PENH_PENTH
ID PENH_PENTH Reviewed; 574 AA.
AC A0A1B2CTB4;
DT 25-MAY-2022, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2016, sequence version 1.
DT 25-MAY-2022, entry version 15.
DE RecName: Full=FAD-linked oxidoreductase penH {ECO:0000303|PubMed:25859931};
DE EC=1.-.-.- {ECO:0000269|PubMed:25859931};
DE AltName: Full=Penigequinolones biosynthesis cluster protein H {ECO:0000303|PubMed:25859931};
DE Flags: Precursor;
GN Name=penH {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, CATALYTIC ACTIVITY, DISRUPTION
RP PHENOTYPE, 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.
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-linked oxidoreductase; 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}.
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000269|PubMed:25859931}.
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:25859931}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of penigequinolone and
CC accumulates the dimethylallyl quinolone intermediate.
CC {ECO:0000269|PubMed:25859931}.
CC -!- SIMILARITY: Belongs to the oxygen-dependent FAD-linked oxidoreductase
CC family. {ECO:0000305}.
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DR EMBL; KX528209; ANY57886.1; -; Genomic_DNA.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR Gene3D; 3.30.465.10; -; 2.
DR InterPro; IPR012951; BBE.
DR InterPro; IPR016166; FAD-bd_PCMH.
DR InterPro; IPR036318; FAD-bd_PCMH-like_sf.
DR InterPro; IPR016169; FAD-bd_PCMH_sub2.
DR InterPro; IPR006094; Oxid_FAD_bind_N.
DR Pfam; PF08031; BBE; 1.
DR Pfam; PF01565; FAD_binding_4; 1.
DR SUPFAM; SSF56176; SSF56176; 1.
DR PROSITE; PS51387; FAD_PCMH; 1.
PE 1: Evidence at protein level;
KW FAD; Flavoprotein; Glycoprotein; Oxidoreductase; Signal.
FT SIGNAL 1..25
FT /evidence="ECO:0000255"
FT CHAIN 26..574
FT /note="FAD-linked oxidoreductase penH"
FT /id="PRO_5008534508"
FT DOMAIN 121..305
FT /note="FAD-binding PCMH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT CARBOHYD 48
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 107
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 193
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 368
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 385
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 574 AA; 61916 MW; 1B20A213D5D4F5D2 CRC64;
MLPRALTLSA LLALLLAIYL ALAPARLSCR CRSWEQCWPS LEAWSHLNAS LNSHLVDLRP
IASVCHEPIL DQPACDIVRR MSNSGRWRTG QPGALINSFW ESGFGSNETC SLSSGQENLC
HQGRIPLYAA VVESTQEVQT AVKFAREHNL RLVIRNTGHD GAGSSSGPDS FQIFTHRLSD
ILYHENFRIT GSNTSVGPAV SIGAGVLFGD LYVHGGQKGF IVTGGDSATV GAAGGFTQGG
GVPGFLGHTW GLAADNVLEF EIVTATGNLV IANAGQHPDL FWALRGGGGG TFGVAVRVTM
RTYPDHPAVK STISITGDGQ SPSFWSEGIA GLLTVLQSLN RQGTAGVFRL WQTPAGLLGA
STEVYFLNQT EVKDASSVIK STLGNASDIY IISSNALDTL SSDVEADAPT INELFGSTLV
SNGLFQSESG PKLIAERMSQ IGLNDGEWIL TSNLGGQVND NKRANTPLHP AWQSSAQLVS
LVVNVDTAPG ARDRAMRRLT NELMPRLYAL DPSQRVSYRN MGDPNEPHFK EVYWGATNYD
RLVQIKRDWD PKDLFISRVG IGSERWDFEG FCKV
