PENE_PENTH
ID PENE_PENTH Reviewed; 475 AA.
AC A0A1B2CTA8;
DT 25-MAY-2022, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2016, sequence version 1.
DT 03-AUG-2022, entry version 13.
DE RecName: Full=FAD-dependent monooxygenase penE {ECO:0000303|PubMed:25859931};
DE EC=1.-.-.- {ECO:0000269|PubMed:25859931, ECO:0000269|PubMed:28114276};
DE AltName: Full=Penigequinolones biosynthesis cluster protein E {ECO:0000303|PubMed:25859931};
GN Name=penE {ECO:0000303|PubMed:25859931};
OS Penicillium thymicola.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX NCBI_TaxID=293382;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE,
RP CATALYTIC ACTIVITY, AND PATHWAY.
RC STRAIN=IBT 5891 / CBS 111225;
RX PubMed=25859931; DOI=10.1021/jacs.5b03022;
RA Zou Y., Zhan Z., Li D., Tang M., Cacho R.A., Watanabe K., Tang Y.;
RT "Tandem prenyltransferases catalyze isoprenoid elongation and complexity
RT generation in biosynthesis of quinolone alkaloids.";
RL J. Am. Chem. Soc. 137:4980-4983(2015).
RN [2]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=28114276; DOI=10.1038/nchembio.2283;
RA Zou Y., Garcia-Borras M., Tang M.C., Hirayama Y., Li D.H., Li L.,
RA Watanabe K., Houk K.N., Tang Y.;
RT "Enzyme-catalyzed cationic epoxide rearrangements in quinolone alkaloid
RT biosynthesis.";
RL Nat. Chem. Biol. 13:325-332(2017).
CC -!- FUNCTION: FAD-dependent monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of penigequinolones, potent insecticidal
CC alkaloids that contain a highly modified 10-carbon prenyl group
CC (PubMed:25859931). The first stage is catalyzed by the nonribosomal
CC pepdide synthetase penN that condenses anthranilic acid and O-methyl-L-
CC tyrosine to produce 4'-methoxycyclopeptin (By similarity). 4'-
CC methoxycyclopeptin is then converted to 4'-methoxydehydrocyclopeptin by
CC the ketoglutarate-dependent dioxygenase penM through dehydrogenation to
CC form a double bond between C-alpha and C-beta of the O-methyltyrosine
CC side chain (By similarity). PenM also converts its first product
CC methoxydehydrocyclopeptin to 4'-methoxycyclopenin (By similarity). The
CC following conversion of 4'methoxycyclopenin into 4'-methoxyviridicatin
CC is catalyzed by the cyclopenase penL (By similarity). 4'-
CC methoxyviridicatin is the precursor of quinolone natural products, and
CC is further converted to quinolinone B (Probable). The prenyltransferase
CC penI then catalyzes the canonical Friedel-Crafts alkylation of
CC quinolinone B with dimethylallyl cation to yield dimethylallyl
CC quinolone, which is subjected to FAD-dependent dehydrogenation by the
CC FAD-linked oxidoreductase penH to yield conjugated aryl diene
CC (PubMed:25859931). The delta(3') double bond then serves as the site of
CC the second alkylation with DMAPP catalyzed by the prenyltransferase
CC penG to yield a carbenium ion intermediate, which can be attacked by
CC H(2)O to yield a styrenyl quinolone containing a C3'-hydroxyprenyl
CC chain, or undergo cyclization to yield yaequinolones J1 and J2
CC (PubMed:25859931). The conversion of the styrenyl quinolone into the
CC tetrahydrofuran-containing yaequinolone C is performed by the FAD-
CC dependent monooxygenase penE and involves epoxidation of the terminal
CC C7'-C8' olefin, followed by epoxide ring opening initiated by the C3'
CC hydroxyl group (PubMed:25859931). The predicted cysteine hydrolase penJ
CC acts as an epoxide hydrolase that enhances the rate of the 5-exo-tet
CC cyclization step, increasing the yield of yaequinolone C
CC (PubMed:25859931, PubMed:28114276). PenF catalyzes the cationic
CC rearrangement of the epoxide formed by penE (before ring opening to
CC produce yaequinolone C) into yaequinolone D (PubMed:28114276). Finally,
CC the short-chain dehydrogenase/reductase (SDR)-like reductase penD,
CC catalyzes both the dehydration of yaequinolone D and the reduction of
CC the resulting oxonium to yield penigequinolone (PubMed:28114276).
CC {ECO:0000250|UniProtKB:C8VJQ3, ECO:0000250|UniProtKB:Q5AR53,
CC ECO:0000250|UniProtKB:Q5AR54, ECO:0000269|PubMed:25859931,
CC ECO:0000269|PubMed:28114276, ECO:0000305|PubMed:25859931}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:25859931, ECO:0000269|PubMed:28114276}.
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000269|PubMed:25859931,
CC ECO:0000269|PubMed:28114276}.
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:25859931,
CC ECO:0000269|PubMed:28114276}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Leads to the disappearance of penigequinolone,
CC and the accumulation of the styrenyl quinolone precusor as well as the
CC minor metabolites yaequinolone J1 and J2.
CC {ECO:0000269|PubMed:25859931}.
CC -!- SIMILARITY: Belongs to the paxM FAD-dependent monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; KX528209; ANY57883.1; -; Genomic_DNA.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
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 FAD; Flavoprotein; Glycoprotein; Membrane; Monooxygenase; Oxidoreductase;
KW Transmembrane; Transmembrane helix.
FT CHAIN 1..475
FT /note="FAD-dependent monooxygenase penE"
FT /id="PRO_0000455358"
FT TRANSMEM 446..466
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 36..37
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 308
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 318..322
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT CARBOHYD 437
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 475 AA; 53122 MW; 2FD993B8CD2D8466 CRC64;
MEKPEFKVII VGGSIAGLTL AHCLAQANID HVVLEKRSAI APQEGAFIGI WPNGARVFEQ
LGIFGDMEKQ TVPFHRMHLR YPDGFSFSSS LPELVSERFG YPIITLDRQR VLEVLHERYP
FKSNIIVNKK VVEIQTLDHG ARVVTEDGAV YTGDLIVGAD GVHSSIRSEM WRLADAISPG
LITEHERKSL TVEYACVFGI SSPIPGLESG ELINSYSDGS CVITFHGEDG RVFWFMIEKL
QRKYVYPDNP RFSVDDAAGF CARLSSVPIW RDICVAHLWR NRISVSMTAL EEGLFQTWHF
GRVVLLGDSV HKMTPNIGQG ANTAVEDAAT LASLINGLLK SGSASHTSDS DINNLLRVFQ
SLRYDRVKRT YQQSCSGARL QTRDDFLKIL VGRYVFPYVG DYISHSMCKD ISGGHVIDFL
PLPKRSKAGW AKYSRSNRSR ATQLQWGSIW LSPVILCLFC MLFLWPWSSS LPISS
