ID   TPZA_ASPTN              Reviewed;        2515 AA.
AC   Q0CG34;
DT   02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT   17-OCT-2006, sequence version 1.
DT   25-MAY-2022, entry version 84.
DE   RecName: Full=Nonribosomal peptide synthetase tpzA {ECO:0000303|PubMed:32843555};
DE            EC=6.3.2.- {ECO:0000269|PubMed:32843555};
DE   AltName: Full=Terreazepine biosynthesis cluster protein A {ECO:0000303|PubMed:32843555};
GN   Name=tpzB {ECO:0000303|PubMed:32843555}; ORFNames=ATEG_07358;
OS   Aspergillus terreus (strain NIH 2624 / FGSC A1156).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC   Aspergillus subgen. Circumdati.
OX   NCBI_TaxID=341663;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=NIH 2624 / FGSC A1156;
RA   Birren B.W., Lander E.S., Galagan J.E., Nusbaum C., Devon K., Henn M.,
RA   Ma L.-J., Jaffe D.B., Butler J., Alvarez P., Gnerre S., Grabherr M.,
RA   Kleber M., Mauceli E.W., Brockman W., Rounsley S., Young S.K., LaButti K.,
RA   Pushparaj V., DeCaprio D., Crawford M., Koehrsen M., Engels R.,
RA   Montgomery P., Pearson M., Howarth C., Larson L., Luoma S., White J.,
RA   Alvarado L., Kodira C.D., Zeng Q., Oleary S., Yandava C., Denning D.W.,
RA   Nierman W.C., Milne T., Madden K.;
RT   "Annotation of the Aspergillus terreus NIH2624 genome.";
RL   Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN   [2]
RP   FUNCTION, DOMAIN, CATALYTIC ACTIVITY, AND PATHWAY.
RX   PubMed=32843555; DOI=10.1128/mbio.01691-20;
RA   Caesar L.K., Robey M.T., Swyers M., Islam M.N., Ye R., Vagadia P.P.,
RA   Schiltz G.E., Thomas P.M., Wu C.C., Kelleher N.L., Keller N.P., Bok J.W.;
RT   "Heterologous expression of the unusual terreazepine biosynthetic gene
RT   cluster reveals a promising approach for identifying new chemical
RT   scaffolds.";
RL   MBio 11:0-0(2020).
CC   -!- FUNCTION: Nonribosomal peptide synthetase; part of the gene cluster
CC       that mediates the biosynthesis of terreazepine, (PubMed:32843555). The
CC       first step of terreazepine biosynthesis is catalyzed by the indoleamine
CC       2,3-dioxygenase tpzB which produces N-formyl-kynurenine through the
CC       catabolism of tryptophan (PubMed:32843555). The two-module NRPS tpzA
CC       then utilizes anthranilate and kynurenine to assemble terreazepine
CC       (PubMed:32843555). The first adenylation domain of tpzA (A1) loads
CC       anthranilate onto the T1 domain, while A2 loads kynurenine, generated
CC       through spontaneous nonenzymatic deformylation of the tzpB-supplied N-
CC       formyl-kynurenine (PubMed:32843555). TpzA produces a 2:1 mixture of S-R
CC       enantiomers, which suggests that the A2 domain accepts both D- and L-
CC       kynurenine (PubMed:32843555). The peptide bond formation between the
CC       tethered amino acids is catalyzed by the first condensation domain (C1)
CC       between anthranilate's carbonyl carbon and kynurenine's aliphatic
CC       primary amine (PubMed:32843555). The second C domain (C2) catalyzes the
CC       final cyclization event between the aromatic amine of kynurenine and
CC       the tethered carbonyl carbon, yielding the final terreazepine product
CC       (PubMed:32843555). The T3 domain may facilitate the interaction with
CC       downstream tailoring enzymes (PubMed:32843555).
CC       {ECO:0000269|PubMed:32843555}.
CC   -!- PATHWAY: Secondary metabolite biosynthesis.
CC       {ECO:0000269|PubMed:32843555}.
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. TpzA has the
CC       following architecture: A1-T1-C1-A2-T2-C2-T3.
