NOTI_ASPVE
ID NOTI_ASPVE Reviewed; 433 AA.
AC L7WR46;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 1.
DT 03-AUG-2022, entry version 24.
DE RecName: Full=FAD-dependent monooxygenase notI' {ECO:0000303|PubMed:23213353};
DE EC=1.-.-.- {ECO:0000305|PubMed:23213353};
DE AltName: Full=Notoamide biosynthesis cluster protein I' {ECO:0000303|PubMed:23213353};
GN Name=notI' {ECO:0000303|PubMed:23213353};
OS Aspergillus versicolor.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Nidulantes.
OX NCBI_TaxID=46472;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND PATHWAY.
RC STRAIN=NRRL 35600;
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 BIOTECHNOLOGY.
RX PubMed=17304611; DOI=10.1002/anie.200604381;
RA Kato H., Yoshida T., Tokue T., Nojiri Y., Hirota H., Ohta T.,
RA Williams R.M., Tsukamoto S.;
RT "Notoamides A-D: prenylated indole alkaloids isolated from a marine-derived
RT fungus, Aspergillus sp.";
RL Angew. Chem. Int. Ed. 46:2254-2256(2007).
RN [3]
RP FUNCTION.
RX PubMed=22660767; DOI=10.1007/s00253-012-4130-0;
RA Yin S., Yu X., Wang Q., Liu X.Q., Li S.M.;
RT "Identification of a brevianamide F reverse prenyltransferase BrePT from
RT Aspergillus versicolor with a broad substrate specificity towards
RT tryptophan-containing cyclic dipeptides.";
RL Appl. Microbiol. Biotechnol. 97:1649-1660(2013).
CC -!- FUNCTION: FAD-dependent monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of notoamide, a fungal indole alkaloid that
CC belongs to a family of natural products containing a characteristic
CC bicyclo[2.2.2]diazaoctane core (PubMed:23213353). The first step of
CC notoamide biosynthesis involves coupling of L-proline and L-tryptophan
CC by the bimodular NRPS notE', to produce cyclo-L-tryptophan-L-proline
CC called brevianamide F (Probable). The reverse prenyltransferase notF'
CC then acts as a deoxybrevianamide E synthase and converts brevianamide F
CC to deoxybrevianamide E via reverse prenylation at C-2 of the indole
CC ring leading to the bicyclo[2.2.2]diazaoctane core (PubMed:22660767)
CC (Probable). Deoxybrevianamide E is further hydroxylated at C-6 of the
CC indole ring, likely catalyzed by the cytochrome P450 monooxygenase
CC notG', to yield 6-hydroxy-deoxybrevianamide E (Probable). 6-hydroxy-
CC deoxybrevianamide E is a specific substrate of the prenyltransferase
CC notC' for normal prenylation at C-7 to produce 6-hydroxy-7-prenyl-
CC deoxybrevianamide, also called notoamide S (Probable). As the proposed
CC pivotal branching point in notoamide biosynthesis, notoamide S can be
CC diverted to notoamide E through an oxidative pyran ring closure
CC putatively catalyzed by either notH' cytochrome P450 monooxygenase or
CC the notD' FAD-linked oxidoreductase (Probable). This step would be
CC followed by an indole 2,3-epoxidation-initiated pinacol-like
CC rearrangement catalyzed by the notB' FAD-dependent monooxygenase
CC leading to the formation of notoamide C and notoamide D (Probable). On
CC the other hand notoamide S is converted to notoamide T by notH' (or
CC notD'), a bifunctional oxidase that also functions as the
CC intramolecular Diels-Alderase responsible for generation of (-)-
CC notoamide T (Probable). To generate antipodal (+)-notoaminide T, notH
CC (or notD) in Aspergillus strain MF297-2 is expected to catalyze a
CC Diels-Alder reaction leading to the opposite stereochemistry
CC (Probable). The remaining oxidoreductase notD' (or notH') likely
CC catalyzes the oxidative pyran ring formation to yield (-)-stephacidin A
CC (Probable). The FAD-dependent monooxygenase notI' is highly similar to
CC notB' and is predicted to catalyze a similar conversion from (-)-
CC stephacidin A to (+)-notoamide B via the 2,3-epoxidation of (-)-
CC stephacidin A followed by a pinacol-type rearrangement (Probable).
CC Finally, it remains unclear which enzyme could be responsible for the
CC final hydroxylation steps leading to notoamide A and sclerotiamide
CC (Probable). {ECO:0000269|PubMed:22660767, ECO:0000269|PubMed:23213353,
CC 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 -!- BIOTECHNOLOGY: Notoamides have been shown to exhibit antitumoral
CC activities (PubMed:17304611). Notoamides A-C show moderate cytotoxicity
CC against HeLa and L1210 cells with IC(50) values in the range of 22-52
CC mg/ml, but the IC(50) value of notoamide D is greater than 100 mg/ml
CC (PubMed:17304611). Moreover, notoamide C induces G2/M-cell cycle arrest
CC at a concentration of 6.3 mg/ml (PubMed:17304611).
CC {ECO:0000269|PubMed:17304611}.
CC -!- SIMILARITY: Belongs to the paxM FAD-dependent monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; JQ708194; AGC83580.1; -; Genomic_DNA.
DR AlphaFoldDB; L7WR46; -.
DR SMR; L7WR46; -.
DR VEuPathDB; FungiDB:ASPVEDRAFT_195793; -.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0009820; P:alkaloid metabolic process; 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; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW Alkaloid metabolism; FAD; Flavoprotein; Monooxygenase; Oxidoreductase.
FT CHAIN 1..433
FT /note="FAD-dependent monooxygenase notI'"
FT /id="PRO_0000448803"
FT BINDING 45..46
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 141
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 242..244
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 243..245
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 314
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 324..328
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
SQ SEQUENCE 433 AA; 47044 MW; 15844C48530C797E CRC64;
MAIDASGAAA PNSSGITVII VGLGPTGLAA AIECHRRGHK VICFERNPKS YRLGDLINVT
GNAARVLQGW GNGSVINDLQ AFQCNLDTLE VYDETGDLKL SAPYNANQAK DNYMLRRSRL
LDIFLQHLKN LDVDIHLGTE VTDYWETESS AGVTVGGKRI AADCVVVADG VHSKGRPQVS
AEPFDLPSTD GTAFRAFFHA SEIAQDPEAS WILQDAGEGD CFKTFYGKGL VMMLGTAENH
EYIFWSCGSK ENVLAQSSAV AQVLDLIGDW PVSKRLAPLI SKTPSDNCLD QTLFTRSPLN
KWVSRKGRMI VLGDAAHPFL PHAGQGANQG IEDAAVLALC LQIAGKDDVP LALRVTEKLR
YQRVAAIQKR GVEARDQSLS VDWENGGFTK KLTLYPAWLH DQDCIKQVYE EFDKAVAAVT
KGHECTFGGI PVD
