PHQK_PENFE
ID PHQK_PENFE Reviewed; 459 AA.
AC L0E4H0;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 06-MAR-2013, sequence version 1.
DT 03-AUG-2022, entry version 26.
DE RecName: Full=FAD-dependent monooxygenase phqK {ECO:0000303|PubMed:23213353};
DE EC=1.-.-.- {ECO:0000305|PubMed:23213353};
DE AltName: Full=Paraherquamide biosynthesis cluster protein K {ECO:0000303|PubMed:23213353};
GN Name=phqK {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: FAD-dependent 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=FAD; Xref=ChEBI:CHEBI:57692;
CC Evidence={ECO:0000250|UniProtKB:A6T923};
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000305|PubMed:23213353}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:23213353}.
CC -!- SIMILARITY: Belongs to the paxM FAD-dependent monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; JQ708195; AGA37278.1; -; Genomic_DNA.
DR PDB; 6PVF; X-ray; 1.69 A; A=1-459.
DR PDB; 6PVG; X-ray; 1.71 A; A=1-459.
DR PDB; 6PVH; X-ray; 1.89 A; A=1-459.
DR PDB; 6PVI; X-ray; 2.09 A; A=1-459.
DR PDB; 6PVJ; X-ray; 1.25 A; A=1-459.
DR PDBsum; 6PVF; -.
DR PDBsum; 6PVG; -.
DR PDBsum; 6PVH; -.
DR PDBsum; 6PVI; -.
DR PDBsum; 6PVJ; -.
DR AlphaFoldDB; L0E4H0; -.
DR SMR; L0E4H0; -.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 3.50.50.60; -; 1.
DR InterPro; IPR002938; FAD-bd.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR Pfam; PF01494; FAD_binding_3; 2.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW 3D-structure; FAD; Flavoprotein; Monooxygenase; Oxidoreductase.
FT CHAIN 1..459
FT /note="FAD-dependent monooxygenase phqK"
FT /id="PRO_0000448872"
FT BINDING 37..38
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 131
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 240..242
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 316
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 326..330
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT STRAND 9..13
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 17..28
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 32..39
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 48..51
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 53..59
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 60..65
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 66..71
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 72..74
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 80..84
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 90..95
FT /evidence="ECO:0007829|PDB:6PVJ"
FT TURN 97..100
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 105..108
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 109..122
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 126..138
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 143..149
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 154..164
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 172..175
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 184..194
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 197..201
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 204..210
FT /evidence="ECO:0007829|PDB:6PVJ"
FT TURN 211..215
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 219..224
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 227..234
FT /evidence="ECO:0007829|PDB:6PVJ"
FT TURN 235..238
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 239..247
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 262..270
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 275..282
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 287..289
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 291..297
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 311..313
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 315..317
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 323..326
FT /evidence="ECO:0007829|PDB:6PVH"
FT HELIX 328..346
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 348..350
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 351..377
FT /evidence="ECO:0007829|PDB:6PVJ"
FT TURN 378..381
FT /evidence="ECO:0007829|PDB:6PVJ"
FT TURN 385..387
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 392..394
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 398..400
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 402..405
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 409..426
FT /evidence="ECO:0007829|PDB:6PVJ"
FT STRAND 433..435
FT /evidence="ECO:0007829|PDB:6PVJ"
FT HELIX 437..443
FT /evidence="ECO:0007829|PDB:6PVJ"
SQ SEQUENCE 459 AA; 51282 MW; 1751E7AE40AE3C6C CRC64;
MGSLGEEVQV IIVGLGIVGL AAAIECREKG HSVHAFEKSN ILKSIGDCIG LQSNATRIIK
RWGDGAVHEA LRPWIVSSKE IRIHNSSGRL IIRQDLSEVC EQPNYLLPRS ELIRVMYEHA
LKIGVEISLG VEVCEPSEDE EGASVVALTR DGERQIVRGD FIICSDGVHS KMRKAIMPQP
VEPRPSGYAA FRALVDTETL KGDPEASWVF EGVEENDRFD VFFLSGAQIA LQSCNKGKVF
SWFCIHQDTR NLLDVWTSPA DPNEMLDLIK VWPIGQRLWS VIRHTQPQKF INYPLLNHKP
LDHWVSSHGR LILIGDAAHP LSPAAGQGAS QGIEDANVLA TSLSLAGRQR VSLALHVAER
IRYARASAVQ LISHRVNEGW RNQDWDAYEP NEQNIASLPL ETWIYGHDSQ AYTEQEFEMV
VRAVQEGEEY HATNLPDKLR VQLGIRNVDV KEPLQNKSP
