NOTC_ASPSM
ID NOTC_ASPSM Reviewed; 426 AA.
AC E0Y3X0;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 02-NOV-2010, sequence version 1.
DT 03-AUG-2022, entry version 33.
DE RecName: Full=6-Hydroxy-7-prenyldeoxybrevianamide E synthase notC {ECO:0000303|PubMed:20722388};
DE EC=2.5.1.- {ECO:0000269|PubMed:20722388};
DE AltName: Full=Notoamide biosynthesis cluster protein C {ECO:0000303|PubMed:20722388};
DE AltName: Full=Prenyltransferase notC {ECO:0000303|PubMed:20722388};
GN Name=notC {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], FUNCTION, CATALYTIC ACTIVITY,
RP BIOPHYSICOCHEMICAL PROPERTIES, ACTIVITY REGULATION, AND PATHWAY.
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: 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: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 -!- 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:0000269|PubMed:20722388};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:62345;
CC Evidence={ECO:0000269|PubMed:20722388};
CC -!- ACTIVITY REGULATION: Addition of 5 mM Mg(2+), Ca(2+) or Mn(2+) slightly
CC enhances catalysis (about 100-120%) (PubMed:20722388). Significant
CC reduction of enzyme activity (2%-35%) is observed with Cu(2+), Zn(2+),
CC Fe(2+), or Sn(2+) (5 mM) (PubMed:20722388).
CC {ECO:0000269|PubMed:20722388}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=2.64 uM for 6-hydroxy-deoxybrevianamide E
CC {ECO:0000269|PubMed:20722388};
CC KM=1.89 uM for dimethylallyl diphosphate (DMAPP)
CC {ECO:0000269|PubMed:20722388};
CC Vmax=1.18 uM/min/mg enzyme toward dimethylallyl diphosphate (DMAPP)
CC {ECO:0000269|PubMed:20722388};
CC Vmax=1.45 uM/min/mg enzyme toward 6-hydroxy-deoxybrevianamide E
CC {ECO:0000269|PubMed:20722388};
CC pH dependence:
CC Optimum pH is 6-9. {ECO:0000269|PubMed:20722388};
CC Temperature dependence:
CC Optimum temperature is 16 to 42 degrees Celsius.
CC {ECO:0000269|PubMed:20722388};
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000269|PubMed:20722388}.
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; GU564534; ADM34131.1; -; Genomic_DNA.
DR EMBL; HM622670; ADM34136.1; -; Genomic_DNA.
DR AlphaFoldDB; E0Y3X0; -.
DR SMR; E0Y3X0; -.
DR BioCyc; MetaCyc:MON-19051; -.
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 notC"
FT /id="PRO_0000448809"
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; 49102 MW; E876B32D1957A3CD CRC64;
MAIEEKSTSA EPGPYDALSR FSSLTGEDDR KWWEHTGPVL EKVMRDSGYE LQSQYIYLYF
VQQHLIPYLG KFPTRGQDDH RWQSNLTPYK VPYELSWNVS HKVVRISWDP VCDASGTEND
AFNKKAIHDC TRQLAELDST VILDRYRLLH KDLVITDEEE QQLLRRDVLP KSGRGQHNLA
VDFQEGGITL KVYFYPYMKF LATGTPIEEL FFSAIEKLRI ADIDEAVGML KCFLSPKSDD
GKPSVDEKVF PSLLACDLCD PSKSRIKYYV IDKWVKWERI ANLWTIGGRR LEDPYCAKGL
ALLKELWDLL AIPEGDRGDI WPNLVLGQPP THLMTTIANY TLSPASRFPE PQVYLTTFGL
NDMAIIDALT AFYERVGFTD MAKSYKKNVQ SYYPNLDLNQ TNWVHEAVSF SYRNSKPYLS
VYYSPF
