ID   CP51A_MACFA             Reviewed;         509 AA.
AC   Q4R8S6; Q4R5W7;
DT   26-MAY-2009, integrated into UniProtKB/Swiss-Prot.
DT   29-SEP-2021, sequence version 3.
DT   24-JAN-2024, entry version 102.
DE   RecName: Full=Lanosterol 14-alpha demethylase {ECO:0000250|UniProtKB:Q16850};
DE            Short=LDM;
DE            EC=1.14.14.154 {ECO:0000250|UniProtKB:Q16850, ECO:0000250|UniProtKB:Q64654};
DE   AltName: Full=CYPLI;
DE   AltName: Full=Cytochrome P450 51A1;
DE            Short=CAP51 {ECO:0000250|UniProtKB:Q64654};
DE   AltName: Full=Cytochrome P450-14DM;
DE            Short=Cytochrome P45014DM;
DE   AltName: Full=Cytochrome P450LI;
DE   AltName: Full=Sterol 14-alpha demethylase;
GN   Name=CYP51A1 {ECO:0000250|UniProtKB:Q16850}; Synonyms=CYP51;
GN   ORFNames=QtsA-11582, QtsA-20162;
OS   Macaca fascicularis (Crab-eating macaque) (Cynomolgus monkey).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC   Cercopithecidae; Cercopithecinae; Macaca.
OX   NCBI_TaxID=9541;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RA   Uno Y., Kito G., Kamataki T., Nagata R.;
RT   "Identification of CYP cDNAs from cynomolgus monkey liver.";
RL   Submitted (MAY-2005) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Testis;
RG   International consortium for macaque cDNA sequencing and analysis;
RT   "DNA sequences of macaque genes expressed in brain or testis and its
RT   evolutionary implications.";
RL   Submitted (JUN-2005) to the EMBL/GenBank/DDBJ databases.
CC   -!- FUNCTION: Sterol 14alpha-demethylase that plays a critical role in the
CC       cholesterol biosynthesis pathway, being cholesterol the major sterol
CC       component in mammalian membranes as well as a precursor for bile acid
CC       and steroid hormone synthesis. Cytochrome P450 monooxygenase that
CC       catalyzes the three-step oxidative removal of the 14alpha-methyl group
CC       (C-32) of sterols such as lanosterol (lanosta-8,24-dien-3beta-ol) and
CC       24,25-dihydrolanosterol (DHL) in the form of formate, and converts the
CC       sterols to 4,4-dimethyl-5alpha-cholesta-8,14,24-trien-3beta-ol and 4,4-
CC       dimethyl-8,14-cholestadien-3beta-ol, respectively, which are
CC       intermediates of cholesterol biosynthesis. Can also demethylate
CC       substrates not intrinsic to mammals, such as eburicol (24-
CC       methylene-24,25-dihydrolanosterol), but at a lower rate than DHL.
CC       {ECO:0000250|UniProtKB:Q64654}.
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:0000250|UniProtKB:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54029;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
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:0000250|UniProtKB:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25287;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=24,25-dihydrolanosterol + 3 O2 + 3 reduced [NADPH--hemoprotein
CC         reductase] = 4,4-dimethyl-8,14-cholestadien-3beta-ol + formate + 4
CC         H(+) + 4 H2O + 3 oxidized [NADPH--hemoprotein reductase];
CC         Xref=Rhea:RHEA:45960, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:15740, ChEBI:CHEBI:28113, ChEBI:CHEBI:57618,
CC         ChEBI:CHEBI:58210, ChEBI:CHEBI:78904;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45961;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
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:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:68061;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
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:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:68065;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
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:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:68069;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
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:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75104;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
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:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75108;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
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:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75112;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=24,25-dihydrolanosterol + O2 + reduced [NADPH--hemoprotein
CC         reductase] = 32-hydroxy-24,25-dihydrolanosterol + H(+) + H2O +
CC         oxidized [NADPH--hemoprotein reductase]; Xref=Rhea:RHEA:75079,
CC         Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965, ChEBI:CHEBI:15377,
CC         ChEBI:CHEBI:15378, ChEBI:CHEBI:15379, ChEBI:CHEBI:28113,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:87057;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75080;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=32-hydroxy-24,25-dihydrolanosterol + O2 + reduced
CC         [NADPH--hemoprotein reductase] = 32-oxo-24,25-dihydrolanosterol +
CC         H(+) + 2 H2O + oxidized [NADPH--hemoprotein reductase];
CC         Xref=Rhea:RHEA:75087, Rhea:RHEA-COMP:11964, Rhea:RHEA-COMP:11965,
CC         ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:57618, ChEBI:CHEBI:58210, ChEBI:CHEBI:87057,
CC         ChEBI:CHEBI:87060; Evidence={ECO:0000250|UniProtKB:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75088;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=32-oxo-24,25-dihydrolanosterol + O2 + reduced
CC         [NADPH--hemoprotein reductase] = 4,4-dimethyl-8,14-cholestadien-
CC         3beta-ol + formate + 2 H(+) + H2O + oxidized [NADPH--hemoprotein
CC         reductase]; Xref=Rhea:RHEA:75083, Rhea:RHEA-COMP:11964, Rhea:RHEA-
CC         COMP:11965, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:15379,
CC         ChEBI:CHEBI:15740, ChEBI:CHEBI:57618, ChEBI:CHEBI:58210,
CC         ChEBI:CHEBI:78904, ChEBI:CHEBI:87060;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
CC       PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:75084;
CC         Evidence={ECO:0000250|UniProtKB:Q64654};
CC   -!- COFACTOR:
CC       Name=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000250|UniProtKB:Q16850};
CC   -!- ACTIVITY REGULATION: Inhibited by azalanstat. Inhibited by azole
CC       antifungal agents ketoconazole, itraconazole and fluconazole.
