POXM_PENOX
ID POXM_PENOX Reviewed; 512 AA.
AC A0A1W5T1Y6;
DT 29-SEP-2021, integrated into UniProtKB/Swiss-Prot.
DT 05-JUL-2017, sequence version 1.
DT 03-AUG-2022, entry version 9.
DE RecName: Full=Cytochrome P450 monooxygenase poxM {ECO:0000303|PubMed:28365998};
DE EC=1.-.-.- {ECO:0000269|PubMed:28365998};
DE AltName: Full=Oxaleimides biosynthesis cluster protein M {ECO:0000303|PubMed:28365998};
GN Name=poxM {ECO:0000303|PubMed:28365998};
OS Penicillium oxalicum.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=69781;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY, INDUCTION,
RP AND PATHWAY.
RC STRAIN=K85;
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 [2]
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, cytotoxic 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:0000269|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; KY764302; ARF05987.1; -; Genomic_DNA.
DR SMR; A0A1W5T1Y6; -.
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 1: Evidence at protein level;
KW Heme; Iron; Membrane; Metal-binding; Monooxygenase; Oxidoreductase;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..512
FT /note="Cytochrome P450 monooxygenase poxM"
FT /id="PRO_0000453765"
FT TRANSMEM 15..35
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 449
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 512 AA; 57495 MW; 5D2089930FE9B62A CRC64;
MNALIGQLLN APVALLKGAT IALSFFSLYL FGLVIYRLIF HPLAQYPGPL LGRITNLYAA
YHAWKGDIHE DIWRCHQKHG NCIRYAPDRL AFDTAKAVSD IYGYGGNVRK SQVYDTLVHR
TANTLTMRDK KQHAQRRRIM SHGFSDAAIR SFEPRVQELI QTLCDLLIVK DASADSEWSA
PQDMAPWFDY LTFDIMSSLI FSASYDTLRQ EKYRSVIRAI EESNVRVSVL LQAPIVTLFR
SDKKLFSQSI LGRNHFTRFI GSTVKERVQK SKLLADRDIF SYFQSSKAAA NGDSMNMNEL
SGEAATLIVA GSDTTATTLA ATMFYLSQSA DIYHRVAQEV RQCFNSEDEI HAGSQLNACR
LLRACIDEAL RMSPPAGSAL WREVEAGGIT VNGRFVPEGY DVGVGIYAVH HNPTVYPQPF
RFDPDRWLVD DTHDVRSAFM PFSLGTRSCI GKGLAQMEAL LTLANIIWRY DFRAVPGGAV
QPEYKLKDHV TGAKTGPVLQ YRRIVRDKIM IG
