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LOLF2_EPIUN
ID   LOLF2_EPIUN             Reviewed;         540 AA.
AC   Q5MNH1;
DT   23-MAY-2018, integrated into UniProtKB/Swiss-Prot.
DT   01-FEB-2005, sequence version 1.
DT   03-AUG-2022, entry version 61.
DE   RecName: Full=FAD-binding monooxygenase lolF2 {ECO:0000303|PubMed:15654104};
DE            EC=1.14.13.- {ECO:0000305|PubMed:15654104};
DE   AltName: Full=Loline biosynthesis cluster 2 protein F {ECO:0000303|PubMed:15654104};
GN   Name=lolF2 {ECO:0000303|PubMed:15654104};
GN   Synonyms=lolF {ECO:0000303|PubMed:15654104};
OS   Epichloe uncinata (Endophyte fungus) (Neotyphodium uncinatum).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC   Hypocreomycetidae; Hypocreales; Clavicipitaceae; Epichloe.
OX   NCBI_TaxID=5050;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], INDUCTION, AND FUNCTION.
RC   STRAIN=CBS 102646;
RX   PubMed=15654104; DOI=10.1534/genetics.104.035972;
RA   Spiering M.J., Moon C.D., Wilkinson H.H., Schardl C.L.;
RT   "Gene clusters for insecticidal loline alkaloids in the grass-endophytic
RT   fungus Neotyphodium uncinatum.";
RL   Genetics 169:1403-1414(2005).
RN   [2]
RP   FUNCTION.
RX   PubMed=15861432; DOI=10.1002/cbic.200400327;
RA   Blankenship J.D., Houseknecht J.B., Pal S., Bush L.P., Grossman R.B.,
RA   Schardl C.L.;
RT   "Biosynthetic precursors of fungal pyrrolizidines, the loline alkaloids.";
RL   ChemBioChem 6:1016-1022(2005).
RN   [3]
RP   FUNCTION.
RX   PubMed=16755627; DOI=10.1002/cbic.200600066;
RA   Faulkner J.R., Hussaini S.R., Blankenship J.D., Pal S., Branan B.M.,
RA   Grossman R.B., Schardl C.L.;
RT   "On the sequence of bond formation in loline alkaloid biosynthesis.";
RL   ChemBioChem 7:1078-1088(2006).
RN   [4]
RP   FUNCTION.
RC   STRAIN=CBS 102646;
RX   PubMed=18655839; DOI=10.1016/j.fgb.2008.07.001;
RA   Spiering M.J., Faulkner J.R., Zhang D.X., Machado C., Grossman R.B.,
RA   Schardl C.L.;
RT   "Role of the LolP cytochrome P450 monooxygenase in loline alkaloid
RT   biosynthesis.";
RL   Fungal Genet. Biol. 45:1307-1314(2008).
RN   [5]
RP   FUNCTION.
RX   PubMed=24374065; DOI=10.1016/j.phytochem.2013.11.015;
RA   Pan J., Bhardwaj M., Faulkner J.R., Nagabhyru P., Charlton N.D.,
RA   Higashi R.M., Miller A.F., Young C.A., Grossman R.B., Schardl C.L.;
RT   "Ether bridge formation in loline alkaloid biosynthesis.";
RL   Phytochemistry 98:60-68(2014).
RN   [6]
RP   FUNCTION, AND BIOTECHNOLOGY.
RX   PubMed=25531527; DOI=10.1371/journal.pone.0115590;
RA   Pan J., Bhardwaj M., Nagabhyru P., Grossman R.B., Schardl C.L.;
RT   "Enzymes from fungal and plant origin required for chemical diversification
RT   of insecticidal loline alkaloids in grass-Epichloe symbiota.";
RL   PLoS ONE 9:E115590-E115590(2014).
RN   [7]
RP   FUNCTION.
RX   PubMed=29537853; DOI=10.1021/acs.biochem.8b00157;
RA   Pan J., Bhardwaj M., Zhang B., Chang W.C., Schardl C.L., Krebs C.,
RA   Grossman R.B., Bollinger J.M. Jr.;
RT   "Installation of the ether bridge of lolines by the iron- and 2-
RT   oxoglutarate-dependent oxygenase, lolO: regio- and stereochemistry of
RT   sequential hydroxylation and oxacyclization reactions.";
RL   Biochemistry 57:2074-2083(2018).
