PRX9_PENRF
ID PRX9_PENRF Reviewed; 579 AA.
AC W6QB15;
DT 07-OCT-2020, integrated into UniProtKB/Swiss-Prot.
DT 16-APR-2014, sequence version 1.
DT 03-AUG-2022, entry version 26.
DE RecName: Full=Cytochrome P450 monooxygenase ORF6 {ECO:0000303|PubMed:27921136};
DE EC=1.-.-.- {ECO:0000305|PubMed:27921136};
DE AltName: Full=PR-toxin biosynthesis cluster protein 6 {ECO:0000303|PubMed:27921136};
GN Name=ORF6 {ECO:0000303|PubMed:27921136}; ORFNames=PROQFM164_S02g001469;
OS Penicillium roqueforti (strain FM164).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=1365484;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=FM164;
RX PubMed=24407037; DOI=10.1038/ncomms3876;
RA Cheeseman K., Ropars J., Renault P., Dupont J., Gouzy J., Branca A.,
RA Abraham A.L., Ceppi M., Conseiller E., Debuchy R., Malagnac F., Goarin A.,
RA Silar P., Lacoste S., Sallet E., Bensimon A., Giraud T., Brygoo Y.;
RT "Multiple recent horizontal transfers of a large genomic region in cheese
RT making fungi.";
RL Nat. Commun. 5:2876-2876(2014).
RN [2]
RP FUNCTION.
RX PubMed=16345540; DOI=10.1128/aem.39.4.770-776.1980;
RA Moreau S., Lablache-Combier A., Biguet J.;
RT "Production of eremofortins A, B, and C relative to formation of PR toxin
RT by Penicillium roqueforti.";
RL Appl. Environ. Microbiol. 39:770-776(1980).
RN [3]
RP FUNCTION.
RX PubMed=8440737; DOI=10.1016/S0021-9258(18)53644-9;
RA Proctor R.H., Hohn T.M.;
RT "Aristolochene synthase. Isolation, characterization, and bacterial
RT expression of a sesquiterpenoid biosynthetic gene (Ari1) from Penicillium
RT roqueforti.";
RL J. Biol. Chem. 268:4543-4548(1993).
RN [4]
RP FUNCTION.
RX PubMed=15186158; DOI=10.1021/ja0499593;
RA Felicetti B., Cane D.E.;
RT "Aristolochene synthase: mechanistic analysis of active site residues by
RT site-directed mutagenesis.";
RL J. Am. Chem. Soc. 126:7212-7221(2004).
RN [5]
RP FUNCTION.
RX PubMed=24239699; DOI=10.1016/j.fgb.2013.10.009;
RA Hidalgo P.I., Ullan R.V., Albillos S.M., Montero O., Fernandez-Bodega M.A.,
RA Garcia-Estrada C., Fernandez-Aguado M., Martin J.F.;
RT "Molecular characterization of the PR-toxin gene cluster in Penicillium
RT roqueforti and Penicillium chrysogenum: cross talk of secondary metabolite
RT pathways.";
RL Fungal Genet. Biol. 62:11-24(2014).
RN [6]
RP FUNCTION.
RX PubMed=26274339; DOI=10.1002/anie.201506128;
RA Riclea R., Dickschat J.S.;
RT "Identification of intermediates in the biosynthesis of PR toxin by
RT Penicillium roqueforti.";
RL Angew. Chem. Int. Ed. 54:12167-12170(2015).
RN [7]
RP FUNCTION, DISRUPTION PHENOTYPE, AND PATHWAY.
RX PubMed=27921136; DOI=10.1007/s00253-016-7995-5;
RA Hidalgo P.I., Poirier E., Ullan R.V., Piqueras J., Meslet-Cladiere L.,
RA Coton E., Coton M.;
RT "Penicillium roqueforti PR toxin gene cluster characterization.";
RL Appl. Microbiol. Biotechnol. 101:2043-2056(2017).
CC -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of PR-toxin, a bicyclic sesquiterpene
CC belonging to the eremophilane class and acting as a mycotoxin
CC (PubMed:24239699, PubMed:27921136). The first step of the pathway is
CC catalyzed by the aristolochene synthase which performs the cyclization
CC of trans,trans-farnesyl diphosphate (FPP) to the bicyclic sesquiterpene
CC aristolochene (PubMed:8440737, PubMed:15186158, PubMed:24239699).
