CP51C_ASPFN
ID CP51C_ASPFN Reviewed; 513 AA.
AC B8NUK6;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 03-MAR-2009, sequence version 1.
DT 03-AUG-2022, entry version 74.
DE RecName: Full=Sterol 14-alpha demethylase {ECO:0000303|PubMed:22314539};
DE EC=1.14.14.154 {ECO:0000250|UniProtKB:Q4WNT5};
DE AltName: Full=Cytochrome P450 monooxygenase 51C {ECO:0000303|PubMed:22314539};
DE AltName: Full=Ergosterol biosynthesis protein cyp51C {ECO:0000303|PubMed:22314539};
GN Name=cyp51c {ECO:0000303|PubMed:22314539}; ORFNames=AFLA_100590;
OS Aspergillus flavus (strain ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357
OS / JCM 12722 / SRRC 167).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=332952;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357 / JCM 12722 / SRRC
RC 167;
RX PubMed=25883274; DOI=10.1128/genomea.00168-15;
RA Nierman W.C., Yu J., Fedorova-Abrams N.D., Losada L., Cleveland T.E.,
RA Bhatnagar D., Bennett J.W., Dean R., Payne G.A.;
RT "Genome sequence of Aspergillus flavus NRRL 3357, a strain that causes
RT aflatoxin contamination of food and feed.";
RL Genome Announc. 3:E0016815-E0016815(2015).
RN [2]
RP MUTAGENESIS OF SER-240.
RX PubMed=22314539; DOI=10.1128/aac.05477-11;
RA Liu W., Sun Y., Chen W., Liu W., Wan Z., Bu D., Li R.;
RT "The T788G mutation in the cyp51C gene confers voriconazole resistance in
RT Aspergillus flavus causing aspergillosis.";
RL Antimicrob. Agents Chemother. 56:2598-2603(2012).
RN [3]
RP MUTAGENESIS OF TYR-319.
RX PubMed=26248359; DOI=10.1128/aac.00637-15;
RA Paul R.A., Rudramurthy S.M., Meis J.F., Mouton J.W., Chakrabarti A.;
RT "A novel Y319H substitution in CYP51C associated with azole resistance in
RT Aspergillus flavus.";
RL Antimicrob. Agents Chemother. 59:6615-6619(2015).
RN [4]
RP FUNCTION, AND INDUCTION.
RX PubMed=29311090; DOI=10.1128/aac.01928-17;
RA Sharma C., Kumar R., Kumar N., Masih A., Gupta D., Chowdhary A.;
RT "Investigation of multiple resistance mechanisms in voriconazole-resistant
RT Aspergillus flavus clinical isolates from a chest hospital surveillance in
RT Delhi, India.";
RL Antimicrob. Agents Chemother. 62:0-0(2018).
RN [5]
RP INDUCTION.
RX PubMed=31321335; DOI=10.18502/cmm.5.2.1158;
RA Akbari Dana M., Hashemi S.J., Daei Ghazvini R., Khodavesi S., Modiri M.,
RA Nazemi L., Darabian S., Rezaie S.;
RT "Effect of benomyl and diazinon on acquired azole resistance in Aspergillus
RT flavus and expression of mdr1 and cyp51c genes.";
RL Curr. Med. Mycol. 5:27-32(2019).
CC -!- FUNCTION: Cytochrome P450 monooxygenase involved in the biosynthesis of
CC ergosterol (By similarity). The existence of several duplicated sterol
CC 14-alpha demethylase genes could be a good strategy to modulate the
CC composition and fluidity of the cell membrane (By similarity).
CC Catalyzes C14-demethylation of erburicol to produce 4,4,24-trimethyl
CC cholesta-8,24(28)-dien-3-beta-ol (By similarity). As a target of azole
CC drugs, plays a crucial role in azole drug susceptibility
CC (PubMed:26248359). {ECO:0000250|UniProtKB:Q4WNT5,
CC ECO:0000269|PubMed:26248359, ECO:0000269|PubMed:29311090}.
