
CC ECO:0000269|PubMed:21907818, ECO:0000269|PubMed:29439966,
CC ECO:0000305|PubMed:21300838, ECO:0000305|PubMed:21871783}.
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:0000269|PubMed:18191972, ECO:0000269|PubMed:26459890,
CC ECO:0000269|PubMed:29439966, ECO:0000269|PubMed:9184358};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54029;
CC Evidence={ECO:0000269|PubMed:18191972, ECO:0000269|PubMed:26459890,
CC ECO:0000269|PubMed:29439966, ECO:0000269|PubMed:9184358};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC -!- ACTIVITY REGULATION: The sterol 14-alpha demethylase activity is
CC inhibited by azole compounds (PubMed:15142553, PubMed:15855543,
CC PubMed:9184358, PubMed:26459890). Activity is inhibited by the novel
CC and long-acting fungicidal azole, PC1244 (PubMed:29439966).
CC {ECO:0000269|PubMed:15142553, ECO:0000269|PubMed:15855543,
CC ECO:0000269|PubMed:26459890, ECO:0000269|PubMed:29439966,
CC ECO:0000269|PubMed:9184358}.
CC -!- PATHWAY: Steroid metabolism; ergosterol biosynthesis.
CC {ECO:0000269|PubMed:18191972, ECO:0000269|PubMed:9184358}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000305};
CC Single-pass membrane protein {ECO:0000255}.
CC -!- INDUCTION: Expression is decreased upon exposure to voriconazole
CC (PubMed:16622700). Expression is regulated by the GATA transcription
CC factor sreA during hypoxia (PubMed:18721228, PubMed:22144905,
CC PubMed:22006005). {ECO:0000269|PubMed:16622700,
CC ECO:0000269|PubMed:18721228, ECO:0000269|PubMed:22006005,
CC ECO:0000269|PubMed:22144905}.
CC -!- DISRUPTION PHENOTYPE: Leads to the accumulation of eburicol
CC (PubMed:18191972). Leads to decreased susceptibility to azoles,
CC especially fluconazole and ketoconazole, as well as to itraconazole in
CC an itraconazole-resistant strain. {ECO:0000269|PubMed:15917566,
CC ECO:0000269|PubMed:18191972}.
CC -!- MISCELLANEOUS: Mutations of Gly-54 or Met-220 lead to the resistance to
CC azoles, clinical drugs used to inhibit the activity and kill
CC Aspergillus fumigatus cells during infections (PubMed:12543662,
CC PubMed:12604551, PubMed:12709346, PubMed:15215142, PubMed:15563516,
CC PubMed:15634974, PubMed:15695702). Duplication in tandem of a 34 bp
CC sequence in the cyp51A promoter located at positions -288 and -322 from
CC the start codon leads also to azole resistance, when associated with a
CC mutation of Leu-98 (PubMed:17371828, PubMed:21907818).
CC {ECO:0000269|PubMed:12543662, ECO:0000269|PubMed:12604551,
CC ECO:0000269|PubMed:12709346, ECO:0000269|PubMed:15215142,
CC ECO:0000269|PubMed:15563516, ECO:0000269|PubMed:15634974,
CC ECO:0000269|PubMed:15695702, ECO:0000269|PubMed:17371828,
CC ECO:0000269|PubMed:21907818}.
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 cytochrome P450 family. {ECO:0000305}.
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DR EMBL; AAHF01000005; EAL90099.1; -; Genomic_DNA.
DR RefSeq; XP_752137.1; XM_747044.1.
DR AlphaFoldDB; Q4WNT5; -.
DR SMR; Q4WNT5; -.
DR STRING; 746128.CADAFUBP00006222; -.
DR BindingDB; Q4WNT5; -.
DR ChEMBL; CHEMBL1681623; -.
DR DrugCentral; Q4WNT5; -.
DR EnsemblFungi; EAL90099; EAL90099; AFUA_4G06890.
DR GeneID; 3509526; -.
DR KEGG; afm:AFUA_4G06890; -.
DR VEuPathDB; FungiDB:Afu4g06890; -.
DR eggNOG; KOG0684; Eukaryota.
DR HOGENOM; CLU_001570_15_0_1; -.
DR InParanoid; Q4WNT5; -.
DR OMA; DMISNLM; -.
DR OrthoDB; 572303at2759; -.
DR UniPathway; UPA00768; -.
DR PHI-base; PHI:2534; -.
DR Proteomes; UP000002530; Chromosome 4.
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:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0004497; F:monooxygenase activity; IBA:GO_Central.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0008398; F:sterol 14-demethylase activity; IEA:UniProtKB-EC.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IBA:GO_Central.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0016125; P:sterol metabolic process; IBA:GO_Central.
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 1: Evidence at protein level;
KW Endoplasmic reticulum; Glycoprotein; Heme; Iron; Lipid biosynthesis;
KW Lipid metabolism; Membrane; Metal-binding; Methyltransferase;
KW Monooxygenase; Oxidoreductase; Reference proteome; Steroid biosynthesis;
KW Steroid metabolism; Sterol biosynthesis; Sterol metabolism; Transferase;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..515
FT /note="Sterol 14-alpha demethylase cyp51A"
FT /id="PRO_0000448855"
FT TRANSMEM 7..29
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 454
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:Q16850"
FT CARBOHYD 33
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 269
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 512
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT MUTAGEN 54
FT /note="G->E,K,R,V,W: Leads to resistance to azole
FT compounds."
FT /evidence="ECO:0000269|PubMed:12543662,
FT ECO:0000269|PubMed:12604551, ECO:0000269|PubMed:12709346,
FT ECO:0000269|PubMed:15563516, ECO:0000269|PubMed:15634974,
FT ECO:0000269|PubMed:15695702"
FT MUTAGEN 98
FT /note="L->H: Leads to resistance to azole compounds; when
FT associated with a 34 bp tandem duplication in the
FT promoter."
FT /evidence="ECO:0000269|PubMed:17371828,
FT ECO:0000269|PubMed:21907818"
FT MUTAGEN 220
FT /note="M->I,K,T,V: Leads to resistance to azole compounds."
FT /evidence="ECO:0000269|PubMed:15215142,
FT ECO:0000269|PubMed:15563516"
SQ SEQUENCE 515 AA; 58068 MW; C46737B1444BB25F CRC64;
MVPMLWLTAY MAVAVLTAIL LNVVYQLFFR LWNRTEPPMV FHWVPYLGST ISYGIDPYKF
FFACREKYGD IFTFILLGQK TTVYLGVQGN EFILNGKLKD VNAEEVYSPL TTPVFGSDVV
YDCPNSKLME QKKFIKYGLT QSALESHVPL IEKEVLDYLR DSPNFQGSSG RVDISAAMAE
ITIFTAARAL QGQEVRSKLT AEFADLYHDL DKGFTPINFM LPWAPLPHNK KRDAAHARMR
SIYVDIITQR RLDGEKDSQK SDMIWNLMNC TYKNGQQVPD KEIAHMMITL LMAGQHSSSS
ISAWIMLRLA SQPKVLEELY QEQLANLGPA GPDGSLPPLQ YKDLDKLPFH QHVIRETLRI
HSSIHSIMRK VKSPLPVPGT PYMIPPGRVL LASPGVTALS DEHFPNAGCW DPHRWENQAT
KEQENDKVVD YGYGAVSKGT SSPYLPFGAG RHRCIGEKFA YVNLGVILAT IVRHLRLFNV
DGKKGVPETD YSSLFSGPMK PSIIGWEKRS KNTSK
