CP51_SCHPO
ID CP51_SCHPO Reviewed; 495 AA.
AC Q09736;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 03-AUG-2022, entry version 160.
DE RecName: Full=Lanosterol 14-alpha demethylase erg11 {ECO:0000303|PubMed:16537923};
DE EC=1.14.14.154 {ECO:0000305|PubMed:27585850};
DE AltName: Full=Cytochrome P450 51 {ECO:0000305};
DE AltName: Full=Ergosterol biosynthetic protein 11 {ECO:0000303|PubMed:16537923};
DE AltName: Full=Sterol 14-alpha demethylase {ECO:0000305};
GN Name=erg11 {ECO:0000303|PubMed:16537923}; Synonyms=cyp51;
GN ORFNames=SPAC13A11.02c;
OS Schizosaccharomyces pombe (strain 972 / ATCC 24843) (Fission yeast).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Taphrinomycotina;
OC Schizosaccharomycetes; Schizosaccharomycetales; Schizosaccharomycetaceae;
OC Schizosaccharomyces.
OX NCBI_TaxID=284812;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=972 / ATCC 24843;
RX PubMed=11859360; DOI=10.1038/nature724;
RA Wood V., Gwilliam R., Rajandream M.A., Lyne M.H., Lyne R., Stewart A.,
RA Sgouros J.G., Peat N., Hayles J., Baker S.G., Basham D., Bowman S.,
RA Brooks K., Brown D., Brown S., Chillingworth T., Churcher C.M., Collins M.,
RA Connor R., Cronin A., Davis P., Feltwell T., Fraser A., Gentles S.,
RA Goble A., Hamlin N., Harris D.E., Hidalgo J., Hodgson G., Holroyd S.,
RA Hornsby T., Howarth S., Huckle E.J., Hunt S., Jagels K., James K.D.,
RA Jones L., Jones M., Leather S., McDonald S., McLean J., Mooney P.,
RA Moule S., Mungall K.L., Murphy L.D., Niblett D., Odell C., Oliver K.,
RA O'Neil S., Pearson D., Quail M.A., Rabbinowitsch E., Rutherford K.M.,
RA Rutter S., Saunders D., Seeger K., Sharp S., Skelton J., Simmonds M.N.,
RA Squares R., Squares S., Stevens K., Taylor K., Taylor R.G., Tivey A.,
RA Walsh S.V., Warren T., Whitehead S., Woodward J.R., Volckaert G., Aert R.,
RA Robben J., Grymonprez B., Weltjens I., Vanstreels E., Rieger M.,
RA Schaefer M., Mueller-Auer S., Gabel C., Fuchs M., Duesterhoeft A.,
RA Fritzc C., Holzer E., Moestl D., Hilbert H., Borzym K., Langer I., Beck A.,
RA Lehrach H., Reinhardt R., Pohl T.M., Eger P., Zimmermann W., Wedler H.,
RA Wambutt R., Purnelle B., Goffeau A., Cadieu E., Dreano S., Gloux S.,
RA Lelaure V., Mottier S., Galibert F., Aves S.J., Xiang Z., Hunt C.,
RA Moore K., Hurst S.M., Lucas M., Rochet M., Gaillardin C., Tallada V.A.,
RA Garzon A., Thode G., Daga R.R., Cruzado L., Jimenez J., Sanchez M.,
RA del Rey F., Benito J., Dominguez A., Revuelta J.L., Moreno S.,
RA Armstrong J., Forsburg S.L., Cerutti L., Lowe T., McCombie W.R.,
RA Paulsen I., Potashkin J., Shpakovski G.V., Ussery D., Barrell B.G.,
RA Nurse P.;
RT "The genome sequence of Schizosaccharomyces pombe.";
RL Nature 415:871-880(2002).
RN [2]
RP FUNCTION.
RX PubMed=8586261; DOI=10.1111/j.1574-6968.1995.tb07929.x;
RA Harmouch N., Coulon J., Bonaly R.;
RT "Identification of 24-methylene-24,25-dihydrolanosterol as a precursor of
RT ergosterol in the yeasts Schizosaccharomyces pombe and Schizosaccharomyces
RT octosporus.";
RL FEMS Microbiol. Lett. 134:147-152(1995).
RN [3]
RP IDENTIFICATION, AND INDUCTION.
RX PubMed=16537923; DOI=10.1128/mcb.26.7.2817-2831.2006;
RA Todd B.L., Stewart E.V., Burg J.S., Hughes A.L., Espenshade P.J.;
RT "Sterol regulatory element binding protein is a principal regulator of
RT anaerobic gene expression in fission yeast.";
RL Mol. Cell. Biol. 26:2817-2831(2006).
RN [4]
RP SUBCELLULAR LOCATION [LARGE SCALE ANALYSIS].
