CP51_CANAL
ID CP51_CANAL Reviewed; 528 AA.
AC P10613; A0A1D8PMZ1; Q5A524; Q92208;
DT 01-JUL-1989, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 2.
DT 03-AUG-2022, entry version 162.
DE RecName: Full=Lanosterol 14-alpha demethylase {ECO:0000303|PubMed:2644625};
DE Short=LDM {ECO:0000303|PubMed:30126961};
DE EC=1.14.14.154 {ECO:0000269|PubMed:28258218, ECO:0000269|PubMed:8647850};
DE AltName: Full=Cytochrome P450 51 {ECO:0000303|PubMed:10393548};
DE AltName: Full=Cytochrome P450-14DM {ECO:0000303|PubMed:2180400};
DE AltName: Full=Cytochrome P450-LIA1 {ECO:0000303|PubMed:2644625};
DE Short=CYPLI {ECO:0000303|PubMed:2644625};
DE AltName: Full=Ergosterol biosynthesis protein 11 {ECO:0000303|PubMed:10991846};
DE AltName: Full=Sterol 14-alpha demethylase {ECO:0000303|PubMed:2180400};
GN Name=ERG11 {ECO:0000303|PubMed:10991846};
GN Synonyms=CYP51 {ECO:0000303|PubMed:10393548}, ERG16;
GN OrderedLocusNames=CAALFM_C500660CA; ORFNames=CaO19.922;
OS Candida albicans (strain SC5314 / ATCC MYA-2876) (Yeast).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Saccharomycotina; Saccharomycetes;
OC Saccharomycetales; Debaryomycetaceae; Candida/Lodderomyces clade; Candida.
OX NCBI_TaxID=237561;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=2644625; DOI=10.1093/nar/17.2.804;
RA Lai M.H., Kirsch D.R.;
RT "Nucleotide sequence of cytochrome P450 L1A1 (lanosterol 14 alpha-
RT demethylase) from Candida albicans.";
RL Nucleic Acids Res. 17:804-804(1989).
RN [2]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=CA100, CA11, CA36, and CA95;
RA Orru G., Ciusa M.L., Pilia F., Taccori F., Cosentino S., Pisano M.B.,
RA Meloni M., Fadda M.E.;
RT "ERG11 mutations in oral strains of Candida albicans isolated in
RT Sardinia.";
RL Submitted (JUN-2008) to the EMBL/GenBank/DDBJ databases.
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=15123810; DOI=10.1073/pnas.0401648101;
RA Jones T., Federspiel N.A., Chibana H., Dungan J., Kalman S., Magee B.B.,
RA Newport G., Thorstenson Y.R., Agabian N., Magee P.T., Davis R.W.,
RA Scherer S.;
RT "The diploid genome sequence of Candida albicans.";
RL Proc. Natl. Acad. Sci. U.S.A. 101:7329-7334(2004).
RN [4]
RP GENOME REANNOTATION.
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=17419877; DOI=10.1186/gb-2007-8-4-r52;
RA van het Hoog M., Rast T.J., Martchenko M., Grindle S., Dignard D.,
RA Hogues H., Cuomo C., Berriman M., Scherer S., Magee B.B., Whiteway M.,
RA Chibana H., Nantel A., Magee P.T.;
RT "Assembly of the Candida albicans genome into sixteen supercontigs aligned
RT on the eight chromosomes.";
RL Genome Biol. 8:RESEARCH52.1-RESEARCH52.12(2007).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], AND GENOME REANNOTATION.
RC STRAIN=SC5314 / ATCC MYA-2876;
RX PubMed=24025428; DOI=10.1186/gb-2013-14-9-r97;
RA Muzzey D., Schwartz K., Weissman J.S., Sherlock G.;
RT "Assembly of a phased diploid Candida albicans genome facilitates allele-
RT specific measurements and provides a simple model for repeat and indel
RT structure.";
RL Genome Biol. 14:RESEARCH97.1-RESEARCH97.14(2013).
RN [6]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-48 AND 467-528, AND VARIANT LYS-467.
