NOTE_ASPVE
ID NOTE_ASPVE Reviewed; 2225 AA.
AC L7WU80;
DT 11-DEC-2019, integrated into UniProtKB/Swiss-Prot.
DT 03-APR-2013, sequence version 1.
DT 25-MAY-2022, entry version 44.
DE RecName: Full=Nonribisomal peptide synthase notE' {ECO:0000303|PubMed:23213353};
DE Short=NRPS notE' {ECO:0000303|PubMed:23213353};
DE EC=6.3.1.- {ECO:0000305|PubMed:23213353};
DE AltName: Full=Notoamide biosynthesis cluster protein E' {ECO:0000303|PubMed:23213353};
GN Name=notE' {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], FUNCTION, DOMAIN, AND PATHWAY.
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: Nonribisomal peptide 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 (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=2 ATP + L-proline + L-tryptophan = 2 AMP + brevianamide F + 2
CC diphosphate + 2 H(+); Xref=Rhea:RHEA:35935, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:30616, ChEBI:CHEBI:33019, ChEBI:CHEBI:57912,
CC ChEBI:CHEBI:60039, ChEBI:CHEBI:64530, ChEBI:CHEBI:456215;
CC Evidence={ECO:0000305|PubMed:23213353};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:35936;
CC Evidence={ECO:0000305|PubMed:23213353};
CC -!- PATHWAY: Alkaloid biosynthesis. {ECO:0000305|PubMed:23213353}.
CC -!- DOMAIN: NRP synthetases are composed of discrete domains (adenylation
CC (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation
CC (C) domains) which when grouped together are referred to as a single
CC module. Each module is responsible for the recognition (via the A
CC domain) and incorporation of a single amino acid into the growing
CC peptide product. Thus, an NRP synthetase is generally composed of one
CC or more modules and can terminate in a thioesterase domain (TE) that
CC releases the newly synthesized peptide from the enzyme. Occasionally,
CC epimerase (E) domains (responsible for L- to D-amino acid conversion)
CC are present within the NRP synthetase (By similarity). NotE has the
CC following architecture: A1-T1-C1-A2-T2-C2. The presence of two intact
CC modules suggests that the two modules condense L-tryptophan and L-
CC phenylalanine together. The C-terminal condensation domain might be
CC responsible for cyclization of the dipeptide to form the
CC diketopiperazine structure (Probable). {ECO:0000250|UniProtKB:Q4WMJ7,
CC 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 NRP synthetase family. {ECO:0000305}.
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DR EMBL; JQ708194; AGC83576.1; -; Genomic_DNA.
DR AlphaFoldDB; L7WU80; -.
DR SMR; L7WU80; -.
DR VEuPathDB; FungiDB:ASPVEDRAFT_89486; -.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0009820; P:alkaloid metabolic process; IEA:UniProtKB-KW.
DR Gene3D; 1.10.1200.10; -; 2.
DR Gene3D; 3.30.300.30; -; 2.
DR Gene3D; 3.30.559.10; -; 2.
DR Gene3D; 3.40.50.12780; -; 2.
DR InterPro; IPR010071; AA_adenyl_domain.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR Pfam; PF00501; AMP-binding; 2.
DR Pfam; PF00668; Condensation; 2.
DR Pfam; PF00550; PP-binding; 2.
DR SUPFAM; SSF47336; SSF47336; 2.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 2.
DR PROSITE; PS00455; AMP_BINDING; 2.
DR PROSITE; PS50075; CARRIER; 2.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Alkaloid metabolism; Ligase; Phosphopantetheine; Phosphoprotein; Repeat.
