ID   FLVI_ASPFN              Reviewed;        1071 AA.
AC   B8NHE4;
DT   23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT   03-MAR-2009, sequence version 1.
DT   03-AUG-2022, entry version 74.
DE   RecName: Full=Nonribosomal peptide synthetase flvI {ECO:0000303|PubMed:31885262};
DE            EC=6.2.1.- {ECO:0000269|PubMed:31885262};
DE   AltName: Full=Flavunoidine biosynthesis cluster protein I {ECO:0000303|PubMed:31885262};
GN   Name=flvI {ECO:0000303|PubMed:31885262};
GN   ORFNames=AFLA_135490, G4B84_005468;
OS   Aspergillus flavus (strain ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357
OS   / JCM 12722 / SRRC 167).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC   Aspergillus subgen. Circumdati.
OX   NCBI_TaxID=332952;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357 / JCM 12722 / SRRC
RC   167;
RX   PubMed=25883274; DOI=10.1128/genomea.00168-15;
RA   Nierman W.C., Yu J., Fedorova-Abrams N.D., Losada L., Cleveland T.E.,
RA   Bhatnagar D., Bennett J.W., Dean R., Payne G.A.;
RT   "Genome sequence of Aspergillus flavus NRRL 3357, a strain that causes
RT   aflatoxin contamination of food and feed.";
RL   Genome Announc. 3:E0016815-E0016815(2015).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=ATCC 200026 / FGSC A1120 / IAM 13836 / NRRL 3357 / JCM 12722 / SRRC
RC   167;
RA   Fountain J.C., Clevenger J.P., Nadon B., Youngblood R.C., Korani W.,
RA   Chang P.-K., Starr D., Wang H., Isett B., Johnston H.R., Wiggins R.,
RA   Chu Y., Agarwal G., Kemerait R.C., Pandey M.K., Bhatnagar D.,
RA   Ozias-Akins P., Varshney R.K., Scheffler B.E., Vaughn J.N., Guo B.;
RT   "Two new chromosome-level Aspergillus flavus reference genomes reveal a
RT   large insertion potentially contributing to isolate stress tolerance and
RT   aflatoxin production.";
RL   Submitted (JUL-2020) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   FUNCTION, DOMAIN, CATALYTIC ACTIVITY, AND PATHWAY.
RX   PubMed=31885262; DOI=10.1021/jacs.9b13046;
RA   Yee D.A., Kakule T.B., Cheng W., Chen M., Chong C.T.Y., Hai Y., Hang L.F.,
RA   Hung Y.S., Liu N., Ohashi M., Okorafor I.C., Song Y., Tang M., Zhang Z.,
RA   Tang Y.;
RT   "Genome mining of alkaloidal terpenoids from a hybrid terpene and
RT   nonribosomal peptide biosynthetic pathway.";
RL   J. Am. Chem. Soc. 142:710-714(2020).
CC   -!- FUNCTION: Nonribosomal peptide synthetase; part of the gene cluster
CC       that mediates the biosynthesis of flavunoidine, an alkaloidal terpenoid
CC       with a tetracyclic cage-like core connected to dimethylcadaverine via a
CC       C-N bond and acylated with 5,5-dimethyl-L-pipecolate (PubMed:31885262).
CC       The tetracyclic core is synthesized by the terpene cyclase flvE and the
CC       cytochrome P450 monooxygenase flvD (PubMed:31885262). The terpene
CC       cyclase flvE catalyzes the cyclization of farnesyl pyrophosphate (FPP)
CC       to form (1R,4R,5S)-(+)-acoradiene and the cytochrome P450 monooxygenase
CC       flvD is then responsible for oxidative conversion of (1R,4R,5S)-(+)-
CC       acoradiene into the tetracyclic cage present in the final product
CC       flavunoidine (PubMed:31885262). The cytochrome monooxygenase flvC then
CC       hydroxylates the C-10 position (PubMed:31885262). The second terpene
CC       cyclase flvF is required for attachment of the C-7 axial
CC       dimethylcadaverine which is itself produced by the N-methyltransferase
CC       flvH and the decarboxylase flvG via methylation of L-lysine to give
CC       N,N-dimethyl-L-Lysine, and decarboxylation to afford
CC       dimethylcadaverine, respectively (PubMed:31885262). The NRPS flvI
CC       acylates the terpenoid core at the hydroxylated C-10 with
CC       dimethylpipecolate to yield final flavunoidine (PubMed:31885262). The
CC       bifunctional enzyme flvA and the dehydrogenase flvB are responsible for
CC       the synthesis of the dimethylpipecolate precursor (PubMed:31885262).
CC       The PLP-dependent lyase domain of flvA might use L-O-acetyl-homoserine
CC       and alpha-keto-isovalerate to form an intermediary ketone that can
CC       cyclize intramolecularly to yield an imine (PubMed:31885262). The imine
CC       can be reduced by flvB to yield the 6-carboxylated pipecolate
CC       (PubMed:31885262). The C-terminal alpha-KG-dependent oxygenase domain
CC       of flvA is then proposed to catalyze the decarboxylation to yield
CC       dimethylpipecolate (PubMed:31885262). {ECO:0000269|PubMed:31885262}.
