ID   INPA_EMENI              Reviewed;        1480 AA.
AC   Q5B7I5; C8V546;
DT   23-MAY-2018, integrated into UniProtKB/Swiss-Prot.
DT   26-APR-2005, sequence version 1.
DT   03-AUG-2022, entry version 114.
DE   RecName: Full=Nonribosomal peptide synthase inpA {ECO:0000303|PubMed:20952652};
DE            EC=6.3.2.- {ECO:0000305|PubMed:18804170};
DE   AltName: Full=Fellutamide B biosynthesis cluster protein A {ECO:0000303|PubMed:27294372};
DE   AltName: Full=Inp cluster protein A {ECO:0000303|PubMed:20952652};
DE   AltName: Full=Interacting NRPS system protein inpA {ECO:0000303|PubMed:18804170};
GN   Name=inpA {ECO:0000303|PubMed:20952652}; ORFNames=ANIA_03495;
OS   Emericella nidulans (strain FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 /
OS   M139) (Aspergillus nidulans).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC   Aspergillus subgen. Nidulantes.
OX   NCBI_TaxID=227321;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC   STRAIN=FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139;
RX   PubMed=16372000; DOI=10.1038/nature04341;
RA   Galagan J.E., Calvo S.E., Cuomo C., Ma L.-J., Wortman J.R., Batzoglou S.,
RA   Lee S.-I., Bastuerkmen M., Spevak C.C., Clutterbuck J., Kapitonov V.,
RA   Jurka J., Scazzocchio C., Farman M.L., Butler J., Purcell S., Harris S.,
RA   Braus G.H., Draht O., Busch S., D'Enfert C., Bouchier C., Goldman G.H.,
RA   Bell-Pedersen D., Griffiths-Jones S., Doonan J.H., Yu J., Vienken K.,
RA   Pain A., Freitag M., Selker E.U., Archer D.B., Penalva M.A., Oakley B.R.,
RA   Momany M., Tanaka T., Kumagai T., Asai K., Machida M., Nierman W.C.,
RA   Denning D.W., Caddick M.X., Hynes M., Paoletti M., Fischer R., Miller B.L.,
RA   Dyer P.S., Sachs M.S., Osmani S.A., Birren B.W.;
RT   "Sequencing of Aspergillus nidulans and comparative analysis with A.
RT   fumigatus and A. oryzae.";
RL   Nature 438:1105-1115(2005).
RN   [2]
RP   GENOME REANNOTATION.
RC   STRAIN=FGSC A4 / ATCC 38163 / CBS 112.46 / NRRL 194 / M139;
RX   PubMed=19146970; DOI=10.1016/j.fgb.2008.12.003;
RA   Wortman J.R., Gilsenan J.M., Joardar V., Deegan J., Clutterbuck J.,
RA   Andersen M.R., Archer D., Bencina M., Braus G., Coutinho P., von Dohren H.,
RA   Doonan J., Driessen A.J., Durek P., Espeso E., Fekete E., Flipphi M.,
RA   Estrada C.G., Geysens S., Goldman G., de Groot P.W., Hansen K.,
RA   Harris S.D., Heinekamp T., Helmstaedt K., Henrissat B., Hofmann G.,
RA   Homan T., Horio T., Horiuchi H., James S., Jones M., Karaffa L.,
RA   Karanyi Z., Kato M., Keller N., Kelly D.E., Kiel J.A., Kim J.M.,
RA   van der Klei I.J., Klis F.M., Kovalchuk A., Krasevec N., Kubicek C.P.,
RA   Liu B., Maccabe A., Meyer V., Mirabito P., Miskei M., Mos M., Mullins J.,
RA   Nelson D.R., Nielsen J., Oakley B.R., Osmani S.A., Pakula T., Paszewski A.,
RA   Paulsen I., Pilsyk S., Pocsi I., Punt P.J., Ram A.F., Ren Q., Robellet X.,
RA   Robson G., Seiboth B., van Solingen P., Specht T., Sun J.,
RA   Taheri-Talesh N., Takeshita N., Ussery D., vanKuyk P.A., Visser H.,
RA   van de Vondervoort P.J., de Vries R.P., Walton J., Xiang X., Xiong Y.,
RA   Zeng A.P., Brandt B.W., Cornell M.J., van den Hondel C.A., Visser J.,
RA   Oliver S.G., Turner G.;
RT   "The 2008 update of the Aspergillus nidulans genome annotation: a community
RT   effort.";
RL   Fungal Genet. Biol. 46:S2-13(2009).
