NANA_ASPNN
ID NANA_ASPNN Reviewed; 2486 AA.
AC A0A6G9KH54;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 12-AUG-2020, sequence version 1.
DT 25-MAY-2022, entry version 7.
DE RecName: Full=Nonribosomal peptide synthetase nanA {ECO:0000303|PubMed:32182055};
DE EC=6.3.2.- {ECO:0000269|PubMed:32182055};
DE AltName: Full=Nanangelenin A biosynthesis cluster protein A {ECO:0000303|PubMed:32182055};
GN Name=nanA {ECO:0000303|PubMed:32182055}; ORFNames=FE257_001452;
OS Aspergillus nanangensis.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus.
OX NCBI_TaxID=2582783;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, PATHWAY, DOMAIN, CATALYTIC
RP ACTIVITY, AND MUTAGENESIS OF HIS-2106 AND SER-2441.
RC STRAIN=CBS 146238 / FRR 6048 / MST FP2251;
RX PubMed=32182055; DOI=10.1021/jacs.0c01605;
RA Li H., Gilchrist C.L.M., Phan C.S., Lacey H.J., Vuong D., Moggach S.A.,
RA Lacey E., Piggott A.M., Chooi Y.H.;
RT "Biosynthesis of a new benzazepine alkaloid nanangelenin A from Aspergillus
RT nanangensis involves an unusual l-kynurenine-incorporating NRPS catalyzing
RT regioselective lactamization.";
RL J. Am. Chem. Soc. 142:7145-7152(2020).
CC -!- FUNCTION: Nonribosomal peptide synthetase; part of the gene cluster
CC that mediates the biosynthesis of the benzazepine alkaloid nanangelenin
CC A which contains an unprecedented 3,4-dihydro-1-benzazepine-2,5-dione-
CC N-prenyl-N-acetoxy-anthranilamide scaffold (PubMed:32182055). The first
CC step of nanangelenin biosynthesis is catalyzed by the indoleamine 2,3-
CC dioxygenase nanC which produces N-formyl-kynurenine through the
CC catabolism of tryptophan (PubMed:32182055). The two-module NRPS nanA
CC then utilizes anthranilate (Ant) and L-kynurenine (L-Kyn) to assemble
CC the dipeptide product nanangelenin B (PubMed:32182055). The first
CC adenylation domain of nanA (A1) loads anthranilate onto the T1 domain,
CC while A2 loads kynurenine, generated through spontaneous nonenzymatic
CC deformylation of the nanC-supplied N-formyl-kynurenine
CC (PubMed:32182055). The peptide bond formation between the tethered
CC amino acids is catalyzed by the first condensation domain (C1) between
CC anthranilate's carbonyl carbon and kynurenine's aliphatic primary amine
CC (PubMed:32182055). The second C domain (C2) catalyzes the final
CC cyclization event between the aromatic amine of kynurenine and the
CC tethered carbonyl carbon, yielding nanangelenin B (PubMed:32182055).
CC The terminal T3 domain enhances the catalytic efficiency of C2,
CC suggesting the T2-tethered Ant-L-Kyn is transferred to T3 prior to
CC cyclization by C2 (PubMed:32182055). Once released from nanA,
CC nanangelenin B is then prenylated by the prenyltransferase nanD to form
CC nanangelenin C (PubMed:32182055). Nanangelenin C is then N-hydroxylated
CC by the FAD-dependent monooxygenase nanF and further acetylated by the
CC acetyltransferase nanB to yield nanangelenin F (PubMed:32182055).
CC Finally, the N-methyltransferase nanE methylates the amide nitrogen of
CC 1-benzazepine to convert nanangelenin F into nanangelenin A
CC (PubMed:32182055). NanE is also able to methylate most of the
CC intermediates of the pathway such as nanangelenin B and nanangelenin C
CC to produce nanangelenin D and nanangelenin E, respectively
CC (PubMed:32182055). {ECO:0000269|PubMed:32182055}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:32182055}.
