NOTD_ASPSM
ID NOTD_ASPSM Reviewed; 620 AA.
AC E1ACP9;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2010, sequence version 1.
DT 25-MAY-2022, entry version 28.
DE RecName: Full=FAD-linked oxidoreductase notD {ECO:0000303|PubMed:20722388};
DE EC=1.-.-.- {ECO:0000305|PubMed:23213353};
DE AltName: Full=Notoamide biosynthesis cluster protein D {ECO:0000303|PubMed:20722388};
DE Flags: Precursor;
GN Name=notD {ECO:0000303|PubMed:20722388};
OS Aspergillus sp. (strain MF297-2).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX NCBI_TaxID=877550;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND FUNCTION.
RC STRAIN=MF297-2;
RX PubMed=20722388; DOI=10.1021/ja1049302;
RA Ding Y., de Wet J.R., Cavalcoli J., Li S., Greshock T.J., Miller K.A.,
RA Finefield J.M., Sunderhaus J.D., McAfoos T.J., Tsukamoto S., Williams R.M.,
RA Sherman D.H.;
RT "Genome-based characterization of two prenylation steps in the assembly of
RT the stephacidin and notoamide anticancer agents in a marine-derived
RT Aspergillus sp.";
RL J. Am. Chem. Soc. 132:12733-12740(2010).
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=22188465; DOI=10.1021/ja2093212;
RA Li S., Finefield J.M., Sunderhaus J.D., McAfoos T.J., Williams R.M.,
RA Sherman D.H.;
RT "Biochemical characterization of NotB as an FAD-dependent oxidase in the
RT biosynthesis of notoamide indole alkaloids.";
RL J. Am. Chem. Soc. 134:788-791(2012).
RN [4]
RP FUNCTION.
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).
CC -!- FUNCTION: FAD-linked oxidoreductase; 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:20722388). 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 (PubMed:20722388). The reverse prenyltransferase
CC notF then acts as a deoxybrevianamide E synthase and converts
CC brevianamide F to deoxybrevianamide E via reverse prenylation at C-2 of
CC the indole ring leading to the bicyclo[2.2.2]diazaoctane core
CC (PubMed:20722388). Deoxybrevianamide E is further hydroxylated at C-6
CC of the indole ring, likely catalyzed by the cytochrome P450
CC monooxygenase notG, to yield 6-hydroxy-deoxybrevianamide E (Probable).
CC 6-hydroxy-deoxybrevianamide E is a specific substrate of the
CC prenyltransferase notC for normal prenylation at C-7 to produce 6-
CC hydroxy-7-prenyl-deoxybrevianamide, also called notoamide S
CC (PubMed:20722388). As the proposed pivotal branching point in notoamide
CC biosynthesis, notoamide S can be diverted to notoamide E through an
CC oxidative pyran ring closure putatively catalyzed by either notH
CC cytochrome P450 monooxygenase or the notD FAD-linked oxidoreductase
CC (Probable). This step would be followed by an indole 2,3-epoxidation-
CC initiated pinacol-like rearrangement catalyzed by the notB FAD-
CC dependent monooxygenase leading to the formation of notoamide C and
CC notoamide D (PubMed:22188465). On the other hand notoamide S is
CC converted to notoamide T by notH (or notD), a bifunctional oxidase that
CC also functions as the intramolecular Diels-Alderase responsible for
CC generation of (+)-notoamide T (Probable). To generate antipodal (-)-
CC notoaminide T, notH' (or notD') in Aspergillus versicolor is expected
CC to catalyze a Diels-Alder reaction leading to the opposite
CC stereochemistry (Probable). The remaining oxidoreductase notD (or notH)
CC 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:20722388,
CC ECO:0000269|PubMed:22188465, ECO:0000305|PubMed:23213353}.
CC -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
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 oxygen-dependent FAD-linked oxidoreductase
CC family. {ECO:0000305}.
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DR EMBL; HM622670; ADM34137.1; -; Genomic_DNA.
DR AlphaFoldDB; E1ACP9; -.
DR SMR; E1ACP9; -.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0009820; P:alkaloid metabolic process; 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 Alkaloid metabolism; FAD; Flavoprotein; Glycoprotein; Oxidoreductase;
KW Signal.
FT SIGNAL 1..21
FT /evidence="ECO:0000255"
FT CHAIN 22..620
FT /note="FAD-linked oxidoreductase notD"
FT /id="PRO_5003143463"
FT DOMAIN 124..313
FT /note="FAD-binding PCMH-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00718"
FT CARBOHYD 50
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 86
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 109
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 403
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 620 AA; 67988 MW; 948215BB5978C959 CRC64;
MHYIRELLIV VFTSCPALSY AHSSLDGSRY CRCQPGEACW PSLADWQALN SSIQGNLVEV
RPIGHVCHEP TYNKAACERV SKLSSNGTWR ANQPGAQQEY AWEVSLSRNE SCYVGPDNPT
EPCSQGRIPR YSAMVETTEQ AQKAIMFARE RQLRLVIKNT GHDSGGRSSA VDSFQILTQR
LKDITFIPEF TPTLGLAEGT YKSKGPSVRI GAGVLTKELY AAADEHGYTV MGGECATVGI
AGGYIQGGGV STALTPMLGL AVDLVQEFEV ITAEGRHVIA NEFQNQDLFW ALRGGGGGTF
GLVTSVTMPV FGAMPAVISE LTFESQEPGE PFWRAVKEVI YATRDLSTGG NSGQYWIGRG
PTGSYFVRLT LFFIGEMDTG KMGGKVGSLL SALQDQEIGF HLNSTAYDRL SSFLAIPQGE
FVGGIAFHQE NILIPRGFYD SPEGPAELVN RLAEVKLNPG DMWVANALGG KVMANKDSVD
NAMHPGWRTA AVLLVGNRIF EPVLEAQRAV QERMTAVEGP LLHSLGPPGP VAIYLNEADA
DLENWQEWFW GEKYNRLRDI KRKWDPDDLF LVRHGVGSED WDEEGMCWIQ MSIEECPVRE
PSQCTCPSFG CPMRHVPGLL