CC       {ECO:0000250|UniProtKB:Q64654}.
CC   -!- PATHWAY: Steroid biosynthesis; zymosterol biosynthesis; zymosterol from
CC       lanosterol: step 1/6. {ECO:0000250|UniProtKB:Q64654}.
CC   -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane
CC       {ECO:0000250|UniProtKB:Q64654}; Single-pass membrane protein
CC       {ECO:0000255}. Microsome membrane {ECO:0000250|UniProtKB:Q64654};
CC       Single-pass membrane protein {ECO:0000255}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
CC   -!- CAUTION: It is uncertain whether Met-1 or Met-7 is the initiator.
CC       {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=BAE01508.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; DQ074804; AAZ29450.1; -; mRNA.
DR   EMBL; AB168372; BAE00495.1; -; mRNA.
DR   EMBL; AB169425; BAE01508.1; ALT_INIT; mRNA.
DR   RefSeq; NP_001274625.1; NM_001287696.1.
DR   AlphaFoldDB; Q4R8S6; -.
DR   SMR; Q4R8S6; -.
DR   STRING; 9541.ENSMFAP00000041467; -.
DR   Ensembl; ENSMFAT00000015743.2; ENSMFAP00000041467.1; ENSMFAG00000041456.2.
DR   VGNC; VGNC:83109; CYP51A1.
DR   eggNOG; KOG0684; Eukaryota.
DR   GeneTree; ENSGT00930000151026; -.
DR   OMA; AWTLIEL; -.
DR   OrthoDB; 5474434at2759; -.
DR   UniPathway; UPA00770; UER00754.
DR   Proteomes; UP000233100; Chromosome 3.
DR   GO; GO:0005789; C:endoplasmic reticulum membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0020037; F:heme binding; ISS:UniProtKB.
DR   GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR   GO; GO:0008398; F:sterol 14-demethylase activity; ISS:UniProtKB.
DR   GO; GO:0006695; P:cholesterol biosynthetic process; IEA:UniProtKB-KW.
DR   GO; GO:0006694; P:steroid biosynthetic process; ISS:UniProtKB.
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   2: Evidence at transcript level;
KW   Cholesterol biosynthesis; Cholesterol metabolism; Endoplasmic reticulum;
KW   Heme; Iron; Lipid biosynthesis; Lipid metabolism; Membrane; Metal-binding;
KW   Microsome; Monooxygenase; Oxidoreductase; Reference proteome;
KW   Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW   Sterol metabolism; Transmembrane; Transmembrane helix.
FT   CHAIN           1..509
FT                   /note="Lanosterol 14-alpha demethylase"
FT                   /id="PRO_0000052000"
FT   TRANSMEM        30..50
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   BINDING         455
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"
SQ   SEQUENCE   509 AA;  57287 MW;  681FFF7E95B2CBCC CRC64;
     MAAAAGMMLL GLLQAGGSVL GQAMEKVTGG NLLSMLLIAC AFTLSLVYLF RLAAGHLVQL
     PAGAKSPPYI FSPIPFLGHA IAFGKSPVEF LENAYEKYGP VFSFTMVGKT FTYLLGSDAA
     ALLFNSKNED LNAEDVYSRL TTPVFGKGVA YDVPNPVFLE QKKMLKSGLN IAHFKQHVSI
     IEKETKEYFQ SWGESGEKNV FEALSELIIL TASHCLHGKE IRSQLNEKVA QLYADLDGGF
     SHAAWLLPGW LPLPSFRRRD RAHREIKNIF YKAIQKRRQS QEKIDDILQT LLDATYKDGR
     PLTDDEVAGM LIGLLLAGQH TSSTTSAWMG FFLARDKTLQ EKCYLEQKTV CGENLPPLTY
     DQLKDLNLLD RCIKETLRLR PPIMIMMRMA RTPQTVAGYT IPPGHQVCVS PTVNQRLKDS
     WVERLDFNPD RYLQDNPASG EKFAYVPFGA GRHRCIGENF AYVQIKTIWS TMLRLYEFDL
     IDGYFPTVNY TTMIHTPENP VIRYKRRSK
//