NOTA_ASPVE
ID NOTA_ASPVE Reviewed; 357 AA.
AC L7WRQ4;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 1.
DT 03-AUG-2022, entry version 20.
DE RecName: Full=NmrA-like family domain-containing oxidoreductase notA' {ECO:0000303|PubMed:23213353};
DE EC=1.-.-.- {ECO:0000305};
DE AltName: Full=Notoamide biosynthesis cluster protein A' {ECO:0000303|PubMed:23213353};
GN Name=notA' {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: NmrA-like family domain-containing oxidoreductase; part of
CC the gene cluster that mediates the biosynthesis of notoamide, a fungal
CC indole alkaloid that belongs to a family of natural products containing
CC a characteristic bicyclo[2.2.2]diazaoctane core (PubMed:23213353). The
CC first step of notoamide biosynthesis involves coupling of L-proline and
CC L-tryptophan by the bimodular NRPS notE', to produce cyclo-L-
CC tryptophan-L-proline called brevianamide F (Probable). The reverse
CC prenyltransferase notF' then acts as a deoxybrevianamide E synthase and
CC converts brevianamide F to deoxybrevianamide E via reverse prenylation
CC at C-2 of the indole ring leading to the bicyclo[2.2.2]diazaoctane core
CC (PubMed:22660767) (Probable). Deoxybrevianamide E is further
CC hydroxylated at C-6 of the indole ring, likely catalyzed by the
CC cytochrome P450 monooxygenase notG', to yield 6-hydroxy-
CC deoxybrevianamide E (Probable). 6-hydroxy-deoxybrevianamide E is a
CC specific substrate of the prenyltransferase notC' for normal
CC prenylation at C-7 to produce 6-hydroxy-7-prenyl-deoxybrevianamide,
CC also called notoamide S (Probable). As the proposed pivotal branching
CC point in notoamide biosynthesis, notoamide S can be diverted to
CC notoamide E through an oxidative pyran ring closure putatively
CC catalyzed by either notH' cytochrome P450 monooxygenase or the notD'
CC FAD-linked oxidoreductase (Probable). This step would be followed by an
CC indole 2,3-epoxidation-initiated pinacol-like rearrangement catalyzed
CC by the notB' FAD-dependent monooxygenase leading to the formation of
CC notoamide C and notoamide D (Probable). On the other hand notoamide S
CC is converted to notoamide T by notH' (or notD'), a bifunctional oxidase
CC that also functions as the intramolecular Diels-Alderase responsible
CC for generation of (-)-notoamide T (Probable). To generate antipodal
CC (+)-notoaminide T, notH (or notD) in Aspergillus strain MF297-2 is
CC expected to catalyze a Diels-Alder reaction leading to the opposite
CC stereochemistry (Probable). The remaining oxidoreductase notD' (or
CC notH') likely catalyzes the oxidative pyran ring formation to yield
CC (-)-stephacidin A (Probable). The FAD-dependent monooxygenase notI' is
CC highly similar to notB' and is predicted to catalyze a similar
CC conversion from (-)-stephacidin A to (+)-notoamide B via the 2,3-
CC epoxidation of (-)-stephacidin A followed by a pinacol-type
CC rearrangement (Probable). Finally, it remains unclear which enzyme
CC could be responsible for the final hydroxylation steps leading to
CC notoamide A and sclerotiamide (Probable). {ECO:0000269|PubMed:22660767,
CC ECO:0000269|PubMed:23213353, 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 NmrA-type oxidoreductase family.
CC {ECO:0000305}.
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DR EMBL; JQ708194; AGC83572.1; -; Genomic_DNA.
DR AlphaFoldDB; L7WRQ4; -.
DR SMR; L7WRQ4; -.
DR VEuPathDB; FungiDB:ASPVEDRAFT_29909; -.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0009820; P:alkaloid metabolic process; IEA:UniProtKB-KW.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR008030; NmrA-like.
DR Pfam; PF05368; NmrA; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
PE 1: Evidence at protein level;
KW Alkaloid metabolism; NADP; Oxidoreductase.
FT CHAIN 1..357
FT /note="NmrA-like family domain-containing oxidoreductase
FT notA'"
FT /id="PRO_0000448814"
FT BINDING 13..18
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 39..43
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 60..61
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 81..83
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 140
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
FT BINDING 164..167
FT /ligand="NADP(+)"
FT /ligand_id="ChEBI:CHEBI:58349"
FT /evidence="ECO:0000250|UniProtKB:Q9HBL8"
SQ SEQUENCE 357 AA; 39737 MW; 96A841481FCE9C9E CRC64;
MTNTNRRTIT VYGATGAQGG PVVRSLLKNN AFKVRAITRK PESEAAKALA DLGAEIVQGD
GWKKEQMVAA FSGSWAAFVN TNSDDPCFWD ANHPTEFDLG KIIIDGIIQA GTVKHLVYSS
FVDTSSFTNG QAIIEAADEK SKIERYAASS GHFDTVCPLY QGWYMDVFRG QEYAHALGGF
PYFEDEDKFR TLRLPRWGTH TDMPLPWISL EDDFGDIVHG IFLTPEDYNG RVVPTVSDIR
TYPEMIDAFQ SGMPSLFWFL VCRLTSVHAL ATGQKARYIP VTDWEAHFGD SHHGKESLAI
FKFGKFTNGK YFGDEPISTD ISATLKAKAA EAQGKDPSDR KLITLVEWFE KHVAPLL