CC   -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC       {ECO:0000269|PubMed:31885262}.
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. FlvI has a monomodular A-T-C architecture.
CC       {ECO:0000305|PubMed:31885262}.
CC   -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR   EMBL; EQ963478; EED50786.1; -; Genomic_DNA.
DR   EMBL; CP059868; QMW30133.1; -; Genomic_DNA.
DR   RefSeq; XP_002379562.1; XM_002379521.1.
DR   STRING; 5059.CADAFLAP00007427; -.
DR   EnsemblFungi; EED50786; EED50786; AFLA_135490.
DR   VEuPathDB; FungiDB:AFLA_135490; -.
DR   eggNOG; KOG1178; Eukaryota.
DR   HOGENOM; CLU_000022_60_3_1; -.
DR   OMA; ALPGWHL; -.
DR   UniPathway; UPA00213; -.
DR   Proteomes; UP000001875; Unassembled WGS sequence.
DR   GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR   GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR   Gene3D; 1.10.1200.10; -; 1.
DR   Gene3D; 3.30.300.30; -; 1.
DR   Gene3D; 3.30.559.10; -; 1.
DR   Gene3D; 3.40.50.12780; -; 1.
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; 1.
DR   Pfam; PF00668; Condensation; 1.
DR   Pfam; PF00550; PP-binding; 1.
DR   SUPFAM; SSF47336; SSF47336; 1.
DR   TIGRFAMs; TIGR01733; AA-adenyl-dom; 1.
DR   PROSITE; PS00455; AMP_BINDING; 1.
DR   PROSITE; PS50075; CARRIER; 1.
DR   PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE   1: Evidence at protein level;
KW   Ligase; Phosphopantetheine; Phosphoprotein.
FT   CHAIN           1..1071
FT                   /note="Nonribosomal peptide synthetase flvI"
FT                   /id="PRO_0000454485"
FT   DOMAIN          552..628
FT                   /note="Carrier"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   REGION          33..417
FT                   /note="Adenylation"
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:31885262"
FT   REGION          689..961
FT                   /note="Condensation"
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:31885262"
FT   MOD_RES         589
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ   SEQUENCE   1071 AA;  119868 MW;  AF96FD6B0DD7B91C CRC64;
     MAKDQSMSRT ASLCQEITVP KTIPVCIQDV FYRRVLEQHD APAVCAWDGE LTYGELDDKS
     SSLARILAQK GIHRGSFVPL CFDRSLWTAV AMLAVLKAGG VFCFLEPKYP LARLEHMCRH
     INAKMVLSGE SRSELARKLG EHLAVNEDLL ATSPSDQELV DVAPNQAAYV AFTSGSTGKP
     KGILVSHQAL VAGILYNDKP MYLNRTSRVL SFASFAFDVS FLEHFWALLV GGCMCIPSES
     DRENNLLEAI ENLQVNWAFL TPSVARVLNP TKLPSLRHLI MGGEPITQTD IDMWSPHVHL
     IGVYGPAECA GCTTIQSDYG KVESAANIGF PYAVTCWIVD ENNHNVLVPT GSIGELVVQG
     PSLSEGYVND PEQSAKSYIT NPLWLSGSKE AEQQLYKTGD LVRRLSDGSL HFISRKDTQV
     KINGQRIELG EVEHHTRAVL GGNREVIVEA VKAGRPSSSL VAFIVTDNIP QSSTELFLAP
     DAGFKDRINT TKSLLRERLP DYMVPETYIS INHLPSTVTG KADRKRLREQ FTLLTRAQIK
     AYFGLEDKVK VMPLTEIELK MQRLWAKVLN LDLHEIARDD DWVSLGGDSL GAMQLASLAR
     SEQFFLTVPE IFRHKTISML CQNIKTDVSE TIEEMKPFAL LCDHELESDR ILQTIADQCQ
     VSQNSIEDAY PITSLQLDAS IIPIQWGLNY TLRLEFKLPP TVDPAQLTLA WEMTVASNPV
     LRTRIVELTK DHYIQAVIRS KIPLENLDSS NMARYEPAVD VWGIGKPLVR VGLQANRFVM
     LIHHAIYDGQ SLPLVFRDIS NAYQGQKLAL IHFAPFVRWS KSLDAPKRQF WIDKFAGFDG
     RVFPPVLDPS LDPVESRELT GHLNIVHDAF TATNKIRVTL AIVISWHHGT NDVVFGGVFA
     RRSAPIPDII DSAVPTTAML PDRIKLDPDE TLRYNLERDQ DNILSLMLHE GIDDRDIEQL
     SPECEAVACK YGTLLAVQPD LATAYPEMFR ERDMQYYGPI CALNALMQCY LSPESATISL
     RLSESTMDGV YHWGRFLDEF EAVFHFIQKN PDVKLCYLRR QLDIPNPRSP A