RC STRAIN=SS;
RX PubMed=9210671; DOI=10.1128/aac.41.7.1488;
RA White T.C.;
RT "The presence of an R467K amino acid substitution and loss of allelic
RT variation correlate with an azole-resistant lanosterol 14-alpha demethylase
RT in Candida albicans.";
RL Antimicrob. Agents Chemother. 41:1488-1494(1997).
RN [7]
RP FUNCTION.
RX PubMed=3065144; DOI=10.1016/0378-1119(88)90025-x;
RA Kirsch D.R., Lai M.H., O'Sullivan J.;
RT "Isolation of the gene for cytochrome P450L1A1 (lanosterol 14 alpha-
RT demethylase) from Candida albicans.";
RL Gene 68:229-237(1988).
RN [8]
RP ACTIVITY REGULATION.
RX PubMed=2180400; DOI=10.1042/bj2660475;
RA Hitchcock C.A., Dickinson K., Brown S.B., Evans E.G., Adams D.J.;
RT "Interaction of azole antifungal antibiotics with cytochrome P-450-
RT dependent 14 alpha-sterol demethylase purified from Candida albicans.";
RL Biochem. J. 266:475-480(1990).
RN [9]
RP 3D-STRUCTURE MODELING.
RX PubMed=7819160; DOI=10.1016/0263-7855(94)80086-3;
RA Boscott P.E., Grant G.H.;
RT "Modeling cytochrome P450 14-alpha demethylase (Candida albicans) from
RT P450cam.";
RL J. Mol. Graph. 12:185-192(1994).
RN [10]
RP ACTIVITY REGULATION.
RX PubMed=7864896; DOI=10.1006/bbrc.1995.1272;
RA Kelly S.L., Lamb D.C., Corran A.J., Baldwin B.C., Kelly D.E.;
RT "Mode of action and resistance to azole antifungals associated with the
RT formation of 14 alpha-methylergosta-8,24(28)-dien-3 beta,6 alpha-diol.";
RL Biochem. Biophys. Res. Commun. 207:910-915(1995).
RN [11]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=8647850; DOI=10.1074/jbc.271.21.12445;
RA Shyadehi A.Z., Lamb D.C., Kelly S.L., Kelly D.E., Schunck W.H.,
RA Wright J.N., Corina D., Akhtar M.;
RT "The mechanism of the acyl-carbon bond cleavage reaction catalyzed by
RT recombinant sterol 14 alpha-demethylase of Candida albicans (other names
RT are: lanosterol 14 alpha-demethylase, P-45014DM, and CYP51).";
RL J. Biol. Chem. 271:12445-12450(1996).
RN [12]
RP ACTIVITY REGULATION.
RX PubMed=9103974; DOI=10.1111/j.1574-6968.1997.tb10303.x;
RA Lamb D.C., Kelly D.E., Baldwin B.C., Gozzo F., Boscott P., Richards W.G.,
RA Kelly S.L.;
RT "Differential inhibition of Candida albicans CYP51 with azole antifungal
RT stereoisomers.";
RL FEMS Microbiol. Lett. 149:25-30(1997).
RN [13]
RP VARIANTS LEU-105; ASP-266; ARG-287; GLU-448; GLU-450; SER-464 AND ILE-488.
RX PubMed=9228762; DOI=10.1111/j.1574-6968.1997.tb12580.x;
RA Loffler J., Kelly S.L., Hebart H., Schumacher U., Lass-Florl C.,
RA Einsele H.;
RT "Molecular analysis of cyp51 from fluconazole-resistant Candida albicans
RT strains.";
RL FEMS Microbiol. Lett. 151:263-268(1997).
RN [14]
RP VARIANTS ALA-129; HIS-132; PHE-405;SER-464 AND LYS-467.
RX PubMed=9527767; DOI=10.1128/aac.42.2.241;
RA Sanglard D., Ischer F., Koymans L., Bille J.;
RT "Amino acid substitutions in the cytochrome P-450 lanosterol 14alpha-
RT demethylase (CYP51A1) from azole-resistant Candida albicans clinical
RT isolates contribute to resistance to azole antifungal agents.";
RL Antimicrob. Agents Chemother. 42:241-253(1998).
