ID   POXD_PENO1              Reviewed;         484 AA.
AC   S8ASK3;
DT   29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT   16-OCT-2013, sequence version 1.
DT   03-AUG-2022, entry version 31.
DE   RecName: Full=Cytochrome P450 monooxygenase poxD {ECO:0000303|PubMed:28365998};
DE            EC=1.-.-.- {ECO:0000305|PubMed:28365998};
DE   AltName: Full=Oxaleimides biosynthesis cluster protein D {ECO:0000303|PubMed:28365998};
GN   Name=poxD {ECO:0000303|PubMed:28365998}; ORFNames=PDE_04016;
OS   Penicillium oxalicum (strain 114-2 / CGMCC 5302) (Penicillium decumbens).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX   NCBI_TaxID=933388;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=114-2 / CGMCC 5302;
RX   PubMed=23383313; DOI=10.1371/journal.pone.0055185;
RA   Liu G., Zhang L., Wei X., Zou G., Qin Y., Ma L., Li J., Zheng H., Wang S.,
RA   Wang C., Xun L., Zhao G.-P., Zhou Z., Qu Y.;
RT   "Genomic and secretomic analyses reveal unique features of the
RT   lignocellulolytic enzyme system of Penicillium decumbens.";
RL   PLoS ONE 8:E55185-E55185(2013).
RN   [2]
RP   FUNCTION, INDUCTION, AND PATHWAY.
RX   PubMed=28365998; DOI=10.1021/jacs.7b02432;
RA   Sato M., Dander J.E., Sato C., Hung Y.S., Gao S.S., Tang M.C., Hang L.,
RA   Winter J.M., Garg N.K., Watanabe K., Tang Y.;
RT   "Collaborative Biosynthesis of Maleimide- and Succinimide-Containing
RT   Natural Products by Fungal Polyketide Megasynthases.";
RL   J. Am. Chem. Soc. 139:5317-5320(2017).
RN   [3]
RP   FUNCTION.
RX   PubMed=32039410; DOI=10.1039/c9cc09590j;
RA   Hantke V., Skellam E.J., Cox R.J.;
RT   "Evidence for enzyme catalysed intramolecular [4+2] Diels-Alder cyclization
RT   during the biosynthesis of pyrichalasin H.";
RL   Chem. Commun. (Camb.) 56:2925-2928(2020).
CC   -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that
CC       mediates the biosynthesis of oxaleimides, ccytotoxic compounds
CC       containing an unusual disubstituted succinimide moiety
CC       (PubMed:28365998). The first step of the pathway is provided by the HR-
CC       PKS poxF that serves in a new mode of collaborative biosynthesis with
CC       the PKS-NRPS poxE, by providing the olefin containing amino acid
CC       substrate via the synthesis of an ACP-bound dec-4-enoate
CC       (PubMed:28365998). The cytochrome P450 monooxygenase poxM-catalyzed
CC       oxidation at the alpha-position creates the enzyme-bound 2-hydroxydec-
CC       4-enoyl-ACP thioester, which may be prone to spontaneous hydrolysis to
CC       yield 2-hydroxydec-4-enoic acid due to increased electrophilicity of
CC       the carbonyl (PubMed:28365998). 2-hydroxydec-4-enoic acid can then be
CC       further oxidized by poxM to yield the alpha-ketoacid 2-oxodec-4-
CC       enoicacid, which is reductively aminated by the aminotransferase poxL
CC       to yield (S,E)-2-aminodec-4-enoic acid (PubMed:28365998). The Hybrid
CC       PKS-NRPS synthetase poxE then performs condensation between the
CC       octaketide product of its PKS modules and the amino group of (S,E)-2-
CC       aminodec-4-enoic acid which is activated and incorporated by the
CC       adenylation domain (PubMed:28365998). The resulting aminoacyl product
CC       can be cyclized by the Diels-Alderase PoxQ and reductively released by
CC       the reductive (R) domain of poxE to yield an aldehyde intermediate
CC       (PubMed:28365998) (Probable). The released aldehyde is then substrate
CC       for a Knoevenagel condensation by the hydrolyase poxO followed by an
CC       oxidation at the 5-position of the pyrrolidone ring (PubMed:28365998).