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. NanA has the
CC following architecture: A1-T1-C1-A2-T2-C2-T3.
CC {ECO:0000269|PubMed:32182055}.
CC -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR EMBL; MT024570; QIQ51365.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A6G9KH54; -.
DR SMR; A0A6G9KH54; -.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR Gene3D; 1.10.1200.10; -; 3.
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; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
DR InterPro; IPR020806; PKS_PP-bd.
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; 3.
DR SMART; SM00823; PKS_PP; 3.
DR SUPFAM; SSF47336; SSF47336; 3.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 1.
DR PROSITE; PS50075; CARRIER; 3.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 3.
PE 1: Evidence at protein level;
KW Ligase; Phosphopantetheine; Phosphoprotein.
FT CHAIN 1..2486
FT /note="Nonribosomal peptide synthetase nanA"
FT /id="PRO_0000452964"
FT DOMAIN 786..860
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:32182055"
FT DOMAIN 1872..1948
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:32182055"
FT DOMAIN 2404..2480
FT /note="Carrier 3"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:32182055"
FT REGION 231..637
FT /note="Adenylation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32182055"
FT REGION 902..1314
FT /note="Condensation 1"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32182055"
FT REGION 1339..1735
FT /note="Adenylation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32182055"
FT REGION 2404..2480
FT /note="Condensation 2"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32182055"
FT MOD_RES 820
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 1909
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 2441
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MUTAGEN 2106
FT /note="H->A: Impairs the cyclization of the Ant-L-Kyn
FT dipeptide."
FT /evidence="ECO:0000269|PubMed:32182055"
FT MUTAGEN 2441
FT /note="S->A: Strongly ddecreases the cyclization rate of
FT the Ant-L-Kyn dipeptide."
FT /evidence="ECO:0000269|PubMed:32182055"
SQ SEQUENCE 2486 AA; 277491 MW; A21F8EE7A67E151F CRC64;
MSLTTDEAGR KSICLFPAIV TNTKSANKPG MQKVALDPIL CRDLNDHDRF QNRGELQLLL
STAWTIVLHR FAEANPVHFA VVVDIKRKKL CESWSVEVRP RSLVSSLLDL ESWTISTLSR
PSYHTFNTAV FIRDEYLTES EMSDVNIVAH TNKSQITVNL VYRCRHLSAF HAENLMSSFS
CAMQSVLREP HQPLGKISLC SLAQQQQISR WQNQPLKEDS KTAMWHRLAE FSARQPLSPA