RN [15]
RP VARFIANTS HIS-132 AND LEU-145.
RX PubMed=10223930; DOI=10.1128/aac.43.5.1163;
RA Asai K., Tsuchimori N., Okonogi K., Perfect J.R., Gotoh O., Yoshida Y.;
RT "Formation of azole-resistant Candida albicans by mutation of sterol 14-
RT demethylase P450.";
RL Antimicrob. Agents Chemother. 43:1163-1169(1999).
RN [16]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=10393548; DOI=10.1021/bi9825089;
RA Lamb D.C., Kelly D.E., Venkateswarlu K., Manning N.J., Bligh H.F.,
RA Schunck W.H., Kelly S.L.;
RT "Generation of a complete, soluble, and catalytically active sterol 14
RT alpha-demethylase-reductase complex.";
RL Biochemistry 38:8733-8738(1999).
RN [17]
RP VARIANTS VAL-149; GLU-153; TYR-165; PHE-279; ALA-452 AND SER-465.
RX PubMed=10537192; DOI=10.1099/00221287-145-10-2701;
RA Marichal P., Koymans L., Willemsens S., Bellens D., Verhasselt P.,
RA Luyten W., Borgers M., Ramaekers F.C.S., Odds F.C., Vanden Bossche H.;
RT "Contribution of mutations in the cytochrome P450 14alpha-demethylase
RT (Erg11p, Cyp51p) to azole resistance in Candida albicans.";
RL Microbiology 145:2701-2713(1999).
RN [18]
RP VARIANT LYS-467.
RX PubMed=10602724; DOI=10.1128/aac.44.1.63-67.2000;
RA Lamb D.C., Kelly D.E., White T.C., Kelly S.L.;
RT "The R467K amino acid substitution in Candida albicans sterol 14alpha-
RT demethylase causes drug resistance through reduced affinity.";
RL Antimicrob. Agents Chemother. 44:63-67(2000).
RN [19]
RP INDUCTION.
RX PubMed=10991846; DOI=10.1128/aac.44.10.2693-2700.2000;
RA Henry K.W., Nickels J.T., Edlind T.D.;
RT "Upregulation of ERG genes in Candida species by azoles and other sterol
RT biosynthesis inhibitors.";
RL Antimicrob. Agents Chemother. 44:2693-2700(2000).
RN [20]
RP 3D-STRUCTURE MODELING, AND INHIBITOR-BINDING.
RX PubMed=10891108; DOI=10.1021/jm990589g;
RA Ji H., Zhang W., Zhou Y., Zhang M., Zhu J., Song Y., Lue J.;
RT "A three-dimensional model of lanosterol 14alpha-demethylase of Candida
RT albicans and its interaction with azole antifungals.";
RL J. Med. Chem. 43:2493-2505(2000).
RN [21]
RP INDUCTION.
RX PubMed=15047513; DOI=10.1128/aac.48.4.1136-1144.2004;
RA Song J.L., Harry J.B., Eastman R.T., Oliver B.G., White T.C.;
RT "The Candida albicans lanosterol 14-alpha-demethylase (ERG11) gene promoter
RT is maximally induced after prolonged growth with antifungal drugs.";
RL Antimicrob. Agents Chemother. 48:1136-1144(2004).
RN [22] {ECO:0007744|PDB:5FSA, ECO:0007744|PDB:5TZ1}
RP X-RAY CRYSTALLOGRAPHY (2.00 ANGSTROMS) OF 48-528 IN COMPLEX WITH INHIBITOR
RP AND HEME, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY
RP REGULATION, AND PATHWAY.
RX PubMed=28258218; DOI=10.1074/jbc.m117.778308;
RA Hargrove T.Y., Friggeri L., Wawrzak Z., Qi A., Hoekstra W.J.,
RA Schotzinger R.J., York J.D., Guengerich F.P., Lepesheva G.I.;
RT "Structural analyses of Candida albicans sterol 14alpha-demethylase
RT complexed with azole drugs address the molecular basis of azole-mediated
RT inhibition of fungal sterol biosynthesis.";
RL J. Biol. Chem. 292:6728-6743(2017).