CC       The presence of the olefin from the amino acid building block allows
CC       for migration of the substituted allyl group to occur
CC       (PubMed:28365998). This allylic transposition reaction takes place in a
CC       conjugate addition, semipinacol-like fashion to yield a succinimide
CC       intermediate (PubMed:28365998). Iterative two-electron oxidations of
CC       the C7 methyl of the succinimide intermediate to the carboxylic acid
CC       can be catalyzed by one of two remaining cytochrome P450
CC       monooxygenasess poxC or poxD to yield oxaleimide A (PubMed:28365998).
CC       Subsequent oxidation yields the maleimide scaffold oxaleimide I
CC       (PubMed:28365998). Both oxaleimide A and oxaleimide I can undergo
CC       oxidative modifications in the decalin ring to yield the series of
CC       products oxaleimides B to H (PubMed:28365998).
CC       {ECO:0000269|PubMed:28365998, ECO:0000305|PubMed:32039410}.
CC   -!- COFACTOR:
CC       Name=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000250|UniProtKB:P04798};
CC   -!- PATHWAY: Secondary metabolite biosynthesis.
CC       {ECO:0000305|PubMed:28365998}.
CC   -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC       protein {ECO:0000255}.
CC   -!- INDUCTION: Expression is positively regulated by the oxaleimides
CC       biosynthesis cluster-specific transcription factor poxB.
CC       {ECO:0000269|PubMed:28365998}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR   EMBL; KB644411; EPS29068.1; -; Genomic_DNA.
DR   SMR; S8ASK3; -.
DR   STRING; 69781.S8ASK3; -.
DR   EnsemblFungi; EPS29068; EPS29068; PDE_04016.
DR   eggNOG; KOG0684; Eukaryota.
DR   HOGENOM; CLU_018012_1_3_1; -.
DR   OrthoDB; 864748at2759; -.
DR   PhylomeDB; S8ASK3; -.
DR   Proteomes; UP000019376; 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   GO; GO:0008152; P:metabolic process; IEA:UniProt.
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   SUPFAM; SSF48264; SSF48264; 1.
DR   PROSITE; PS00086; CYTOCHROME_P450; 1.
PE   2: Evidence at transcript level;
KW   Heme; Iron; Membrane; Metal-binding; Monooxygenase; Oxidoreductase;
KW   Reference proteome; Transmembrane; Transmembrane helix.
FT   CHAIN           1..484
FT                   /note="Cytochrome P450 monooxygenase poxD"
FT                   /id="PRO_0000453764"
FT   TRANSMEM        2..24
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   BINDING         429
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   484 AA;  55105 MW;  240316B4EB7DCBEE CRC64;
     MVSPVVLATT AMIVVFLLAQ RYLSLPVLPN EPLLIPHWMP FFGHAFRFAR SKRSFFRWAN
     AKTGGQPFSV PMGGRRHYIF SDPADIAGIH KNGKTLSIRG FVRFIYISIW GFKPADADAM
     WEIKPEWHRM DIEWLLSDKN DQIAVQYLRR IEEQLRALDA EVEGAPDKAI VRPGLKTVVD
     VQGKATCQVL YGATTLEKHP GLLDDLTIMV RDGFWGLLFR APRFLFRNAY EARDRIINTY
     ADLVENIETR KDVSQYLYER TVYLTQQGIS PQAQGADMLR TMFASLLNSM PTGYLALLHI
     LAEPGLADEV RKELIDCGYL ERSPEEMLEI LPGKMPLLRS IWHETLRMHN NSLTVREVTA
     DTKFMGKTKW QVQKGGVINI PCGLMHFNEA LHPDPESFHA RRFMDKELGG EGESHARTTK
     PFGGGSTHCP GRVFAEKQMI GLVAALLMRY DMGIVNADWK MPLVSEFDDI TKQPTVWIRI
     SKRV