NOTB_ASPVE
ID NOTB_ASPVE Reviewed; 455 AA.
AC L7WME6;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 1.
DT 03-AUG-2022, entry version 28.
DE RecName: Full=Notoamide E oxidase notB' {ECO:0000250|UniProtKB:E1ACP7};
DE EC=1.14.13.- {ECO:0000250|UniProtKB:E1ACP7};
DE AltName: Full=FAD-dependent monooxygenase notB' {ECO:0000303|PubMed:23213353};
DE AltName: Full=Notoamide biosynthesis cluster protein B' {ECO:0000303|PubMed:23213353};
GN Name=notB' {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], AND FUNCTION.
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 -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + NADPH + notoamide E + O2 = H2O + NADP(+) + notoamide C;
CC Xref=Rhea:RHEA:62348, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:145684, ChEBI:CHEBI:145685;
CC Evidence={ECO:0000250|UniProtKB:E1ACP7};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62349;
CC Evidence={ECO:0000250|UniProtKB:E1ACP7};
CC -!- CATALYTIC ACTIVITY:
CC Reaction=H(+) + NADPH + notoamide E + O2 = H2O + NADP(+) + notoamide D;
CC Xref=Rhea:RHEA:62352, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:15379, ChEBI:CHEBI:57783, ChEBI:CHEBI:58349,
CC ChEBI:CHEBI:145684, ChEBI:CHEBI:145686;
CC Evidence={ECO:0000250|UniProtKB:E1ACP7};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62353;
CC Evidence={ECO:0000250|UniProtKB:E1ACP7};
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000250|UniProtKB:E1ACP7}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
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; AGC83573.1; -; Genomic_DNA.
DR AlphaFoldDB; L7WME6; -.
DR SMR; L7WME6; -.
DR VEuPathDB; FungiDB:ASPVEDRAFT_195793; -.
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: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; 2.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW Alkaloid metabolism; FAD; Flavoprotein; Glycoprotein; Membrane;
KW Monooxygenase; Oxidoreductase; Transmembrane; Transmembrane helix.
FT CHAIN 1..455
FT /note="Notoamide E oxidase notB'"
FT /id="PRO_0000448802"
FT TRANSMEM 11..31
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 48..49
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 145
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 235..237
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 246..248
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 324
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 334..338
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT CARBOHYD 75
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 455 AA; 49194 MW; D44EAE8F213C3555 CRC64;
MTKSQTNPRG PAILSPADLT VIIVGLGIAG LTAAIECHRK GYTVIGLEKK PDANQLGDII
GLSGNSMRIL AEWNNGSLAH LIDDDITCDV TALELFDAEG HRKLAMPYNA NNPIQGYLFR
RTGLLTSLCH YASQLGIDLR FGVTVDDYWE TDSNAGVYAN NEKITGDCVV AADGFHSKAR
GIITGENPEP KDIGVVAYRS IFDANAIADV PEAQWILKNA QTADIFHSYY GKDTMVAIGT
AARGRYVHWG CAVRGALEEK YEAWMQPAPP DPILKCLESW PVGSKLAAGI ARTPPGKCFQ
QSLRAMPPLK RWVSTGGRMI VIGDAAHSFL PYAGQGGNQA IEDAAVLGIC LELAGTSNVP
LALRVVEKLR HKRVSLIQKG SAEAGDSFLN AAWESDNAAE KPTAFTHQAW VYAHNCVDHA
YEQFNAAAEA VMNGWEYTPT NIPANGKFRQ EEGNI