RN [23] {ECO:0007744|PDB:5V5Z}
RP X-RAY CRYSTALLOGRAPHY (2.90 ANGSTROMS) IN COMPLEX WITH INHIBITOR AND HEME.
RX PubMed=30126961; DOI=10.1128/aac.01134-18;
RA Keniya M.V., Sabherwal M., Wilson R.K., Woods M.A., Sagatova A.A.,
RA Tyndall J.D.A., Monk B.C.;
RT "Crystal Structures of Full-Length Lanosterol 14alpha-Demethylases of
RT Prominent Fungal Pathogens Candida albicans and Candida glabrata Provide
RT Tools for Antifungal Discovery.";
RL Antimicrob. Agents Chemother. 62:0-0(2018).
CC -!- FUNCTION: Lanosterol 14-alpha demethylase; part of the third module of
CC ergosterol biosynthesis pathway that includes the late steps of the
CC pathway (PubMed:2180400, PubMed:8647850, PubMed:10393548,
CC PubMed:28258218). The lanosterol 14-alpha-demethylase ERG11 (also known
CC as CYP51) catalyzes C14-demethylation of lanosterol to produce 4,4'-
CC dimethyl cholesta-8,14,24-triene-3-beta-ol, which is critical for
CC ergosterol biosynthesis (PubMed:8647850, PubMed:10393548,
CC PubMed:28258218). The third module or late pathway involves the
CC ergosterol synthesis itself through consecutive reactions that mainly
CC occur in the endoplasmic reticulum (ER) membrane. Firstly, the squalene
CC synthase ERG9 catalyzes the condensation of 2 farnesyl pyrophosphate
CC moieties to form squalene, which is the precursor of all steroids.
CC Squalene synthase is crucial for balancing the incorporation of
CC farnesyl diphosphate (FPP) into sterol and nonsterol isoprene
CC synthesis. Secondly, the squalene epoxidase ERG1 catalyzes the
CC stereospecific oxidation of squalene to (S)-2,3-epoxysqualene, which is
CC considered to be a rate-limiting enzyme in steroid biosynthesis. Then,
CC the lanosterol synthase ERG7 catalyzes the cyclization of (S)-2,3
CC oxidosqualene to lanosterol, a reaction that forms the sterol core. In
CC the next steps, lanosterol is transformed to zymosterol through a
CC complex process involving various demethylation, reduction and
CC desaturation reactions. The lanosterol 14-alpha-demethylase ERG11 (also
CC known as CYP51) catalyzes C14-demethylation of lanosterol to produce
CC 4,4'-dimethyl cholesta-8,14,24-triene-3-beta-ol, which is critical for
CC ergosterol biosynthesis. The C-14 reductase ERG24 reduces the C14=C15
CC double bond of 4,4-dimethyl-cholesta-8,14,24-trienol to produce 4,4-
CC dimethyl-cholesta-8,24-dienol. 4,4-dimethyl-cholesta-8,24-dienol is
CC substrate of the C-4 demethylation complex ERG25-ERG26-ERG27 in which
CC ERG25 catalyzes the three-step monooxygenation required for the
CC demethylation of 4,4-dimethyl and 4alpha-methylsterols, ERG26 catalyzes
CC the oxidative decarboxylation that results in a reduction of the 3-
CC beta-hydroxy group at the C-3 carbon to an oxo group, and ERG27 is
CC responsible for the reduction of the keto group on the C-3. ERG28 has a
CC role as a scaffold to help anchor ERG25, ERG26 and ERG27 to the
CC endoplasmic reticulum and ERG29 regulates the activity of the iron-
CC containing C4-methylsterol oxidase ERG25. Then, the sterol 24-C-
CC methyltransferase ERG6 catalyzes the methyl transfer from S-adenosyl-
CC methionine to the C-24 of zymosterol to form fecosterol. The C-8 sterol
CC isomerase ERG2 catalyzes the reaction which results in unsaturation at
CC C-7 in the B ring of sterols and thus converts fecosterol to episterol.