CC       {ECO:0000269|PubMed:32843555}.
CC   -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR   EMBL; CH476603; EAU32742.1; -; Genomic_DNA.
DR   RefSeq; XP_001210044.1; XM_001210044.1.
DR   AlphaFoldDB; Q0CG34; -.
DR   SMR; Q0CG34; -.
DR   STRING; 341663.Q0CG34; -.
DR   EnsemblFungi; EAU32742; EAU32742; ATEG_07358.
DR   GeneID; 4319033; -.
DR   VEuPathDB; FungiDB:ATEG_07358; -.
DR   eggNOG; KOG1178; Eukaryota.
DR   HOGENOM; CLU_000022_60_4_1; -.
DR   OMA; VDSICEI; -.
DR   OrthoDB; 4243at2759; -.
DR   Proteomes; UP000007963; Unassembled WGS sequence.
DR   GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
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; 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   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; Reference proteome; Repeat.
FT   CHAIN           1..2515
FT                   /note="Nonribosomal peptide synthetase tpzA"
FT                   /id="PRO_0000452965"
FT   DOMAIN          794..867
FT                   /note="Carrier 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT                   ECO:0000305|PubMed:32843555"
FT   DOMAIN          1900..1976
FT                   /note="Carrier 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT                   ECO:0000305|PubMed:32843555"
FT   DOMAIN          2436..2512
FT                   /note="Carrier 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT                   ECO:0000305|PubMed:32843555"
FT   REGION          246..648
FT                   /note="Adenylation 1"
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:32843555"
FT   REGION          924..1332
FT                   /note="Condensation 1"
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:32843555"
FT   REGION          1357..1758
FT                   /note="Adenylation 2"
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:32843555"
FT   REGION          2013..2431
FT                   /note="Condensation 2"
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:32843555"
FT   MOD_RES         828
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   MOD_RES         1937
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   MOD_RES         2473
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ   SEQUENCE   2515 AA;  278716 MW;  9F5974873FAC443D CRC64;
     MRLTIPPSSM EEPKGKLSEE ENVCLFPKLT QVGLPAPASV AIETVGLGLE ISRAMNERFS
     YDRLLELQVM LSTVWAIVIH RFVEANPVFF AMVIDDEVSA STESCRNLWK TLIDPTTSVG
     VLNDIKRWEI CPLAEHHQGS FNTGLFILSK NLETAQMLDV NLVAQPKGSE FTLELVYQPK
     HLSPFHAQHL MSAVSSAIHG VASAEPNRSL CDISLCTSSQ QKQILYWQNS RLKEGPSLAM
     YQIVAELATR QPGAQAVQSS KSALTYLELD DLSSRLAIHL QARYNLAPGA MIMLCATKDV
