ID   PHQO_PENFE              Reviewed;         436 AA.
AC   L0E307;
DT   26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT   06-MAR-2013, sequence version 1.
DT   03-AUG-2022, entry version 29.
DE   RecName: Full=Cytochrome P450 monooxygenase phqO {ECO:0000303|PubMed:23213353};
DE            EC=1.-.-.- {ECO:0000305|PubMed:23213353};
DE   AltName: Full=Paraherquamide biosynthesis cluster protein O {ECO:0000303|PubMed:23213353};
GN   Name=phqO {ECO:0000303|PubMed:23213353};
OS   Penicillium fellutanum.
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX   NCBI_TaxID=70095;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND PATHWAY.
RC   STRAIN=ATCC 20841 / MF5123;
RX   PubMed=23213353; DOI=10.1039/c2md20029e;
RA   Li S., Anand K., Tran H., Yu F., Finefield J.M., Sunderhaus J.D.,
RA   McAfoos T.J., Tsukamoto S., Williams R.M., Sherman D.H.;
RT   "Comparative analysis of the biosynthetic systems for fungal
RT   bicyclo[2.2.2]diazaoctane indole alkaloids: the (+)/(-)-notoamide,
RT   paraherquamide and malbrancheamide pathways.";
RL   Med. Chem. Commun. 3:987-996(2012).
RN   [2]
RP   FUNCTION.
RX   PubMed=31548667; DOI=10.1038/s41557-019-0326-6;
RA   Dan Q., Newmister S.A., Klas K.R., Fraley A.E., McAfoos T.J., Somoza A.D.,
RA   Sunderhaus J.D., Ye Y., Shende V.V., Yu F., Sanders J.N., Brown W.C.,
RA   Zhao L., Paton R.S., Houk K.N., Smith J.L., Sherman D.H., Williams R.M.;
RT   "Fungal indole alkaloid biogenesis through evolution of a bifunctional
RT   reductase/Diels-Alderase.";
RL   Nat. Chem. 11:972-980(2019).
CC   -!- FUNCTION: Cytochrome P450 monooxygenase; part of the gene cluster that
CC       mediates the biosynthesis of paraherquamide, a fungal indole alkaloid
CC       that belongs to a family of natural products containing a
CC       characteristic bicyclo[2.2.2]diazaoctane core (PubMed:23213353). The
CC       first steps in the biosynthesis of paraherquamide is the production of
CC       the beta-methyl-proline precursor from L-isoleucine (Probable). They
CC       require oxidation of a terminally hydroxylated L-isoleucine to the
CC       corresponding aldehyde by enzymes which have still to be identified
CC       (Probable). Spontaneous cyclization and dehydration would yield the 4-
CC       methyl pyrolline-5-carboxylic acid, which is then reduced by the
CC       pyrroline-5-carboxylate reductase phqD leading to the beta-methyl-
CC       proline precursor (Probable). The next step of paraherquamide
CC       biosynthesis involves coupling of beta-methyl-proline and L-tryptophan
CC       by the bimodular NRPS phqB, to produce a monooxopiperazine intermediate
CC       (Probable). The reductase (R) domain of phqB utilizes NADPH for hydride
CC       transfer to reduce the thioester bond of the T domain-tethered linear
CC       dipeptide to a hemithioaminal intermediate, which spontaneously cleaves
CC       the C-S bond to release the aldehyde product (PubMed:31548667). This
CC       compound undergoes spontaneous cyclization and dehydration to give a
CC       dienamine which is reverse prenylated at C-2 by the reverse
CC       prenyltransferase phqJ (Probable). The other prenyltransferase present
CC       in the cluster, phqI may be a redundant gene in the pathway (Probable).
CC       During biosynthetic assembly, the key step to produce the polycyclic
CC       core is catalyzed by the bifunctional reductase and intramolecular
CC       [4+2] Diels-Alderase, phqE, resulting in formation of the [2.2.2]
CC       diazaoctane intermediate preparaherquamide (PubMed:31548667). Following
CC       formation of preparaherquamide, an indole 2,3-epoxidation-initiated
CC       pinacol-like rearrangement is catalyzed by the phqK FAD-dependent
CC       monooxygenase (Probable). The prenyltransferase phqA, the cytochrome
CC       P450 monooxygenase phqL, and the FAD-linked oxidoreductase phqH (or the
CC       cytochrome P450 monooxygenase phqM), are proposed to be involved in the
CC       formation of the pyran ring (Probable). The FAD-dependent monooxygenase
CC       phqK is likely responsible for generation of the spiro-oxindole, and
CC       the N-methylation is likely mediated by the phqN methyltransferase
CC       leading to the isolable natural product paraherquamide F (Probable).
CC       However, the order of these biosynthetic steps has still to be
CC       determined (Probable). In late-stage paraherquamide biosynthesis, the
CC       third P450 monooxygenase, phqO, is probably responsible for the C-14
CC       hydroxylation, transforming paraherquamide F to paraherquamide G, and
CC       paraherquamide E to the final product paraherquamide A (Probable). The
CC       expansion from the 6-membered ring pyran (in paraherquamides F and G)
CC       to the 7-membered dioxepin ring (in paraherquamides A and E) represents
CC       a poorly understood but intriguing process that probably involves the
CC       2-oxoglutarate-dependent dioxygenase phqC (Probable). Finally, the
CC       remaining members of the paraherquamide cluster, including phqI as well
CC       as phqM (or phqH), do not have a clearly prescribed role and appear to
CC       be redundant (Probable). {ECO:0000269|PubMed:23213353,
CC       ECO:0000269|PubMed:31548667, ECO:0000305|PubMed:23213353}.
CC   -!- COFACTOR:
CC       Name=heme; Xref=ChEBI:CHEBI:30413;
CC         Evidence={ECO:0000250|UniProtKB:P04798};
CC   -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000305|PubMed:23213353}.
CC   -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR   EMBL; JQ708195; AGA37282.1; -; Genomic_DNA.
DR   AlphaFoldDB; L0E307; -.
DR   SMR; L0E307; -.
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   PRINTS; PR00385; P450.
DR   SUPFAM; SSF48264; SSF48264; 1.
DR   PROSITE; PS00086; CYTOCHROME_P450; 1.
PE   3: Inferred from homology;
KW   Heme; Iron; Metal-binding; Monooxygenase; Oxidoreductase.
FT   CHAIN           1..436
FT                   /note="Cytochrome P450 monooxygenase phqO"
FT                   /id="PRO_0000448875"
FT   BINDING         377
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   436 AA;  49906 MW;  A4EF5C49ED167E62 CRC64;
     MSKYLLMSFT EGSMSTWHYL AMLTTIWLVY QYLKPVPIVP GLPVINRAER WDFFSIKMKR
     RFLNNAAALM KEGFEQPKLV LSPDYADELK NDARFSLEDA GLRRHYRMKP ASLFKIIGQT
     TPISGRAFLG PEVCGDIRWI EATMGYLEMG VRTAFLLQVF PRFLFPLQRW FPLCRKVRKH
     IDMAGTILRP VIDSRRADGR PAQDAISWFD EAAAGETYNP VYSQLSLSFA STHTTADTMT
     KVIIHLAENP AVVTDLRKEV VEAIAKHGEL TKTALSQMNL LDSTLKESQR LEPLASATMN
     RVTREEVTLS NGLWIPRNMY VLVSGHRMRD PTLYPDPEKF DAYRFVKMRE IEKKKSDCAY
     TAATVDHMGF GYGKHSCPGR FFAAHEVKII LCHLILKYEF KLPEDQARTY LLAGFFTSAG
     PENELLVRRR VEEIAL