CC The sterol-C5-desaturase ERG3 then catalyzes the introduction of a C-5
CC double bond in the B ring to produce 5-dehydroepisterol. The C-22
CC sterol desaturase ERG5 further converts 5-dehydroepisterol into
CC ergosta-5,7,22,24(28)-tetraen-3beta-ol by forming the C-22(23) double
CC bond in the sterol side chain. Finally, ergosta-5,7,22,24(28)-tetraen-
CC 3beta-ol is substrate of the C-24(28) sterol reductase ERG4 to produce
CC ergosterol (Probable). {ECO:0000269|PubMed:10393548,
CC ECO:0000269|PubMed:2180400, ECO:0000269|PubMed:28258218,
CC ECO:0000269|PubMed:8647850, ECO:0000305}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=lanosterol + 3 O2 + 3 reduced [NADPH--hemoprotein reductase] =
CC 4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol + formate + 4
CC H(+) + 4 H2O + 3 oxidized [NADPH--hemoprotein reductase];
CC Xref=Rhea:RHEA:25286, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC ChEBI:CHEBI:15740, ChEBI:CHEBI:16521, ChEBI:CHEBI:17813,
CC ChEBI:CHEBI:57618, ChEBI:CHEBI:58210; EC=1.14.14.154;
CC Evidence={ECO:0000269|PubMed:10393548, ECO:0000269|PubMed:28258218,
CC ECO:0000269|PubMed:8647850};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25287;
CC Evidence={ECO:0000269|PubMed:10393548, ECO:0000269|PubMed:28258218,
CC ECO:0000269|PubMed:8647850};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000269|PubMed:28258218, ECO:0000269|PubMed:30126961};
CC -!- ACTIVITY REGULATION: The catalytic activity is inhibited by the binding
CC of azoles clotrimazole, miconazole, fluconazole, ketoconazole,
CC oteseconazole (VT-1161), tetraconazole, the triazole SCH39304, and the
CC triazole derivative ICI 153066. {ECO:0000269|PubMed:10891108,
CC ECO:0000269|PubMed:2180400, ECO:0000269|PubMed:28258218,
CC ECO:0000269|PubMed:7864896, ECO:0000269|PubMed:9103974}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=6.3 uM for lanosterol {ECO:0000269|PubMed:28258218};
CC -!- PATHWAY: Steroid biosynthesis; zymosterol biosynthesis; zymosterol from
CC lanosterol: step 1/6. {ECO:0000269|PubMed:28258218,
CC ECO:0000269|PubMed:8647850}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000305};
CC Single-pass membrane protein {ECO:0000255}.
CC -!- INDUCTION: Induced after prolonged growth with antifungal drugs such as
CC clotrimazole, miconazole, fluconazole, itraconazole, ketoconazole,
CC terbinafine and fenpropimorph. {ECO:0000269|PubMed:10991846,
CC ECO:0000269|PubMed:15047513}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; X13296; CAA31658.1; -; Genomic_DNA.
DR EMBL; EU819548; ACF34636.1; -; Genomic_DNA.
DR EMBL; EU819551; ACF34639.1; -; Genomic_DNA.
DR EMBL; FJ002303; ACH91036.1; -; Genomic_DNA.
DR EMBL; FJ403378; ACJ23064.1; -; Genomic_DNA.
DR EMBL; CP017627; AOW29509.1; -; Genomic_DNA.
DR EMBL; U67192; AAB08099.1; -; Genomic_DNA.
DR EMBL; U67193; AAB08100.1; -; Genomic_DNA.
DR PIR; S02713; O4CK51.
DR RefSeq; XP_716761.1; XM_711668.2.
DR PDB; 5FSA; X-ray; 2.86 A; A/B=49-528.
DR PDB; 5TZ1; X-ray; 2.00 A; A/B=48-528.
DR PDB; 5V5Z; X-ray; 2.90 A; A=1-528.
DR PDBsum; 5FSA; -.
DR PDBsum; 5TZ1; -.
DR PDBsum; 5V5Z; -.
DR AlphaFoldDB; P10613; -.
DR SMR; P10613; -.
DR STRING; 237561.P10613; -.
DR BindingDB; P10613; -.
DR ChEMBL; CHEMBL1780; -.
DR ChEMBL; CHEMBL4662933; -.