CC Following the formation of aristolochene, the non-oxygenated
CC aristolochene is converted to the trioxygenated intermediate
CC eremofortin B, via 7-epi-neopetasone (PubMed:24239699,
CC PubMed:26274339). This conversion appears to involve three enzymes, a
CC hydroxysterol oxidase-like enzyme, the quinone-oxidase prx3 that forms
CC the quinone-type-structure in the bicyclic nucleus of aristolochene
CC with the C8-oxo group and the C-3 hydroxyl group, and the P450
CC monooxygenase ORF6 that introduces the epoxide at the double bond
CC between carbons 1 and 2 (PubMed:24239699, PubMed:27921136). No monoxy
CC or dioxy-intermediates have been reported to be released to the broth,
CC so these three early oxidative reactions may be coupled together
CC (PubMed:24239699). Eremofortin B is further oxidized by another P450
CC monooxygenase, that introduces a second epoxide between carbons 7 and
CC 11 prior to acetylation to eremofortin A by the acetyltransferase ORF8
CC (PubMed:16345540, PubMed:24239699, PubMed:27921136). The second
CC epoxidation may be performed by a second P450 monooxygenase
CC (PubMed:24239699). After the acetylation step, eremofortin A is
CC converted to eremofortin C and then to PR-toxin (PubMed:24239699).
CC First the conversion of eremofortin A to eremofortin C proceeds by
CC oxidation of the side chain of the molecule at C-12 and is catalyzed by
CC the short-chain oxidoreductase prx1 (PubMed:16345540, PubMed:24239699).
CC The cytochrome P450 monooxygenase ORF6 is probably also involved in
CC this step (PubMed:27921136). The primary alcohol formed at C-12 is
CC finally oxidized by the short-chain alcohol dehydrogenase prx4 that
CC forms PR-toxin (PubMed:16345540, PubMed:24239699).
CC {ECO:0000269|PubMed:15186158, ECO:0000269|PubMed:16345540,
CC ECO:0000269|PubMed:24239699, ECO:0000269|PubMed:26274339,
CC ECO:0000269|PubMed:27921136, ECO:0000269|PubMed:8440737}.
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Sesquiterpene biosynthesis. {ECO:0000269|PubMed:27921136,
CC ECO:0000305|PubMed:24239699}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of PR-toxin as well as of
CC the intermediates eremofortin A and B. {ECO:0000269|PubMed:27921136}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; HG792016; CDM31319.1; -; Genomic_DNA.
DR AlphaFoldDB; W6QB15; -.
DR SMR; W6QB15; -.
DR EnsemblFungi; CDM31319; CDM31319; PROQFM164_S02g001469.
DR OrthoDB; 786853at2759; -.
DR Proteomes; UP000030686; Unassembled WGS sequence.
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; 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 3: Inferred from homology;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Transmembrane; Transmembrane helix.
FT CHAIN 1..579
FT /note="Cytochrome P450 monooxygenase ORF6"
FT /id="PRO_0000451224"
FT TRANSMEM 7..29
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 512
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"
FT CARBOHYD 2
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 194
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 390
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 579 AA; 65686 MW; 3B00751CA31AB3D1 CRC64;
MNASKLPLGS FVGTTLLLFI LYKLVKLAYY VGQAKKTGLP YTLVPVLETE FLGKLLTPLI
RPLFTSRLSR GEGWPRWIRF SILDWAWEEK RRVHEELGDV FLLVSPEGLI CYTADADMCW
DVMNRRNEFL KPRDKYKVLE PYGPNVATTE GKAYNFHVRI TAPPFNDGSG ANDLVWNEAS
DQARALMESW SQENTTRDLS LDINRLTLAV ISYTGFGKRL DFETEVSDLR NKIPPGYKMS
LHHALHLVTT FMVKILLIPK WIMKMTSMKE IAIAHGELEK YMREMIRTET AKLSKDSEYQ
SADAKGNLLT SVLRASAFEA KAAGRKQAFS EDEVLGNLFL YLLAGYETTA NAMTYGFITL
ALRQDLQDRI IQEVDGVYAE AAAEGRTSLN YTDDFEKFQY TYGFMYEVFR LYPGVCIITK
MVPKDTTITV YPENNSPQQH VLPAECRVYL NVNAVHYHER YWPDPWALKP DRWMGTIGVT
PNSRPNKKVV AQDKSRQVRG TLMTFSGGAR ACLGRKFTQS EYISVLATVL GKYRIVLGEG
MDAKVVKQEI DHLAAGTVTL APLKYVKLAL KKRTDVKTG