CC   -!- FUNCTION: FAD-binding monooxygenase; part of the gene cluster that
CC       mediates the biosynthesis of loline alkaloids, potent insecticidal
CC       agents composed of a pyrrolizidine ring system and an uncommon ether
CC       bridge linking carbons 2 and 7 (PubMed:15654104). Lolines are
CC       structurally differentiated by the various modifications of the L-amino
CC       group and include norloline, loline, N-methylloline, N-acetylloline, N-
CC       acetylnorloline, and N-formylloline (PubMed:15861432, PubMed:25531527).
CC       The first committed step is the condensation of O-acetyl-L-homoserine
CC       (derived from L-aspartic acid) and L-proline, probably catalyzed by the
CC       gamma-type pyridoxal 5'-phosphate(PLP)-dependent enzyme lolC, to give
CC       the diamino diacid, NACPP (PubMed:15861432, PubMed:16755627). Ensuing
CC       cyclization, decarboxylation, and acetylation steps yield 1-exo-
CC       acetamidopyrrolizidine (AcAP)(PubMed:24374065). LolO is required for
CC       installation of the ether bridge upon the pathway intermediate, 1-exo-
CC       acetamidopyrrolizidine (AcAP) (PubMed:29537853). In sequential 2-
CC       oxoglutarate- and O(2)-consuming steps, lolO removes hydrogens from C2
CC       and C7 of AcAP to form both carbon-oxygen bonds in N-acetylnorloline
CC       (NANL), the precursor to all other lolines (PubMed:24374065,
CC       PubMed:29537853). The enzymes lolD, lolE, lolF and lolT have also been
CC       proposed to be involved in the ether-bridge installation
CC       (PubMed:15654104). Further processing of the exocyclic moiety of NANL
CC       by fungal N-acetamidase (LolN), methyltransferase (LolM), and
CC       cytochrome P450 (LolP) enzymes, with occasional involvement of a plant
CC       acetyltransferase, generates the other known lolines (PubMed:25531527,
CC       PubMed:18655839). LolN transforms NANL to norlonine which is
CC       monomethylated and dimethylated to respectively lonine and N-
CC       methyllonine (NML) by lolM (PubMed:25531527). LolP catalyzes
CC       hydroxylation of the methyl group in N-methylloline (NML) and further
CC       oxygenation to N-formylloline (NFL) (PubMed:18655839). A plant
CC       acetyltransferase is responsible for the acetylation of loline to form
CC       N-acetylloline (NAL) (PubMed:25531527). LolA might interact with
CC       aspartate kinase to prevent feedback inhibition of its activity by
CC       these end products and thereby promote production of l-homoserine from
CC       l-aspartate (PubMed:15654104). {ECO:0000269|PubMed:15654104,
CC       ECO:0000269|PubMed:15861432, ECO:0000269|PubMed:16755627,
CC       ECO:0000269|PubMed:18655839, ECO:0000269|PubMed:24374065,
CC       ECO:0000269|PubMed:25531527, ECO:0000269|PubMed:29537853}.
CC   -!- COFACTOR:
CC       Name=FAD; Xref=ChEBI:CHEBI:57692;
CC         Evidence={ECO:0000250|UniProtKB:H3JQW0};
CC       Note=Binds 1 FAD per subunit. {ECO:0000250|UniProtKB:H3JQW0};
CC   -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000305|PubMed:15654104}.
CC   -!- INDUCTION: Expression is induced in loline alkaloid-producing cultures
CC       as well as in planta (PubMed:15654104). {ECO:0000269|PubMed:15654104}.
