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   27-MAR-2024, entry version 170.
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   FUNCTION, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX   PubMed=9559662; DOI=10.1016/s0014-5793(98)00247-6;
RA   Lamb D.C., Kelly D.E., Kelly S.L.;
RT   "Molecular diversity of sterol 14alpha-demethylase substrates in plants,
RT   fungi and humans.";
RL   FEBS Lett. 425:263-265(1998).
RN   [15]
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   [16]
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   [17]
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   [18]
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   [19]
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   [20]
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   [21]
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   [22]
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   [23] {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, FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES,
RP   ACTIVITY 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   [24] {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: Sterol 14alpha-demethylase that plays a critical role in the
CC       third module of ergosterol biosynthesis pathway, being ergosterol the
CC       major sterol component in fungal membranes that participates in a
CC       variety of functions (PubMed:8647850, PubMed:9559662, 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 (By similarity). In
CC       filamentous fungi, during the initial step of this module, lanosterol
CC       (lanosta-8,24-dien-3beta-ol) can be metabolized to eburicol (By
CC       similarity). Sterol 14alpha-demethylase catalyzes the three-step
CC       oxidative removal of the 14alpha-methyl group (C-32) of both these
CC       sterols in the form of formate, and converts eburicol and lanosterol to
CC       14-demethyleburicol (4,4,24-trimethylergosta-8,14,24(28)-trienol) and
CC       4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol, respectively,
CC       which are further metabolized by other enzymes in the pathway to
CC       ergosterol (PubMed:8647850, PubMed:10393548, PubMed:28258218,
CC       PubMed:9559662). Can also use substrates not intrinsic to fungi, such
CC       as 24,25-dihydrolanosterol (DHL), producing 4,4-dimethyl-8,14-
CC       cholestadien-3-beta-ol, but at lower rates than the endogenous
CC       substrates (By similarity). {ECO:0000250|UniProtKB:P10614,
CC       ECO:0000250|UniProtKB:Q4WNT5, ECO:0000269|PubMed:10393548,
CC       ECO:0000269|PubMed:28258218, ECO:0000269|PubMed:8647850,
CC       ECO:0000269|PubMed:9559662}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 14alpha-methyl steroid + 3 O2 + 3 reduced
CC         [NADPH--hemoprotein reductase] = a Delta(14) steroid + formate + 4
CC         H(+) + 4 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:10393548, ECO:0000269|PubMed:28258218,
CC         ECO:0000269|PubMed:8647850, ECO:0000269|PubMed:9559662};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54029;
CC         Evidence={ECO:0000269|PubMed:10393548, ECO:0000269|PubMed:28258218,
CC         ECO:0000269|PubMed:8647850, ECO:0000305|PubMed:9559662};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 14alpha-methyl steroid + O2 + reduced [NADPH--hemoprotein
CC         reductase] = a 14alpha-hydroxymethyl steroid + H(+) + H2O + oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:68060, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57618,
CC         ChEBI:CHEBI:58210, ChEBI:CHEBI:138029, ChEBI:CHEBI:176901;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:68061;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 14alpha-hydroxymethyl steroid + O2 + reduced
CC         [NADPH--hemoprotein reductase] = a 14alpha-formyl steroid + H(+) + 2
CC         H2O + oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:68064,
CC         Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57618,
CC         ChEBI:CHEBI:58210, ChEBI:CHEBI:176901, ChEBI:CHEBI:176902;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:68065;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=a 14alpha-formyl steroid + O2 + reduced [NADPH--hemoprotein
CC         reductase] = a Delta(14) steroid + formate + 2 H(+) + H2O + oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:68068, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:15740,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:138031,
CC         ChEBI:CHEBI:176902; Evidence={ECO:0000250|UniProtKB:P10614};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:68069;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
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, ECO:0000269|PubMed:9559662};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25287;
CC         Evidence={ECO:0000269|PubMed:10393548, ECO:0000269|PubMed:28258218,
CC         ECO:0000269|PubMed:8647850, ECO:0000305|PubMed:9559662};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=lanosterol + O2 + reduced [NADPH--hemoprotein reductase] = 32-
