NOTC_ASPVE
ID NOTC_ASPVE Reviewed; 426 AA.
AC L7WRX9;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 1.
DT 03-AUG-2022, entry version 27.
DE RecName: Full=6-Hydroxy-7-prenyldeoxybrevianamide E synthase notC' {ECO:0000250|UniProtKB:E0Y3X0};
DE EC=2.5.1.- {ECO:0000250|UniProtKB:E0Y3X0};
DE AltName: Full=Notoamide biosynthesis cluster protein C' {ECO:0000303|PubMed:23213353};
DE AltName: Full=Prenyltransferase notC {ECO:0000303|PubMed:23213353};
GN Name=notC' {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: Prenyltransferase; part of the gene cluster that mediates the
CC biosynthesis of notoamide, a fungal indole alkaloid that belongs to a
CC 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=6-hydroxydeoxybrevianamide E + dimethylallyl diphosphate =
CC diphosphate + notoamide S; Xref=Rhea:RHEA:62344, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:57623, ChEBI:CHEBI:145682, ChEBI:CHEBI:145683;
CC Evidence={ECO:0000250|UniProtKB:E0Y3X0};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62345;
CC Evidence={ECO:0000250|UniProtKB:E0Y3X0};
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000250|UniProtKB:E0Y3X0}.
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 tryptophan dimethylallyltransferase family.
CC {ECO:0000305}.
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DR EMBL; JQ708194; AGC83574.1; -; Genomic_DNA.
DR AlphaFoldDB; L7WRX9; -.
DR SMR; L7WRX9; -.
DR VEuPathDB; FungiDB:ASPVEDRAFT_187638; -.
DR GO; GO:0004659; F:prenyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0009820; P:alkaloid metabolic process; IEA:UniProtKB-KW.
DR GO; GO:0044249; P:cellular biosynthetic process; IEA:UniProt.
DR GO; GO:1901576; P:organic substance biosynthetic process; IEA:UniProt.
DR CDD; cd13929; PT-DMATS_CymD; 1.
DR InterPro; IPR033964; Aro_prenylTrfase.
DR InterPro; IPR017795; Aro_prenylTrfase_DMATS.
DR InterPro; IPR012148; DMATS-type_fun.
DR PANTHER; PTHR40627; PTHR40627; 1.
DR Pfam; PF11991; Trp_DMAT; 1.
DR PIRSF; PIRSF000509; Trp_DMAT; 1.
DR SFLD; SFLDS00036; Aromatic_Prenyltransferase; 1.
DR TIGRFAMs; TIGR03429; arom_pren_DMATS; 1.
PE 1: Evidence at protein level;
KW Alkaloid metabolism; Prenyltransferase; Transferase.
FT CHAIN 1..426
FT /note="6-Hydroxy-7-prenyldeoxybrevianamide E synthase
FT notC'"
FT /id="PRO_0000448810"
FT BINDING 94
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 105
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 191
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 193
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 195
FT /ligand="substrate"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 267
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 269
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 352
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 354
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 418
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 422
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
SQ SEQUENCE 426 AA; 48991 MW; FA1771FB01C2DE95 CRC64;
MAIEESPTYA EPGPYEALSR FSSLTREDHR KWWEHTGPVL EKVLKDSGYE LQSQYTYLYF
VQQHLVPYLG TFPTRGEDEH RWQSNLTPYK VPYELSWNIS NKVVRISWDP VCDASGTEAD
AFNKKAIHDC TRQIAQLSNT IVLDRYRILH QELVISDQEE QELLRRDDLP KSGRGQHNLA
VDFQNGGIAL KVYFYPYMKF LATGSPVEQL FFAAIEKIGT ADIQEPVKML RCFLSPSFDD
GKPSVDQKVF PSLLACDLCD PSKSRIKYYV IDKWVKWERI ASLWTIGGRR LEDPSCAKGL
ALLKELWDLL AIPEGDRGDI WPNLVLGQPP THLMTTMANY TLSPASRFPE PQVYLTTFGM
NDMAIMDALT AFYERAGLTD MAKSYKKNVQ SYYPNLDLSQ TNWVHEAISF SYRNSKPYLS
VYYSPF
