PHQG_PENFE
ID PHQG_PENFE Reviewed; 338 AA.
AC L0E2U6;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 06-MAR-2013, sequence version 1.
DT 03-AUG-2022, entry version 19.
DE RecName: Full=NmrA-like family domain-containing oxidoreductase phqG {ECO:0000303|PubMed:23213353};
DE EC=1.-.-.- {ECO:0000305|PubMed:23213353};
DE AltName: Full=Paraherquamide biosynthesis cluster protein G {ECO:0000303|PubMed:23213353};
GN Name=phqG {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: NmrA-like family domain-containing oxidoreductase; part of
CC the gene cluster that mediates the biosynthesis of paraherquamide, a
CC fungal indole alkaloid that belongs to a family of natural products
CC containing a characteristic bicyclo[2.2.2]diazaoctane core
CC (PubMed:23213353). The first steps in the biosynthesis of
CC paraherquamide is the production of the beta-methyl-proline precursor
CC from L-isoleucine (Probable). They require oxidation of a terminally
CC hydroxylated L-isoleucine to the corresponding aldehyde by enzymes
CC which have still to be identified (Probable). Spontaneous cyclization
CC and dehydration would yield the 4-methyl pyrolline-5-carboxylic acid,
CC which is then reduced by the pyrroline-5-carboxylate reductase phqD
CC leading to the beta-methyl-proline precursor (Probable). The next step
CC of paraherquamide biosynthesis involves coupling of beta-methyl-proline
CC and L-tryptophan by the bimodular NRPS phqB, to produce a
CC monooxopiperazine intermediate (Probable). The reductase (R) domain of
CC phqB utilizes NADPH for hydride transfer to reduce the thioester bond
CC of the T domain-tethered linear dipeptide to a hemithioaminal
CC intermediate, which spontaneously cleaves the C-S bond to release the
CC aldehyde product (PubMed:31548667). This compound undergoes spontaneous
CC cyclization and dehydration to give a dienamine which is reverse
CC prenylated at C-2 by the reverse prenyltransferase phqJ (Probable). The
CC other prenyltransferase present in the cluster, phqI may be a redundant
CC gene in the pathway (Probable). During biosynthetic assembly, the key
CC step to produce the polycyclic core is catalyzed by the bifunctional
CC reductase and intramolecular [4+2] Diels-Alderase, phqE, resulting in
CC formation of the [2.2.2] diazaoctane intermediate preparaherquamide
CC (PubMed:31548667). Following formation of preparaherquamide, an indole
CC 2,3-epoxidation-initiated pinacol-like rearrangement is catalyzed by
CC the phqK FAD-dependent monooxygenase (Probable). The prenyltransferase
CC phqA, the cytochrome P450 monooxygenase phqL, and the FAD-linked
CC oxidoreductase phqH (or the cytochrome P450 monooxygenase phqM), are
CC proposed to be involved in the formation of the pyran ring (Probable).
CC The FAD-dependent monooxygenase phqK is likely responsible for
CC generation of the spiro-oxindole, and the N-methylation is likely
CC mediated by the phqN methyltransferase leading to the isolable natural
CC product paraherquamide F (Probable). However, the order of these
CC biosynthetic steps has still to be determined (Probable). In late-stage
CC paraherquamide biosynthesis, the third P450 monooxygenase, phqO, is
CC probably responsible for the C-14 hydroxylation, transforming
CC paraherquamide F to paraherquamide G, and paraherquamide E to the final
CC product paraherquamide A (Probable). The expansion from the 6-membered
CC ring pyran (in paraherquamides F and G) to the 7-membered dioxepin ring
CC (in paraherquamides A and E) represents a poorly understood but
CC intriguing process that probably involves the 2-oxoglutarate-dependent
CC dioxygenase phqC (Probable). Finally, the remaining members of the
CC paraherquamide cluster, including phqI as well as phqM (or phqH), do
CC not have a clearly prescribed role and appear to be redundant
CC (Probable). {ECO:0000269|PubMed:23213353, ECO:0000269|PubMed:31548667,
CC ECO:0000305|PubMed:23213353}.
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000305|PubMed:23213353}.
CC -!- SIMILARITY: Belongs to the NmrA-type oxidoreductase family.
CC {ECO:0000305}.
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DR EMBL; JQ708195; AGA37274.1; -; Genomic_DNA.
DR AlphaFoldDB; L0E2U6; -.
DR SMR; L0E2U6; -.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0009820; P:alkaloid metabolic process; IEA:UniProtKB-KW.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR008030; NmrA-like.
DR Pfam; PF05368; NmrA; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 3: Inferred from homology;
KW Alkaloid metabolism; NADP; Oxidoreductase.
FT CHAIN 1..338
FT /note="NmrA-like family domain-containing oxidoreductase
FT phqG"
FT /id="PRO_0000448871"
FT BINDING 13..18
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 41..45
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 62..63
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 83..85
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 141
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 164..167
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
SQ SEQUENCE 338 AA; 37315 MW; 0A2D4B7B7724453F CRC64;
MTIQVKRVVT VFGGTGNQGS SVARSLLAHK AKIFHVRVIT RDPQSDKAKA IASLGAELVQ
ADGFNLGEMT NAFAGSWGVF INTNSDDEAL KSLDGPSDYD LGVSVIDSAK KAGVQHVVYS
SGPSITNATK GRMHLEGFET KYHVEQYGRR KGFTSFTPIL CASFMECFFY DPFVDAFGGF
PWIPEPETGE VVFRTPDYGG KGDMPWVSCE EDLGDIVHGI FLNPCKYDQV LVQATSQQIT
MFDVAASYTQ ATGIPARYEE LPSWSSIKLN GTRCRAETRQ MFWYMKHCGG RWFAEHESDM
STAVALKESA MLSQDRVGGL VTFQAWFKKA KVLKDQNV