CC   -!- BIOTECHNOLOGY: Loline alkaloids show broad-spectrum anti-insect
CC       activity, and different lolines may have different biological
CC       activities (PubMed:25531527). In vitro tests of NFL, NAL, NML, and
CC       semisynthetic loline derivatives with long carbon-chain acylations on
CC       the 1-amine have shown that many are effective against both fall
CC       armyworm larvae and European corn borer larvae, but the effects seem to
CC       differ depending on the modifications (PubMed:25531527). N-Formylloline
CC       reduces the weight gain of fall armyworms by deterring feeding, and
CC       does not significantly affect corn borers (PubMed:25531527). In
CC       contrast, NAL reduces the weight gain of corn borer larvae without
CC       changing larval feeding behavior, indicating that its effect is due to
CC       metabolic toxicity. N-formylloline, NAL, and NML are almost as potent
CC       as nicotine in insecticidal activity against green bugs
CC       (PubMed:25531527). {ECO:0000305|PubMed:25531527}.
CC   -!- SIMILARITY: Belongs to the FAD-binding monooxygenase family.
CC       {ECO:0000305}.
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DR   EMBL; AY724686; AAV68694.1; -; Genomic_DNA.
DR   AlphaFoldDB; Q5MNH1; -.
DR   SMR; Q5MNH1; -.
DR   GO; GO:0050660; F:flavin adenine dinucleotide binding; IEA:InterPro.
DR   GO; GO:0004499; F:N,N-dimethylaniline monooxygenase activity; IEA:InterPro.
DR   GO; GO:0050661; F:NADP binding; IEA:InterPro.
DR   GO; GO:0009820; P:alkaloid metabolic process; IEA:UniProtKB-KW.
DR   Gene3D; 3.50.50.60; -; 2.
DR   InterPro; IPR036188; FAD/NAD-bd_sf.
DR   InterPro; IPR020946; Flavin_mOase-like.
DR   Pfam; PF00743; FMO-like; 1.
DR   SUPFAM; SSF51905; SSF51905; 2.
PE   2: Evidence at transcript level;
KW   Alkaloid metabolism; FAD; Flavoprotein; Monooxygenase; NADP;
KW   Oxidoreductase.
FT   CHAIN           1..540
FT                   /note="FAD-binding monooxygenase lolF2"
FT                   /id="PRO_0000444360"
FT   BINDING         43..46
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:H3JQW0"
FT   BINDING         53..55
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:H3JQW0"
FT   BINDING         55..58
FT                   /ligand="FAD"
FT                   /ligand_id="ChEBI:CHEBI:57692"
FT                   /evidence="ECO:0000250|UniProtKB:H3JQW0"
FT   BINDING         182..188
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:H3JQW0"
FT   BINDING         205..206
FT                   /ligand="NADP(+)"
FT                   /ligand_id="ChEBI:CHEBI:58349"
FT                   /evidence="ECO:0000250|UniProtKB:H3JQW0"
FT   SITE            329
FT                   /note="Transition state stabilizer"
FT                   /evidence="ECO:0000250|UniProtKB:H3JQW0"
SQ   SEQUENCE   540 AA;  61573 MW;  CDACE3B1937223A4 CRC64;
     MTLTNLDAIV VGAGFSGILA VYRLRKLGFR VQGFERQERL GGVWRENAYP GAAVDSLFPF
     YQFYDAELLQ DWEWGEQFPT RAEMLRYFDH VDKRWEISAS FEFGVSVSAA RYSETTQRWT
     VTLEDGRRAE ARWFIPAVGF SSVLNIPRIP GMSRFRGAIY HTAKWPHDAV SMRGKRVAVI
     GTGPSGVQII QSVGKIAKAM TIFQQSPCLT LRKYGSPNQT ATALCMRPDD HREALRLGLQ
     TSNGFGYVPR DQDTLDVPIE ERNHFYQQRY LAGGWAFWMA GFRDLCQNIQ ANRDAYDFWA
     RRTRARIGDV TKRELLVPQI PSFAFGIKRP CLEEDLYEIM DQPHVKIIDI SNQQIELITE
     TSIRVHGQTV ECEAIIFATG FGDEASGLRS LHIRGRNGIR LEDAWSDGVE SHLGMAIHSF
     PNMFFLYGPQ CPTLLVNSPA VITVQVEWLC EIISKCQQAG ICQLEATSKS HCQWEKKMSL
     LWDKTLYHTH ARKSKKTAEA NKEEKTWVGG LILYRRELEN CLANNLEGFQ AWYVEETALL
 
 
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