CP51A_MOUSE
ID CP51A_MOUSE Reviewed; 503 AA.
AC Q8K0C4; Q8BSQ7; Q9JIP8; Q9JIY3;
DT 16-JUN-2009, integrated into UniProtKB/Swiss-Prot.
DT 01-OCT-2002, sequence version 1.
DT 03-AUG-2022, entry version 163.
DE RecName: Full=Lanosterol 14-alpha demethylase {ECO:0000305};
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 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:0000312|EMBL:AAF74562.1}; Synonyms=Cyp51;
OS Mus musculus (Mouse).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC Murinae; Mus; Mus.
OX NCBI_TaxID=10090;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC STRAIN=129/Sv;
RX PubMed=10864439; DOI=10.1006/abbi.2000.1859;
RA Debeljak N., Horvat S., Vouk K., Lee M., Rozman D.;
RT "Characterization of the mouse lanosterol 14alpha-demethylase (CYP51), a
RT new member of the evolutionarily most conserved cytochrome P450 family.";
RL Arch. Biochem. Biophys. 379:37-45(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC STRAIN=129/Sv;
RX PubMed=10653123; DOI=10.1007/s004240000070;
RA Debeljak N., Horvat S., Komel R., Rozman D.;
RT "Molecular cloning and partial characterisation of the mouse Cyp51 cDNA.";
RL Pflugers Arch. 439:R7-R8(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Embryo, Placenta, Skin, and Testis;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Adams M.D., Myers E.W., Smith H.O., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=FVB/N; TISSUE=Salivary gland;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC TISSUE=Brain, Brown adipose tissue, Kidney, Liver, Pancreas, and Testis;
RX PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL Cell 143:1174-1189(2010).
RN [7]
RP DISRUPTION PHENOTYPE, AND FUNCTION.
RX PubMed=21705796; DOI=10.1074/jbc.m111.253245;
RA Keber R., Motaln H., Wagner K.D., Debeljak N., Rassoulzadegan M.,
RA Acimovic J., Rozman D., Horvat S.;
RT "Mouse knockout of the cholesterogenic cytochrome P450 lanosterol 14alpha-
RT demethylase (Cyp51) resembles Antley-Bixler syndrome.";
RL J. Biol. Chem. 286:29086-29097(2011).
CC -!- FUNCTION: A cytochrome P450 monooxygenase involved in sterol
CC biosynthesis. Catalyzes 14-alpha demethylation of lanosterol and 24,25-
CC dihydrolanosterol likely through sequential oxidative conversion of 14-
CC alpha methyl group to hydroxymethyl, then to carboxylaldehyde, followed
CC by the formation of the delta 14,15 double bond in the sterol core and
CC concomitant release of formic acid. Mechanistically, uses molecular
CC oxygen inserting one oxygen atom into a substrate, and reducing the
CC second into a water molecule, with two electrons provided by NADPH via
CC cytochrome P450 reductase (CPR; NADPH-ferrihemoprotein reductase).
CC {ECO:0000250|UniProtKB:Q16850, ECO:0000250|UniProtKB:Q64654}.
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:0000250|UniProtKB:Q16850,
CC ECO:0000250|UniProtKB:Q64654};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54029;
CC Evidence={ECO:0000250|UniProtKB:Q16850,
CC 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:Q16850,
CC ECO:0000250|UniProtKB:Q64654};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:25287;
CC Evidence={ECO:0000250|UniProtKB:Q16850,
CC 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:Q16850,
CC ECO:0000250|UniProtKB:Q64654};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:45961;
CC Evidence={ECO:0000250|UniProtKB:Q16850,
CC 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 -!- DISRUPTION PHENOTYPE: Embryonic lethality at 15 dpc, likely due to
CC heart failure. Mutant mice present complete block of de novo
CC cholesterol synthesis at 14.5 dpc. Heart abnormalities include
CC hypoplasia combined with ventricle septum and epicardial and
CC vasculogenesis defects. Skeletal abnormalities include facial
CC hypoplasia, brachycephaly, and bowed and jointed bones of the
CC extremities with camptodactyly. Can serve as an animal model for
CC studying Antley-Bixler syndrome. {ECO:0000269|PubMed:21705796}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
CC -!- SEQUENCE CAUTION:
CC Sequence=AAF73986.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR EMBL; AF204804; AAF74562.1; -; Genomic_DNA.
DR EMBL; AF204796; AAF74562.1; JOINED; Genomic_DNA.
DR EMBL; AF204797; AAF74562.1; JOINED; Genomic_DNA.
DR EMBL; AF204798; AAF74562.1; JOINED; Genomic_DNA.
DR EMBL; AF204799; AAF74562.1; JOINED; Genomic_DNA.
DR EMBL; AF204800; AAF74562.1; JOINED; Genomic_DNA.
DR EMBL; AF204801; AAF74562.1; JOINED; Genomic_DNA.
DR EMBL; AF204802; AAF74562.1; JOINED; Genomic_DNA.
DR EMBL; AF204803; AAF74562.1; JOINED; Genomic_DNA.
DR EMBL; AF166266; AAF73986.1; ALT_INIT; mRNA.
DR EMBL; AK028355; BAC25900.1; -; mRNA.
DR EMBL; AK028815; BAC26134.1; -; mRNA.
DR EMBL; AK031059; BAC27231.1; -; mRNA.
DR EMBL; AK076983; BAC36548.1; -; mRNA.
DR EMBL; CH466600; EDL14627.1; -; Genomic_DNA.