DR DrugBank; DB04794; Bifonazole.
DR DrugBank; DB00257; Clotrimazole.
DR DrugBank; DB01127; Econazole.
DR DrugBank; DB00196; Fluconazole.
DR DrugBank; DB08933; Luliconazole.
DR DrugBank; DB01110; Miconazole.
DR DrugBank; DB00239; Oxiconazole.
DR DrugBank; DB01263; Posaconazole.
DR DrugBank; DB01153; Sertaconazole.
DR DrugBank; DB00251; Terconazole.
DR DrugBank; DB01007; Tioconazole.
DR DrugBank; DB00582; Voriconazole.
DR DrugCentral; P10613; -.
DR PRIDE; P10613; -.
DR GeneID; 3641571; -.
DR KEGG; cal:CAALFM_C500660CA; -.
DR CGD; CAL0000176310; ERG11.
DR VEuPathDB; FungiDB:C5_00660C_A; -.
DR eggNOG; KOG0684; Eukaryota.
DR HOGENOM; CLU_001570_15_0_1; -.
DR InParanoid; P10613; -.
DR OrthoDB; 572303at2759; -.
DR BRENDA; 1.14.13.70; 11936.
DR BRENDA; 1.14.14.154; 1096.
DR UniPathway; UPA00770; UER00754.
DR PHI-base; PHI:8030; -.
DR PHI-base; PHI:8187; -.
DR PRO; PR:P10613; -.
DR Proteomes; UP000000559; Chromosome 5.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IDA:CGD.
DR GO; GO:0016020; C:membrane; IDA:CGD.
DR GO; GO:0005886; C:plasma membrane; IDA:CGD.
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; IBA:GO_Central.
DR GO; GO:0016491; F:oxidoreductase activity; IBA:GO_Central.
DR GO; GO:0008398; F:sterol 14-demethylase activity; IDA:CGD.
DR GO; GO:0036187; P:cell growth mode switching, budding to filamentous; IMP:CGD.
DR GO; GO:0006696; P:ergosterol biosynthetic process; IGI:CGD.
DR GO; GO:0001766; P:membrane raft polarization; IMP:CGD.
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 3D-structure; Endoplasmic reticulum; Heme; Iron; Lipid biosynthesis;
KW Lipid metabolism; Membrane; Metal-binding; Monooxygenase; Oxidoreductase;
KW Reference proteome; Steroid biosynthesis; Steroid metabolism;
KW Sterol biosynthesis; Sterol metabolism; Transmembrane; Transmembrane helix.
FT CHAIN 1..528
FT /note="Lanosterol 14-alpha demethylase"
FT /id="PRO_0000052003"
FT TRANSMEM 15..37
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 64
FT /ligand="oteseconazole"
FT /ligand_id="ChEBI:CHEBI:188153"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0007744|PDB:5TZ1"
FT BINDING 118
FT /ligand="itraconazole"
FT /ligand_id="ChEBI:CHEBI:6076"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0007744|PDB:5V5Z"
FT BINDING 307
FT /ligand="posaconazole"
FT /ligand_id="ChEBI:CHEBI:64355"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0007744|PDB:5FSA"
FT BINDING 377
FT /ligand="oteseconazole"
FT /ligand_id="ChEBI:CHEBI:188153"
FT /ligand_note="inhibitor"
FT /evidence="ECO:0007744|PDB:5TZ1"
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:0007744|PDB:5FSA, ECO:0007744|PDB:5TZ1,
FT ECO:0007744|PDB:5V5Z"
FT VARIANT 105
FT /note="F -> L (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:9228762"
FT VARIANT 129
FT /note="G -> A (in strain: azole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:9527767"
FT VARIANT 132
FT /note="Y -> H (in strain: azole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:10223930,
FT ECO:0000269|PubMed:9527767"
FT VARIANT 145
FT /note="F -> L (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:10223930"
FT VARIANT 149
FT /note="A -> V (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:10537192"
FT VARIANT 153
FT /note="D -> E (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:10537192"
FT VARIANT 165
FT /note="E -> Y (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:10537192"
FT VARIANT 266
FT /note="E -> D (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:9228762"
FT VARIANT 279
FT /note="S -> F (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:10537192"
FT VARIANT 287
FT /note="K -> R (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:9228762"
FT VARIANT 405
FT /note="S -> F (in strain: azole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:9527767"
FT VARIANT 448
FT /note="G -> E (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:9228762"
FT VARIANT 450
FT /note="G -> E (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:9228762"