     WAVVAMLAIN KTGACFVPCD ASHPVSRRQT MAGKCQSELA LVSPEHETLF QGIIKESFII
     SEATVTKLPQ ETRDSWTVGE RFPVAPSTPA YCFFTSGSLG EPKGCLGTHS ALAAVAHQVP
     ALRMDTKSRV LQFAKFGFGI SFIEIFCTLA AGGTVCIASE HERLNALDAA IRRMEVNWAL
     ITPTLAQSLS PEEIPTLRKL FLGGEAPNDD LISRWQSKAS LFQVFGTTEM AGVTMVSSEI
     TSTAQRKIVG FPANSRIWLV ESTGKDSNDT RLAPIGAVAE LLIEGPSLAE GYLGDPVRTQ
     ASFLSLPSWL PDGYSGSTRL YKTGDLVRYN GDGSLSYIGR MGTQVKLRGQ RIELEEVECH
     LVRLLPGTHS FSEARLVIAL VVEPRGDAEK RTLAAFVLVP PKVNSPRSSD TGRLEFVKPD
     TPHLYEELED IRQRLQGTLP SFMVPQLLFV LTDVPRTVTG KIDRSGLQRQ INALPYDELR
     RISGRRVDMQ VPGSEVEHLI HAIVCEILAI RSDQVSMRDD FFHLGGNSMS AIKLAAAAKR
     RSLKLVVADI FKHSVLADMA TVALKTSNGV HAHTTIHGTT IHGAPTKTTL ERFKLLSEYS
     VTREDINEAV ATQCGISYSS LTVDAYPCSP LQEGMMSMTE KSATMYRAQV VCKLHSGIQI
     DRFQAAWEGV VENNDILRTR LISVSSKGMW QIVISEPFEW DRDASRAVSD SMGLGTRLVR
     AAIETSKDGA VFILTIHHVL CDLWTIRLLL DQLWSSYDSI TDGVAGPNYY RPFIEYVLER
     SRDPASASYW KARFSGLEAE AFPRLPQPDL SPSPDEKTTC HINLPPLVTG GITVATYLRL
     AWAMVVSHHT AVDDVVFGET LNGRSGRLQE QSDESLEKIV GPAIVTVPQR ILLDPERSVA
     ETLSLIQEQQ TQMISFEQVG LQHIRRLSPE ADCACMFQSH LVFQPAWKPP GQLFKSVEAG
     ASEVGGFSSY ALGLECGLSE DENEVDITAY FDSRVVSRAQ AARLLNHLEM VLQSLVQEPY
     QTIRSVPHIT PEDLDQIHAW NVTLPDGLKE CAHEAIRKQS QETPSAPAIR AWDGDLTYEE
     LEHYSNQIAV AIVDRGIRQG SLIPLLFEKS MWMTVAMIGV NKAGGAFVPM DSAQPLQRLR
     VIAELTECTV ILCSKSNTEL AKQISPNAII LPVPGCREGG SIMQDSGQGL VDLQCLPKVQ
     PHDLMYAVFT SGSTGTPKGV LIEHGSYCTA ARECSSAHEI DRQSRMLQFA SYSFDAFLAE
     SLNTLVVGGC VCVPSEKDRQ NGLAKAMREM QVTHAMLTPA ISRLFRHEDV PSLRSLILMG
     EAMRSADFDY WGSHIQLFNG YGPTECTIAL SCREYQAGVH VNDIGWPRAA AAWIIDPRNP
     NRLMPIGAVG ELVVEGPPVA RGYLKSPDQT SKAFISPPSW RPQTHQSHRM YRTGDLVSYT
     EDRSLRIVGR MNDQIKLRSQ RLERGEVESR LRQFWQPPGV EVAVDVIVPA GDADRVSLAA
     FIVQEGSEQN NSDKNADHGT DCRSLCRNPT AEFSRVATQV EAQLQQELPR FMVPSIFVPV
     SRMPHMPSGK IDRPRLKREL EASPWEELRR YLPSAAPSRL ATTNEERTLQ EIWAQVLHLP
     SSKVGIDDNF FHLGGDSVNG MQAVVQARAR NIPHTLEEIF RWKTIAAILS HLTGRKHQER
     PPRHHDSNLT KTNNHLESFR GTLARSRLPF EGVEDIYPCG PIQQNILLVH SRRPAFYHVA
     FTWEIHDATV DMVVRAVKQL IARHAIFRTR FLEPDIVDGS FLQIVLRQGQ QDIPIRSVSE
     GLIDFPGDFQ PTARCPSQFT IYHRDWSSVH VRLDITHALW DGGPATVVER ELGLASHSKP
     LPPDPPLYRD YISYVQSQDL AAGEAFWSSH IKDTSPCHFP SLRATRMYEP DVPQDLHFEL
     DQHAEVGPFC RRHNVTAPNM FCLAWGLVLR AVTSMDEVCF GNVVSGRDLP LTGALEMVGP
     LINLLPCRIN LREGTVIETL QRIYHDYAAC LSHQAFPIAN LPHSSGRSAL TLFNTQLSIR
     RATTASQPGE EAPKACLRAI QSWDPHECRI NVYVIMEESR TRVEMRYWKS AMSPAQAALI
     EKCFSAAVSQ ILAHGDQPLT ELGILPPEEQ KRVWEPSLSA AVVRLRELWA KVLDIPHHLI
     GGEDDFFRLG GNSVRALQVT GLAREAGMDL RVADVFTAST LHAMARRSLV VSQSG