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:Q4WNT5};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:54029;
CC Evidence={ECO:0000250|UniProtKB:Q4WNT5};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC -!- PATHWAY: Steroid biosynthesis; sterol biosynthesis.
CC {ECO:0000250|UniProtKB:Q4WNT5}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum membrane {ECO:0000305};
CC Single-pass membrane protein {ECO:0000255}.
CC -!- INDUCTION: Over-expressed in azole-resistant clinical isolates
CC (PubMed:29311090). Expression decreases upon exposure to diazinon and
CC increases upon exposure to benomyl (PubMed:31321335).
CC {ECO:0000269|PubMed:29311090, ECO:0000269|PubMed:31321335}.
CC -!- MISCELLANEOUS: Mutations of Ser-240 or Tyr-319 lead to the resistance
CC to azoles, clinical drugs used to inhibit the activity and kill
CC Aspergillus fumigatus cells during infections.
CC {ECO:0000269|PubMed:22314539, ECO:0000269|PubMed:26248359}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; EQ963484; EED46395.1; -; Genomic_DNA.
DR RefSeq; XP_002383931.1; XM_002383890.1.
DR AlphaFoldDB; B8NUK6; -.
DR SMR; B8NUK6; -.
DR STRING; 5059.CADAFLAP00011796; -.
DR EnsemblFungi; EED46395; EED46395; AFLA_100590.
DR VEuPathDB; FungiDB:AFLA_100590; -.
DR eggNOG; KOG0684; Eukaryota.
DR HOGENOM; CLU_001570_15_0_1; -.
DR OMA; DMISNLM; -.
DR UniPathway; UPA00766; -.
DR Proteomes; UP000001875; Unassembled WGS sequence.
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:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0008398; F:sterol 14-demethylase activity; TAS:PHI-base.
DR GO; GO:0016126; P:sterol biosynthetic process; IEA:UniProtKB-UniPathway.
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; Glycoprotein; Heme; Iron; Membrane; Metal-binding;
KW Monooxygenase; Oxidoreductase; Transmembrane; Transmembrane helix.
FT CHAIN 1..513
FT /note="Sterol 14-alpha demethylase"
FT /id="PRO_0000448856"
FT TRANSMEM 8..28
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 453
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"
FT CARBOHYD 32
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 332
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT MUTAGEN 240
FT /note="S->A: Leads to resistance to azole compounds."
FT /evidence="ECO:0000269|PubMed:22314539"
FT MUTAGEN 319
FT /note="Y->H: Leads to resistance to azole compounds."
FT /evidence="ECO:0000269|PubMed:26248359"
SQ SEQUENCE 513 AA; 57500 MW; 84124102924868B5 CRC64;
MSWPRIGAYA LLAFVAIMAL NVTYQFLFRM LNKTRPPLVF HWIPFIGSTI HYGMDPYGFF
FSCREKYGDI FTFILLGRPT TVYLGTQGNE FILNGKLKDV NAEEVYSPLT TPVFGSDVVY
DCPNSKLIEQ KKFIKFGLSQ AALEAHVPLI EKEVEDYLAM SPNFHGTSGE VDIPAAMAEI
TIFTAGSALQ GEEVRSKLTT EFAVLYHDLD KGFTPINFML PWAPLPHNKK RDAAHARMRS
IYIDIINKRR NAGDNVPEKL DMIGNLMQCT YKNGQPLPDK EIAHIMITLL MAGQHSSSSI
SSWIMLRLAS QPAVVEELYQ EQLANLERTG PNGSLAPLQY KDFDNLPLHQ NVIRETLRLH
SSIHSLLRKV KNPLPVPGTP YVIPTSHVLL AAPGVTALSD EYFPNAMAWD PHRWETQAPQ
ENNKDDIVDY GYGAMSKGTS SPYLPFGAGR HRCIGEKFAY LNLAVIVATM VRHLRFSNLD
GQTGVPDTDY SSLFSGPMKP ARIRWERRAA KSG