RX PubMed=16823372; DOI=10.1038/nbt1222;
RA Matsuyama A., Arai R., Yashiroda Y., Shirai A., Kamata A., Sekido S.,
RA Kobayashi Y., Hashimoto A., Hamamoto M., Hiraoka Y., Horinouchi S.,
RA Yoshida M.;
RT "ORFeome cloning and global analysis of protein localization in the fission
RT yeast Schizosaccharomyces pombe.";
RL Nat. Biotechnol. 24:841-847(2006).
RN [5]
RP IDENTIFICATION BY MASS SPECTROMETRY, AND INTERACTION WITH DAP1.
RX PubMed=17276356; DOI=10.1016/j.cmet.2006.12.009;
RA Hughes A.L., Powell D.W., Bard M., Eckstein J., Barbuch R., Link A.J.,
RA Espenshade P.J.;
RT "Dap1/PGRMC1 binds and regulates cytochrome P450 enzymes.";
RL Cell Metab. 5:143-149(2007).
RN [6]
RP FUNCTION.
RX PubMed=18310029; DOI=10.1099/mic.0.2007/011155-0;
RA Iwaki T., Iefuji H., Hiraga Y., Hosomi A., Morita T., Giga-Hama Y.,
RA Takegawa K.;
RT "Multiple functions of ergosterol in the fission yeast Schizosaccharomyces
RT pombe.";
RL Microbiology 154:830-841(2008).
RN [7]
RP FUNCTION, MUTAGENESIS OF GLY-189, AND PATHWAY.
RX PubMed=27585850; DOI=10.1534/genetics.116.191536;
RA Xu Y.J., Singh A., Alter G.M.;
RT "Hydroxyurea induces cytokinesis arrest in cells expressing a mutated
RT sterol-14alpha-demethylase in the egosterol biosynthesis pathway.";
RL Genetics 204:959-973(2016).
RN [8]
RP FUNCTION.
RX PubMed=28893786; DOI=10.1128/aac.00734-17;
RA Singh A., Agarwal A., Xu Y.J.;
RT "Novel cell-killing mechanisms of hydroxyurea and the implication toward
RT combination therapy for the treatment of fungal infections.";
RL Antimicrob. Agents Chemother. 61:0-0(2017).
CC -!- FUNCTION: Lanosterol 14-alpha demethylase; part of the third module of
CC ergosterol biosynthesis pathway that includes by the late steps of the
CC pathway (PubMed:27585850, PubMed:28893786). Erg11/cyp1 catalyzes C14-
CC demethylation of lanosterol to produce 4,4'-dimethyl cholesta-8,14,24-
CC triene-3-beta-ol (PubMed:27585850). The third module or late pathway
CC involves the ergosterol synthesis itself through consecutive reactions
CC that mainly occur in the endoplasmic reticulum (ER) membrane. Firstly,
CC the squalene synthase erg9 catalyzes the condensation of 2 farnesyl
CC pyrophosphate moieties to form squalene, which is the precursor of all
CC steroids. Secondly, squalene is converted into lanosterol by the
CC consecutive action of the squalene epoxidase erg1 and the lanosterol
CC synthase erg7. The lanosterol 14-alpha-demethylase erg11/cyp1 catalyzes
CC C14-demethylation of lanosterol to produce 4,4'-dimethyl cholesta-
CC 8,14,24-triene-3-beta-ol. In the next steps, a complex process
CC involving various demethylation, reduction and desaturation reactions
CC catalyzed by the C-14 reductase erg24 and the C-4 demethylation complex
CC erg25-erg26-erg27 leads to the production of zymosterol. Erg28 likely
CC functions in the C-4 demethylation complex reaction by tethering erg26
CC and Erg27 to the endoplasmic reticulum or to facilitate interaction
CC between these proteins. Then, the sterol 24-C-methyltransferase erg6
CC catalyzes the methyl transfer from S-adenosyl-methionine to the C-24 of
CC zymosterol to form fecosterol. The C-8 sterol isomerase erg2 catalyzes
CC the reaction which results in unsaturation at C-7 in the B ring of
CC sterols and thus converts fecosterol to episterol. The sterol-C5-
CC desaturases erg31 and erg32 then catalyze 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 (PubMed:18310029) (Probable). In the genus
CC Schizosaccharomyces, a second route exists between lanosterol and
CC fecosterol, via the methylation of lanosterol to eburicol by erg6,
CC followed by C14-demethylation by erg11/cyp1 and C4-demethylation by the
CC demethylation complex erg25-erg26-erg27 (PubMed:8586261) (Probable).
CC {ECO:0000269|PubMed:27585850, ECO:0000269|PubMed:28893786,
CC ECO:0000305|PubMed:18310029, ECO:0000305|PubMed:8586261}.
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:0000305|PubMed:27585850};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54029;
CC Evidence={ECO:0000305|PubMed:27585850};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P10614};
CC -!- PATHWAY: Steroid biosynthesis; zymosterol biosynthesis; zymosterol from
CC lanosterol: step 1/6. {ECO:0000269|PubMed:27585850}.