FT CHAIN 1..2225
FT /note="Nonribisomal peptide synthase notE'"
FT /id="PRO_0000448812"
FT DOMAIN 614..690
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:23213353"
FT DOMAIN 1699..1775
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:23213353"
FT REGION 24..59
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 83..482
FT /note="Adenylation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:23213353"
FT REGION 730..1142
FT /note="Condensation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:23213353"
FT REGION 1164..1563
FT /note="Adenylation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:23213353"
FT REGION 1827..2138
FT /note="Condensation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:23213353"
FT MOD_RES 651
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1736
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2225 AA; 243280 MW; 680A2307547A292E CRC64;
MDSTQITESN RECSVLQGKL ATETVRESLS SSPSPLPSLA SPVSSGSEPP AFGETQPQSR
DSTLLFNAQV PEFWETCVHD VIQERCKEAP QSTAVAAWDG SFTYGELDDL SNRLASALTL
LGVKAETFVP ICMEKSRWAT VAVLGVMKAG GAFTLLDASY PLPRLKTICQ ELSSLVVLSS
TAQSERCTQL ANMIVVEHLC RAWHPVAHTT QSPATVCPSN ALYVSFTSGS TGRPKGVLIE
HRAYSSGARE HLKAFRIDQT SRVLQFSSYA FDVSIMETLS TLMAGGCLCV LGDAQRSDVC
LFAAAVDEFQ VSHALLTPSF ARTVPWENVR HLQTLVLGGE EMRVSDAAMC VERGVRLINA
YGTAECSVNA TARPGVQPGD NLSTIGHPTG AVAWLIDPDD PETPIGPGME GELLLEGPIV
GRGYLNNPAA TAAAFIGPPK WLQQLRKTDY QHQLYRTGDL AVQDSTGALM LLGRRDGQLK
IRGQRVEVAE IEQHIDRVLA AVKEVIVEKV TPECEQREIL MAFVQTGATS QAWTEGSPLF
LPPGPTSVQE FRTAQSQLRG QLPSYMVPTI FIGVAAVPRT ASGKMDRRLL RVTAGRLSRE
ELQAFTGSPV DSRSPTTATE LMLQRLYAEV LELPTTSISM EDSFVRLGGD SIMAVRLLGA
ARRAGLVLDI GDVLGTARLE EQAQRATPMT EGTACETYIP FSALGSRYMN REEVLRLAAE
QCGTSLSEIE DIYPCTPLQE GMLALASSQT WMYVGHIVFG LPEGVDVSRF KAAWQSTADT
TPILRTRIIE TPQGLLQVVL RGSLVWETYN EPPDACVADG GSQIGSPGAP LMRFALGDGD
HRDEFVLTVH HAVWDAWSMR LIHDAVERSF QGEQVKKQPF HPFIQHLQQV DGGMDEFWRT
ELANLEAVPF PALPSTHYRP SPTAMLRHTV EKIEICAPRS HTMASYIHLA WSLLVAHYTD
STEAVYGATM SGRNAPVEAI NELAGPTIAT VPVRVHVRPE DTISAALEQI QSCMVRMVPH
EQAGLLRIAK TSSDAARACA FQSHLNIQVV EPERRLFPVR RGIASTGMDL TRFSSYALNL
MLLLSPDNTS VIVNIAYDPQ VLSAWEVYRM IHQWEHILRQ VCREPTGSLQ ELDLASPLDQ
DLLRVWNAKT PAVDRRCLHD LVLAQAMQQP SRQAVSAWDG GFTYGELAHL SSNFARLLSL
FAVGRGSFVP ICMDKSRWAV VSILAVLQAG ATCVLLDPQY PRQRMKDIIT GLSVPVLVNA
PSTAPVTRGL SAIQLCVSAK FTEQLWTSNP SGSHFQAHVD PDDLAFVIFT SGSTGAPKGI
AMPHSTISSS IRHNSAAMRF DADTRTLHFS SYAFDVSIYE IFTTLASGGC VCVPSEFQRT
NELADFIQQW RVNWAFLTPS TAQSLHPSEV PGLATLVLGG EAVTPDHVEV WAPGRTLING
YGPAEATICA VGPLPEHGWV PGKIGHVVGG VGWVTVPSDP NRLAAIGAIG ELLLEGPFLA
RGYLNQHEAT AASFITPPPW RRKLLPGCDA DTTRLYRTGD LVRYQEDGSL RYIGRRDTQV
KVRGQRIDLG EIETQLHRSF PGAHDVVAET VQLPVLQDRT VLVAFIGRQE GLVMESALGE
EVVAAVDAGF QQAVSSAQAR LQDILPSYML PSVFLPLAHC PKTLTGKTDR RYLRQVVLGL
EPHELQRYRV ASRQKTRIPV SHGAELRLQS IWADLLHIPC DEIGAEDTFL LHGGDSVAAM
RMVALARRAD FTFRVTDVLN NCTLSDLARC TGEEQCLAAE TLPTVHDVES DDQVVASQTD
SDAIAVYPTT QAQSFLIQRY PWTHWRFAFH GEVSIDRLRT ACARLVAAHS ILRTLFVGGK
GQRDRQVVMK ALDIPLHTVT TNKSLEEYCQ SICDAEQQMD VVETVLPTRL TLVSDVLHTA
HIFVLRLSHA QYDGICVPKI FAGLESFYNR TETVAPTIFE RYLDQRQRFE GEGPHEFWRA
YLAGSSPPCT MPGKSTPPTT ADSGPVAPPS VISASQTVKF TAIPSQVTLA TVVKAAACLV
LARLTGRSDI TVGQTVNGRS LPLPWVNEVV GPCVNYIPFR ATLQQSMSTQ DYLVDMQRQH
NRCVPFDGAE LDTIVKNCTD WEPTAEFGFI LQHQNIDMDL SLTLDGNRCV SCASSGQLRP
SNEVWICSTP SPSGVDLDVV ASSHILTADA AKNLVDDIAD MIQTLLYNLE TPLRDAVELN
WSDGS
