NOTF_ASPVE
ID NOTF_ASPVE Reviewed; 435 AA.
AC I4AY86; L7WRR0;
DT 29-OCT-2014, integrated into UniProtKB/Swiss-Prot.
DT 05-SEP-2012, sequence version 1.
DT 03-AUG-2022, entry version 35.
DE RecName: Full=Deoxybrevianamide E synthase;
DE EC=2.5.1.109 {ECO:0000269|PubMed:22660767};
DE AltName: Full=Brevianamide F reverse prenyltransferase {ECO:0000303|PubMed:22660767};
DE AltName: Full=Notoamide biosynthesis cluster protein A' {ECO:0000303|PubMed:23213353};
GN Name=brePT {ECO:0000303|PubMed:22660767};
GN Synonyms=notF' {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], SUBUNIT, PATHWAY, FUNCTION, CATALYTIC
RP ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RC STRAIN=NRRL 573;
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).
RN [2]
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 [3]
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).
CC -!- FUNCTION: Deoxybrevianamide E synthase; 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 Deoxybrevianamide E is further hydroxylated at C-6 of the indole ring,
CC likely catalyzed by the cytochrome P450 monooxygenase notG', to yield
CC 6-hydroxy-deoxybrevianamide E (Probable). 6-hydroxy-deoxybrevianamide E
CC is a 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 -!- CATALYTIC ACTIVITY:
CC Reaction=brevianamide F + dimethylallyl diphosphate = deoxybrevianamide
CC E + diphosphate; Xref=Rhea:RHEA:35943, ChEBI:CHEBI:33019,
CC ChEBI:CHEBI:57623, ChEBI:CHEBI:64530, ChEBI:CHEBI:72948;
CC EC=2.5.1.109; Evidence={ECO:0000269|PubMed:22660767};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35944;
CC Evidence={ECO:0000269|PubMed:22660767};
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=32 uM for brevianamide F {ECO:0000269|PubMed:22660767};
CC KM=98 uM for Dimethylallyl diphosphate (DMAPP)
CC {ECO:0000269|PubMed:22660767};
CC KM=32 uM for cyclo-L-Trp-L-Pro {ECO:0000269|PubMed:22660767};
CC KM=82 uM for cyclo-L-Trp-D-Pro {ECO:0000269|PubMed:22660767};
CC KM=709 uM for cyclo-D-Trp-D-Pro {ECO:0000269|PubMed:22660767};
CC KM=2906 uM for cyclo-D-Trp-L-Pro {ECO:0000269|PubMed:22660767};
CC KM=942 uM for cyclo-L-Trp-L-Ala {ECO:0000269|PubMed:22660767};
CC KM=793 uM for cyclo-L-Trp-D-Ala {ECO:0000269|PubMed:22660767};
CC KM=1318 uM for cyclo-D-Trp-D-Ala {ECO:0000269|PubMed:22660767};
CC KM=139 uM for cyclo-D-Trp-L-Ala {ECO:0000269|PubMed:22660767};
CC KM=1300 uM for cyclo-L-Trp-Gly {ECO:0000269|PubMed:22660767};
CC KM=106 uM for cyclo-L-Trp-L-Leu {ECO:0000269|PubMed:22660767};
CC KM=94 uM for cyclo-L-Trp-L-Phe {ECO:0000269|PubMed:22660767};
CC KM=2148 uM for cyclo-L-Trp-L-Tyr {ECO:0000269|PubMed:22660767};
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000269|PubMed:22660767}.
CC -!- SUBUNIT: Monomer. {ECO:0000269|PubMed:22660767}.
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; JQ013953; AFM09725.1; -; Genomic_DNA.
DR EMBL; JQ708194; AGC83577.1; -; Genomic_DNA.
DR AlphaFoldDB; I4AY86; -.
DR SMR; I4AY86; -.
DR KEGG; ag:AFM09725; -.
DR VEuPathDB; FungiDB:ASPVEDRAFT_133177; -.
DR BioCyc; MetaCyc:MON-19052; -.
DR BRENDA; 2.5.1.109; 542.
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..435
FT /note="Deoxybrevianamide E synthase"
FT /id="PRO_0000430694"
FT REGION 1..28
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT BINDING 96
FT /ligand="brevianamide F"
FT /ligand_id="ChEBI:CHEBI:64530"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 110
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 195
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 197
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 265
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
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 354
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 419
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT BINDING 423
FT /ligand="dimethylallyl diphosphate"
FT /ligand_id="ChEBI:CHEBI:57623"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT SITE 112
FT /note="Required for regioselectivity"
FT /evidence="ECO:0000250|UniProtKB:Q4WAW7"
FT VARIANT 7
FT /note="R -> S (in strain: NRRL 35600)"
FT /evidence="ECO:0000269|PubMed:23213353"
FT VARIANT 435
FT /note="D -> G (in strain: NRRL 35600)"
FT /evidence="ECO:0000269|PubMed:23213353"
SQ SEQUENCE 435 AA; 49567 MW; 83F02CCCC2845127 CRC64;
MTAPELRAPA GHPQEPPARS SPAQALSSYH HFPTSDQERW YQETGSLCSR FLEAGQYGLH
QQYQFMFFFM HHLIPALGPY PQKWRSTISR SGLPIEFSLN FQKGSHRLLR IGFEPVNFLS
GSSQDPFNRI PIADLLAQLA RLQLRGFDTQ CFQQLLTRFQ LSLDEVRQLP PDDQPLKSQG
AFGFDFNPDG AILVKGYVFP YLKAKAAGVP VATLIAESVR AIDADRNQFM HAFSLINDYM
QESTGYNEYT FLSCDLVEMS RQRVKIYGAH TEVTWAKIAE MWTLGGRLIE EPEIMEGLAR
LKQIWSLLQI GEGSRAFKGG FDYGKASATD QIPSPIIWNY EISPGSSFPV PKFYLPVHGE
NDLRVARSLA QFWDSLGWSE HACAYPDMLQ QLYPDLDVSR TSRLQSWISY SYTAKKGVYM
SVYFHSQSTY LWEED