CC -!- PATHWAY: Steroid metabolism; ergosterol biosynthesis.
CC {ECO:0000269|PubMed:27585850}.
CC -!- SUBUNIT: Interacts with dap1. {ECO:0000269|PubMed:17276356}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum
CC {ECO:0000269|PubMed:16823372}. Membrane {ECO:0000305}; Single-pass
CC membrane protein {ECO:0000305}.
CC -!- INDUCTION: Expression is anaerobically up-regulated via the sterol
CC regulatory element binding protein sre1. {ECO:0000269|PubMed:16537923}.
CC -!- MISCELLANEOUS: In Aspergillus, the biosynthesis pathway of the sterol
CC precursors leading to the prevalent sterol ergosterol differs from
CC yeast. The ringsystem 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. In the genus
CC Schizosaccharomyces, 2 routes exist from lanosterol to erposterol: the
CC classical one via zymosterol and the second one via the formation of
CC eburicol followed by demethylation. {ECO:0000269|PubMed:8586261}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; CU329670; CAA90803.1; -; Genomic_DNA.
DR PIR; T37609; T37609.
DR RefSeq; NP_592990.1; NM_001018389.2.
DR AlphaFoldDB; Q09736; -.
DR SMR; Q09736; -.
DR BioGRID; 279053; 8.
DR STRING; 4896.SPAC13A11.02c.1; -.
DR iPTMnet; Q09736; -.
DR MaxQB; Q09736; -.
DR PaxDb; Q09736; -.
DR PRIDE; Q09736; -.
DR EnsemblFungi; SPAC13A11.02c.1; SPAC13A11.02c.1:pep; SPAC13A11.02c.
DR GeneID; 2542599; -.
DR KEGG; spo:SPAC13A11.02c; -.
DR PomBase; SPAC13A11.02c; erg11.
DR VEuPathDB; FungiDB:SPAC13A11.02c; -.
DR eggNOG; KOG0684; Eukaryota.
DR HOGENOM; CLU_001570_15_0_1; -.
DR InParanoid; Q09736; -.
DR OMA; AWTLIEL; -.
DR PhylomeDB; Q09736; -.
DR Reactome; R-SPO-191273; Cholesterol biosynthesis.
DR Reactome; R-SPO-211976; Endogenous sterols.
DR UniPathway; UPA00768; -.
DR UniPathway; UPA00770; UER00754.
DR PRO; PR:Q09736; -.
DR Proteomes; UP000002485; Chromosome I.
DR GO; GO:0005783; C:endoplasmic reticulum; HDA:PomBase.
DR GO; GO:0005789; C:endoplasmic reticulum membrane; ISS:PomBase.
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: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:PomBase.
DR GO; GO:0006696; P:ergosterol biosynthetic process; ISO:PomBase.
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; Heme; Iron; Lipid biosynthesis; Lipid metabolism;
KW Membrane; Metal-binding; Monooxygenase; Oxidoreductase; Reference proteome;
KW Steroid biosynthesis; Steroid metabolism; Sterol biosynthesis;
KW Sterol metabolism; Stress response; Transmembrane; Transmembrane helix.
FT CHAIN 1..495
FT /note="Lanosterol 14-alpha demethylase erg11"
FT /id="PRO_0000052009"
FT TRANSMEM 2..22
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 442
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 MUTAGEN 189
FT /note="G->D: In erg11-1: Impairs the production of
FT ergosterol and leads to hydroxyurea hypersensitivity."
FT /evidence="ECO:0000269|PubMed:27585850"
SQ SEQUENCE 495 AA; 56331 MW; 193333395F6C8B31 CRC64;
MAFSLVSILL SIALAWYVGY IINQLTSRNS KRPPIVFHWI PFVGSAVAYG MDPYVFFREC
RAKYGDVFTF VCMGRKMTAF LGVQGNDFLF NGKLADLNAE EAYSHLTTPV FGKDVVYDIP
NHVFMEHKKF IKSGLGFSQF RSYVPLILNE MDAFLSTSPD FGPGKEGVAD LLKTMPVMTI
YTASRTLQGA EVRKGFDAGF ADLYHDLDQG FSPVNFVFPW LPLPRNRRRD RAHKIMQKTY
LKIIKDRRSS TENPGTDMIW TLMSCKYRDG RPLKEHEIAG MMIALLMAGQ HTSAATIVWV
LALLGSKPEI IEMLWEEQKR VVGENLELKF DQYKDMPLLN YVIQETLRLH PPIHSHMRKV
KRDLPVPGSK IVIPANNYLL AAPGLTATEE EYFTHATDFD PKRWNDRVNE DENAEQIDYG
YGLVTKGAAS PYLPFGAGRH RCIGEQFAYM HLSTIISKFV HDYTWTLIGK VPNVDYSSMV
ALPLGPVKIA WKRRN