VQSTSGYLTY ADLDELSSRM AVCLQDKHRV KPGDMVLLCV QKTPWAIVAM LAINKTGGCF
VPCDPTHPVA RRQVMATRCQ ARLAVVSPGY EDLLARIVPE ISINPEPAMT EWRESFVPGD
DNRTHRPIFS PSAPAYCFFT SGSTGEPKGC IGSHSALAAL AHQVPALRMS TESRVLQFAK
FGFGISFIEI FCTLAAGGTV CILSDGERLD ALPDAMNQMR VNWALLTPTV TQSLVPEQIP
GLGMLFLGGE APDDGLILRW KDKVSLFQVF GTTEMAGVTL VSSRITSPAQ RKTVGFGANA
RVWLCDVSEE EENNAGNLSL APIGAVGELV IGGPSLGAGY LGDPQRTHAL FLELPTSVVA
GFSSNLQRVY KTGDLVRYNH DGSLSYIGRR GTQVKLRGQR LELEEVECHI IRLLAGTKTW
TGALRVIALV IDPSGQDQTQ VDRCTLAAFI LMPQASREPR TSSNGTLEFL KLREQDHRDL
DMVQEKLRDT LPPFMVPQIF LALVDVPRTA TGKVDRNRIQ RQINALPYQD LQHLAGRRVQ
MLRAQTDIEL KVHALICDVL QIQPEDVSML DDFFQLGGNS MTAITLVSAA KKQEALKLAV
ADVFKHPVLA DLARSAKETS KVSTVQIATQ RPFMMLDEES LDLNELKQTV VTQCNIGLSS
LEDAYPCTPL QEGMMALTEQ RRFSYRAKVQ CHLQPEIDLS QFRRAWERVV VRNEILRTRL
VSVSSQGVWQ VVLRGSFAWD DTESQADEAP MGLGAKLVRG VIISTRSKGT FFILTIHHAI
CDLWAIRLLL DQVWREYTNV HAGTGSAAPN RFSQFVRYVR RMRNDPASEA YWKGQFAGLD
SQVFPELPQP NFIPSPDDEI QHQISLPVRI SETSTLSNYI RLAWAMVISH YTATDDVVFG
EILNGRGAIM SEHGEDAVEH IVGPTLVSVP RRVELDYEMS VSEALSRIQE QRTEMIPFEQ
VGLQYIQRYS PETEVACMFQ SHIVVQSAWN PPGQIFQSVQ AGASITGGFA SYAIGLECRL
SMNESRLGLT ACFDSRVVSR PHMQRLLNHL HMVLESMIQD PYQRLKSVPR VSSQDLDRIY
TWNVGIPTNI CGNVHESIRA QARKTPLAPA IDAWDGKLNF NELEHHSNQA ALELQRRGLV
PGDFVPLLFE RSMWTPVAMI AVNKAGAAFV PMDTEQPLPR LQAMAKQVKC TVIVCSDSMR
SMACQVTPAA TVIPFSNVRS SGLRHCPLEL QQLPTVTAHG AMYAAFTSGS TGTPKGVVIE
HGSYCVAAQE YNKQTLIDRH SRVLQFASYS FDAHIGETIS TLMAGACVCI PSDQDRQNAL
AQAASSMQIT HAMLTPAVAR LIRREEMPSL RTLTLMGEAM RPSDYAYWAE KVRLFNGYGP
TECTVAISCR EYRPGDAVQD IGWPRAAGVW ITDPRDYHQL MPMGAVGELL LEGPPVARGY
LNNPEQTAKA FISRPRWRPD IGHAHRIYRT GDLVRYTEDK SLQYVGRIGD QMKIRGQRIE
RGEVESQLRR FWLPTGVEMA VDAVLAGDNR DRVCLVAFIE HNRKKVDGTD QGLCQSMLTS
PDGDFSLQVI RVETQLQQHL PRFMVPVIFV PIYRLPHMLS GKIDRPRLKR ELQAYTWEEL
RQFFPAAAPT RPPSTDQERA LQDVWAHVLQ VPASRIGVDD NFFHIGGDSV TGMQAVAQAR
TKHLDHSLAD IFRYKTIAEI LSHTSSASKT GADLANDIGG PVQLLGGRDA LEQLDVSKEE
IEDIYPCAPV QQGILLVQAR KPAFYHVAFS WEVTNSTVEK TGRAIEQIIA RHAIFRTCFL
QPGSNSSSFF QVVLRCRKQE IPIRALSDEI HQFPGDFQPS ARVSSRFSIY YNHGNTSIFV
RLDISHALWD GGPIMVVQRE LDLGSQGQLI RYPEPSLYRN YIAYIARQDQ EAAAGFWTTH
LKDMAACHFP SLLTSDLRGP DTPEDLNFEL RDYAAIRPYC RRINVTVPNF FCLVWAMVLR
CVTLKDQICF GNLVSGRDLP LDDVLNIAGP MINLLPCRID LSNGKVAEIL QQIYSDYAAS
LSHQTFPIAN LRSPCGRSPM AQFDTQLSIR RADSTNDTRN VHLCNIQSWD PHESRVNCYV
ILEDTRTQVN IRYWKSTMST EQAALVRTCF CSAVSQLLDG ENARVADLAL ISAVQRARIW
GFLSSSETIV EPLERIWAEV LNRAQTQIGG NDDFFRLGGD SILAVRMVSL ARKGGIDIRV
ADVFKFSTIY KLARLLQTQA QTAEGE
