PHQL_PENFE
ID PHQL_PENFE Reviewed; 563 AA.
AC L0E2V1;
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 phqL {ECO:0000303|PubMed:23213353};
DE EC=1.-.-.- {ECO:0000305|PubMed:23213353};
DE AltName: Full=Paraherquamide biosynthesis cluster protein L {ECO:0000303|PubMed:23213353};
GN Name=phqL {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 -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Multi-pass membrane
CC protein {ECO:0000255}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; JQ708195; AGA37279.1; -; Genomic_DNA.
DR AlphaFoldDB; L0E2V1; -.
DR SMR; L0E2V1; -.
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; 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.
PE 3: Inferred from homology;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Transmembrane; Transmembrane helix.
FT CHAIN 1..563
FT /note="Cytochrome P450 monooxygenase phqL"
FT /id="PRO_0000448873"
FT TRANSMEM 20..40
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 52..72
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 80..100
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TRANSMEM 362..382
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 502
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 279
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 419
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 563 AA; 63886 MW; 2D1DF5A1DACC2A40 CRC64;
MEPHHDGHIL KVLPMLASNE NFSRLTTAFV AGIAAHIIIF RRGEWDIAAA RIPVGLFILQ
SCLFSYYLFV PGPPTSIYTA LWLVGQITLG FIAGTTVSIL SYRAFFHRLN SFPGPFPARL
SMWYVTSLYA QNPDAFNTVR GLHQQYGDFV RTGPTELSVN HPDALQAVHS GRSECTKGPW
YSMLHPFISL FAIRDKAEHS RRRKPWELAF RPNAVLEYLP ALEKGTNELL EQVERRKGKS
MDMTYWINLF TFDLTGRVAF SQEYECVKHN KRHPIMEIND SSNLVTGVVS HVVWLISFIK
ATPGLNANMK ALIGFSEEQV QNRQKMQTSG QRDVFSWLWE DFKEQGMETP QSKLDLVADA
SLVIFAGSGT VAVTIIGCLY FLTSTSPDYL TQIRQELDTL DEINSHTLSK VQTLNAVINE
TLRLHYPALS GFQRQTPPGG LHIAGRYIPG NTNIKIPFYT LFLDERNFAE PEKFIPERWT
TRKELVKNPE AFAPFLLGPY NCLGKSLALM QVRHVLVELI RRYEIVLAPG ADPEKYWRER
TDGFVMGLAP LDLAFTEREM AGF