FT VARIANT 452
FT /note="V -> A (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:10537192"
FT VARIANT 464
FT /note="G -> S (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:9228762,
FT ECO:0000269|PubMed:9527767"
FT VARIANT 465
FT /note="G -> S (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:10537192"
FT VARIANT 467
FT /note="R -> K (in strain: Isolate 13; azole-resistant)"
FT /evidence="ECO:0000269|PubMed:10602724,
FT ECO:0000269|PubMed:9210671, ECO:0000269|PubMed:9527767"
FT VARIANT 488
FT /note="V -> I (in strain: fluconazole-resistant isolates)"
FT /evidence="ECO:0000269|PubMed:9228762"
FT CONFLICT 19
FT /note="V -> D (in Ref. 6; AAB08099)"
FT /evidence="ECO:0000305"
FT HELIX 28..40
FT /evidence="ECO:0007829|PDB:5V5Z"
FT TURN 56..58
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 61..66
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 68..79
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 81..87
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 90..95
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 98..105
FT /evidence="ECO:0007829|PDB:5TZ1"
FT TURN 109..111
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 114..126
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 128..130
FT /evidence="ECO:0007829|PDB:5FSA"
FT HELIX 136..147
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 152..172
FT /evidence="ECO:0007829|PDB:5TZ1"
FT TURN 174..176
FT /evidence="ECO:0007829|PDB:5TZ1"
FT TURN 178..180
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 182..187
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 188..205
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 207..212
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 215..225
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 231..234
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 241..266
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 272..274
FT /evidence="ECO:0007829|PDB:5V5Z"
FT HELIX 276..282
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 294..325
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 327..344
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 348..350
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 353..356
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 360..372
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 379..383
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 387..389
FT /evidence="ECO:0007829|PDB:5FSA"
FT STRAND 392..396
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 401..404
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 406..410
FT /evidence="ECO:0007829|PDB:5TZ1"
FT TURN 413..415
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 416..418
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 424..428
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 430..434
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 438..440
FT /evidence="ECO:0007829|PDB:5FSA"
FT STRAND 444..454
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 466..468
FT /evidence="ECO:0007829|PDB:5TZ1"
FT HELIX 473..490
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 491..494
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 496..499
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 506..509
FT /evidence="ECO:0007829|PDB:5TZ1"
FT STRAND 517..522
FT /evidence="ECO:0007829|PDB:5TZ1"
SQ SEQUENCE 528 AA; 60675 MW; 026948CEE4AF1B88 CRC64;
MAIVETVIDG INYFLSLSVT QQISILLGVP FVYNLVWQYL YSLRKDRAPL VFYWIPWFGS
AASYGQQPYE FFESCRQKYG DVFSFMLLGK IMTVYLGPKG HEFVFNAKLS DVSAEDAYKH
LTTPVFGKGV IYDCPNSRLM EQKKFAKFAL TTDSFKRYVP KIREEILNYF VTDESFKLKE
KTHGVANVMK TQPEITIFTA SRSLFGDEMR RIFDRSFAQL YSDLDKGFTP INFVFPNLPL
PHYWRRDAAQ KKISATYMKE IKSRRERGDI DPNRDLIDSL LIHSTYKDGV KMTDQEIANL
LIGILMGGQH TSASTSAWFL LHLGEKPHLQ DVIYQEVVEL LKEKGGDLND LTYEDLQKLP
SVNNTIKETL RMHMPLHSIF RKVTNPLRIP ETNYIVPKGH YVLVSPGYAH TSERYFDNPE
DFDPTRWDTA AAKANSVSFN SSDEVDYGFG KVSKGVSSPY LPFGGGRHRC IGEQFAYVQL
GTILTTFVYN LRWTIDGYKV PDPDYSSMVV LPTEPAEIIW EKRETCMF