DR EMBL; BC031813; AAH31813.1; -; mRNA.
DR CCDS; CCDS19071.1; -.
DR RefSeq; NP_064394.2; NM_020010.2.
DR AlphaFoldDB; Q8K0C4; -.
DR SMR; Q8K0C4; -.
DR STRING; 10090.ENSMUSP00000001507; -.
DR ChEMBL; CHEMBL3774294; -.
DR iPTMnet; Q8K0C4; -.
DR PhosphoSitePlus; Q8K0C4; -.
DR SwissPalm; Q8K0C4; -.
DR EPD; Q8K0C4; -.
DR jPOST; Q8K0C4; -.
DR MaxQB; Q8K0C4; -.
DR PaxDb; Q8K0C4; -.
DR PeptideAtlas; Q8K0C4; -.
DR PRIDE; Q8K0C4; -.
DR ProteomicsDB; 283933; -.
DR Antibodypedia; 34871; 275 antibodies from 30 providers.
DR DNASU; 13121; -.
DR Ensembl; ENSMUST00000001507; ENSMUSP00000001507; ENSMUSG00000001467.
DR GeneID; 13121; -.
DR KEGG; mmu:13121; -.
DR UCSC; uc008wie.1; mouse.
DR CTD; 13121; -.
DR MGI; MGI:106040; Cyp51.
DR VEuPathDB; HostDB:ENSMUSG00000001467; -.
DR eggNOG; KOG0684; Eukaryota.
DR GeneTree; ENSGT00930000151026; -.
DR HOGENOM; CLU_001570_15_0_1; -.
DR InParanoid; Q8K0C4; -.
DR OMA; AWTLIEL; -.
DR OrthoDB; 572303at2759; -.
DR PhylomeDB; Q8K0C4; -.
DR TreeFam; TF105091; -.
DR Reactome; R-MMU-191273; Cholesterol biosynthesis.
DR Reactome; R-MMU-211976; Endogenous sterols.
DR UniPathway; UPA00770; UER00754.
DR BioGRID-ORCS; 13121; 3 hits in 73 CRISPR screens.
DR PRO; PR:Q8K0C4; -.
DR Proteomes; UP000000589; Chromosome 5.
DR RNAct; Q8K0C4; protein.
DR Bgee; ENSMUSG00000001467; Expressed in embryonic post-anal tail and 278 other tissues.
DR Genevisible; Q8K0C4; MM.
DR GO; GO:0001669; C:acrosomal vesicle; ISO:MGI.
DR GO; GO:0005737; C:cytoplasm; ISO:MGI.
DR GO; GO:0005783; C:endoplasmic reticulum; ISO:MGI.
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:0043231; C:intracellular membrane-bounded organelle; ISO:MGI.
DR GO; GO:0020037; F:heme binding; ISS:UniProtKB.
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; ISS:UniProtKB.
DR GO; GO:0006695; P:cholesterol biosynthetic process; TAS:MGI.
DR GO; GO:0033488; P:cholesterol biosynthetic process via 24,25-dihydrolanosterol; ISO:MGI.
DR GO; GO:1900222; P:negative regulation of amyloid-beta clearance; IMP:ARUK-UCL.
DR GO; GO:0042177; P:negative regulation of protein catabolic process; IMP:ARUK-UCL.
DR GO; GO:0050709; P:negative regulation of protein secretion; IMP:ARUK-UCL.
DR GO; GO:0060282; P:positive regulation of oocyte development; ISO:MGI.
DR GO; GO:0006694; P:steroid biosynthetic process; ISS:UniProtKB.
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 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..503
FT /note="Lanosterol 14-alpha demethylase"
FT /id="PRO_0000376796"
FT TRANSMEM 24..44
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 449
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"
FT CONFLICT 19
FT /note="E -> A (in Ref. 1; AAF74562)"
FT /evidence="ECO:0000305"
FT CONFLICT 98
FT /note="F -> L (in Ref. 1; AAF74562 and 2; AAF73986)"
FT /evidence="ECO:0000305"
FT CONFLICT 235
FT /note="T -> A (in Ref. 3; BAC27231)"
FT /evidence="ECO:0000305"
SQ SEQUENCE 503 AA; 56776 MW; 6A4BBA350F1D85C7 CRC64;
MVLLGLLQSG GWVLGQAMEQ VTGGNLLSTL LIACAFTLSL VYLFRLAVGH MVQLPAGAKS
PPHIYSPIPF LGHAIAFGKS PIEFLENAYE KYGPVFSFTM VGKTFTYLLG SDAAALLFNS
KNEDLNAEEV YGRLTTPVFG KGVAYDVPNA IFLEQKKIIK SGLNIAHFKQ YVPIIEKEAK
EYFQSWGESG ERNVFEALSE LIILTASHCL HGKEIRSQLN EKVAQLYADL DGGFTHAAWL
LPAWLPLPSF RRRDRAHREI KNIFYKAIQK RRLSKEPAED ILQTLLDSTY KDGRPLTDEE
ISGMLIGLLL AGQHTSSTTS AWMGFFLAKD KPLQEKCYLE QKAVCGEDLP PLTYDQLKDL
NLLDRCIKET LRLRPPIMTM MRMAKTPQTV AGYTIPPGHQ VCVSPTVNQR LKDSWAERLD
FNPDRYLQDN PASGEKFAYV PFGAGRHRCV GENFAYVQIK TIWSTMLRLY EFDLINGYFP
TVNYTTMIHT PENPVIRYKR RSK
