ID   BREF4_EUPBR             Reviewed;         508 AA.
AC   A0A068AA98;
DT   18-JUL-2018, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-2014, sequence version 1.
DT   03-AUG-2022, entry version 15.
DE   RecName: Full=Cytochrome P450 monooxygenase orf4 {ECO:0000303|PubMed:24845309};
DE            EC=1.-.-.- {ECO:0000305|PubMed:24845309};
DE   AltName: Full=Brefeldin A biosynthesis cluster protein orf4 {ECO:0000303|PubMed:24845309};
GN   Name=orf4 {ECO:0000303|PubMed:24845309};
OS   Eupenicillium brefeldianum (Penicillium brefeldianum).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX   NCBI_TaxID=1131482;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND INDUCTION.
RC   STRAIN=ATCC 58665;
RX   PubMed=24845309; DOI=10.1021/cb500284t;
RA   Zabala A.O., Chooi Y.H., Choi M.S., Lin H.C., Tang Y.;
RT   "Fungal polyketide synthase product chain-length control by partnering
RT   thiohydrolase.";
RL   ACS Chem. Biol. 9:1576-1586(2014).
CC   -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that
CC       mediates the biosynthesis of brefeldin A (BFA), a protein transport
CC       inhibitor that shows antiviral, antifungal, and antitumor properties
CC       (PubMed:24845309). The proposed biosynthesis of BFA involves formation
CC       of an acyclic polyketide chain that is differentially tailored
CC       throughout the backbone (PubMed:24845309). The highly reducing
CC       polyketide synthase Bref-PKS is proposed to synthesize the precisely
CC       reduced octaketide precursor, which could then be directly offloaded by
CC       the thiohydrolase enzyme Bref-TH followed by a cytochrome P450
CC       monooxygenase-mediated formation of the cyclopentane ring and
CC       macrocyclization to afford 7-deoxy BFA. Alternatively, the first ring
CC       annulation can also occur on the ACP-tethered intermediate before the
CC       thiohydrolase release and lactonization (PubMed:24845309). The C7-
CC       hydroxylation by another cytochrome P450 monooxygenase is believed to
CC       be the final step in the process to obtain the final structure of BFA
CC       (PubMed:24845309). In addition to the HRPKS Bref-PKS and the
CC       thiohydrolase Bref-TH, the brefeldin A biosynthesis cluster contains 4
CC       cytochrome p450 monooxygenases (called orf3 to orf6), as well a the
CC       probable cluster-specific transcription regulator orf8
CC       (PubMed:24845309). {ECO:0000269|PubMed:24845309}.
CC   -!- COFACTOR:
CC       Name=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000250|UniProtKB:P04798};
CC   -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000305|PubMed:24845309}.
CC   -!- INDUCTION: Coexpressed with the other cluster genes on brefeldin A
CC       production optimized medium. {ECO:0000269|PubMed:24845309}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR   EMBL; KJ728786; AIA58896.1; -; Genomic_DNA.
DR   AlphaFoldDB; A0A068AA98; -.
DR   SMR; A0A068AA98; -.
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; IEA:UniProtKB-KW.
DR   GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR   Gene3D; 1.10.630.10; -; 1.
DR   InterPro; IPR001128; Cyt_P450.
DR   InterPro; IPR017972; Cyt_P450_CS.
DR   InterPro; IPR002401; Cyt_P450_E_grp-I.
DR   InterPro; IPR036396; Cyt_P450_sf.
DR   Pfam; PF00067; p450; 1.
DR   PRINTS; PR00463; EP450I.
DR   PRINTS; PR00385; P450.
DR   SUPFAM; SSF48264; SSF48264; 1.
DR   PROSITE; PS00086; CYTOCHROME_P450; 1.
PE   2: Evidence at transcript level;
KW   Heme; Iron; Metal-binding; Monooxygenase; Oxidoreductase.
FT   CHAIN           1..508
FT                   /note="Cytochrome P450 monooxygenase orf4"
FT                   /id="PRO_0000444932"
FT   BINDING         447
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:P04798"
SQ   SEQUENCE   508 AA;  57951 MW;  2D32596E9F81D7E2 CRC64;
     MYHLIPFAAI LGMTYALSLA IYRLFLSPLA KFPGPKLAAV TGWVETYYQL FYGEGGQFIF
     LYKEWHQKYG PIIRINPWEV HISDSCFFEI LYSTNRPLKK LPHLAKVFDN ELSGFSTVSP
     ELHRIRRKAV SHLFSKGEVL KRGAQIQSAM DRLSERLKLD FLGHGNRVIC MNDMWSVYTA
     DLIAEYAFGR HYGFIDQPNF EADFTKALVH LLEPTHLAQQ FPWLTDILKA LPTSVLEFLH
     PHMAAFNKFK AANQVRIAKA NFAKDLSKGG TMFSAIFNSD LPDEEKSIER AHQEALAFAA
     AGAETVAATL SVASFHLLHD PKIRRRLDEE LATVVPDSRS SDASMPSLEI LWQLPYLTGI
     INEALRLSYG SYARIPRTSD TPIQYDEWTI PPGVVFSMDI APAHHDERIF PDSYSFKPER
     WLDNPQAFDG KPLTRYLFSF SRGTRSCLGM QLALAEMYIG IVSFFSRFDA HLFETDLTDI
     TFVRDRFAPR PRIGSRGVRV NRLTTRKF