CC         hydroxylanosterol + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:75103, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:16521, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC         ChEBI:CHEBI:166806; Evidence={ECO:0000250|UniProtKB:P10614};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75104;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=32-hydroxylanosterol + O2 + reduced [NADPH--hemoprotein
CC         reductase] = 32-oxolanosterol + H(+) + 2 H2O + oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:75107, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57618,
CC         ChEBI:CHEBI:58210, ChEBI:CHEBI:166681, ChEBI:CHEBI:166806;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75108;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=32-oxolanosterol + O2 + reduced [NADPH--hemoprotein reductase]
CC         = 4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol + formate + 2
CC         H(+) + H2O + oxidized [NADPH--hemoprotein reductase];
CC         Xref=Rhea:RHEA:75111, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:15740, ChEBI:CHEBI:17813, ChEBI:CHEBI:57618,
CC         ChEBI:CHEBI:58210, ChEBI:CHEBI:166681;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75112;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=eburicol + 3 O2 + 3 reduced [NADPH--hemoprotein reductase] =
CC         14-demethyleburicol + formate + 4 H(+) + 4 H2O + 3 oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:75439, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:15740,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:70315,
CC         ChEBI:CHEBI:194330; Evidence={ECO:0000269|PubMed:9559662};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75440;
CC         Evidence={ECO:0000305|PubMed:9559662};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=eburicol + O2 + reduced [NADPH--hemoprotein reductase] = 32-
CC         hydroxyeburicol + H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:75427, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:70315,
CC         ChEBI:CHEBI:194328; Evidence={ECO:0000250|UniProtKB:P10614};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75428;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=32-hydroxyeburicol + O2 + reduced [NADPH--hemoprotein
CC         reductase] = 32-oxoeburicol + H(+) + 2 H2O + oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:75431, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:57618,
CC         ChEBI:CHEBI:58210, ChEBI:CHEBI:194328, ChEBI:CHEBI:194329;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75432;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=32-oxoeburicol + O2 + reduced [NADPH--hemoprotein reductase] =
CC         14-demethyleburicol + formate + 2 H(+) + H2O + oxidized
CC         [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:75435, Rhea:RHEA-
CC         COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:15740,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:194329,
CC         ChEBI:CHEBI:194330; Evidence={ECO:0000250|UniProtKB:P10614};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75436;
CC         Evidence={ECO:0000250|UniProtKB:P10614};
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=15 uM for lanosterol {ECO:0000269|PubMed:9559662};
CC         KM=6.3 uM for lanosterol {ECO:0000269|PubMed:28258218};
CC         KM=25 uM for 24,25-dihydrolanosterol {ECO:0000269|PubMed:9559662};
CC         KM=11 uM for eburicol {ECO:0000269|PubMed:9559662};
CC         KM=28.5 uM for obtusifoliol {ECO:0000269|PubMed:9559662};
CC         Vmax=0.25 nmol/min/nmol enzyme towards lanosterol
CC         {ECO:0000269|PubMed:9559662};
CC         Vmax=0.12 nmol/min/nmol enzyme towards 24,25-dihydrolanosterol
CC         {ECO:0000269|PubMed:9559662};
CC         Vmax=0.3 nmol/min/nmol enzyme towards eburicol
CC         {ECO:0000269|PubMed:9559662};
CC         Vmax=0.26 nmol/min/nmol enzyme towards obtusifoliol
CC         {ECO:0000269|PubMed:9559662};
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; DB13055; Oteseconazole.
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   EnsemblFungi; C5_00660C_A-T; C5_00660C_A-T-p1; C5_00660C_A.
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; 5474434at2759; -.
DR   BRENDA; 1.14.13.70; 11936.
DR   BRENDA; 1.14.14.154; 1096.
DR   UniPathway; UPA00770; UER00754.
DR   PHI-base; PHI:10625; -.
DR   PHI-base; PHI:11160; -.
DR   PHI-base; PHI:8030; -.
DR   PHI-base; PHI:8187; -.
DR   PRO; PR:P10613; -.
DR   Proteomes; UP000000559; Chromosome 5.
DR   GO; GO:0032541; C:cortical endoplasmic reticulum; IEA:EnsemblFungi.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0016020; C:membrane; IDA:CGD.
DR   GO; GO:0097038; C:perinuclear endoplasmic reticulum; IEA:EnsemblFungi.
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: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:0007032; P:endosome organization; IMP:CGD.
DR   GO; GO:0006696; P:ergosterol biosynthetic process; IGI:CGD.
DR   GO; GO:0001766; P:membrane raft polarization; IMP:CGD.
DR   CDD; cd11042; CYP51-like; 1.
DR   Gene3D; 1.10.630.10; Cytochrome P450; 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   PANTHER; PTHR24304:SF2; 24-HYDROXYCHOLESTEROL 7-ALPHA-HYDROXYLASE; 1.
DR   PANTHER; PTHR24304; CYTOCHROME P450 FAMILY 7; 1.
DR   Pfam; PF00067; p450; 1.
DR   PRINTS; PR00465; EP450IV.
DR   PRINTS; PR00385; P450.
DR   SUPFAM; SSF48264; Cytochrome P450; 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
//