RN   [3]
RP   IDENTIFICATION, AND FUNCTION.
RX   PubMed=18804170; DOI=10.1016/j.fgb.2008.08.008;
RA   von Doehren H.;
RT   "A survey of nonribosomal peptide synthetase (NRPS) genes in Aspergillus
RT   nidulans.";
RL   Fungal Genet. Biol. 46:S45-S52(2009).
RN   [4]
RP   INDUCTION.
RX   PubMed=20952652; DOI=10.1128/aem.00683-10;
RA   Bergmann S., Funk A.N., Scherlach K., Schroeckh V., Shelest E., Horn U.,
RA   Hertweck C., Brakhage A.A.;
RT   "Activation of a silent fungal polyketide biosynthesis pathway through
RT   regulatory cross talk with a cryptic nonribosomal peptide synthetase gene
RT   cluster.";
RL   Appl. Environ. Microbiol. 76:8143-8149(2010).
RN   [5]
RP   FUNCTION, DISRUPTION PHENOTYPE, AND PATHWAY.
RX   PubMed=27294372; DOI=10.1021/acschembio.6b00213;
RA   Yeh H.H., Ahuja M., Chiang Y.M., Oakley C.E., Moore S., Yoon O.,
RA   Hajovsky H., Bok J.W., Keller N.P., Wang C.C., Oakley B.R.;
RT   "Resistance gene-guided genome mining: serial promoter exchanges in
RT   Aspergillus nidulans reveal the biosynthetic pathway for fellutamide B, a
RT   proteasome inhibitor.";
RL   ACS Chem. Biol. 11:2275-2284(2016).
CC   -!- FUNCTION: Nonribosomal peptide synthase; part of the inp gene cluster
CC       that mediates the biosynthesis of fellutamide B, a mycotoxin that acts
CC       as a proteasome inhibitor (PubMed:18804170, PubMed:20952652,
CC       PubMed:27294372). In the first step of fellutabmide B biosynthesis,
CC       inpC activates 3-hydroxydodecanoic acid to generate 3-
CC       hydroxydodecanoyl-AMP that is then loaded onto the T0 domain of inpB
CC       (PubMed:27294372). The 3-hydroxydodecanoyl-S-phosphopantetheinyl-T0 is
CC       sequentially extended with L-Asn and L-Gln by the two CAT modules of
CC       inpB (PubMed:27294372). The linear lipodipeptide from inpB is then
CC       transferred onto inpA for the addition of the third amino acid, L-Leu
CC       (PubMed:27294372). Reductive releasing of the lipotripeptide by the TE
CC       domain of inpA produces (2S)-fellutamide B (PubMed:27294372). InpF
CC       might be involved in the release and transfer of the lipodipeptide from
CC       inpB to inpA (PubMed:27294372). The inp cluster-encoded proteasome
CC       subunit inpE confers resistance to internally produced fellutamides
CC       (PubMed:27294372). The MFS efflux transporter inpD may contribute to
CC       fellutamide resistance as well (PubMed:27294372).
CC       {ECO:0000269|PubMed:27294372, ECO:0000305|PubMed:18804170,
CC       ECO:0000305|PubMed:20952652}.
CC   -!- PATHWAY: Secondary metabolite biosynthesis.
CC       {ECO:0000269|PubMed:27294372}.
CC   -!- INDUCTION: Expression is positively regulated by the secondary
CC       metabolism cross-pathway regulator scpR (PubMed:20952652).
CC       {ECO:0000269|PubMed:20952652}.
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 (By similarity). Each module is responsible for the recognition
CC       (via the A domain) and incorporation of a single amino acid into the
CC       growing peptide product (By similarity). Thus, an NRP synthetase is
CC       generally composed of one or more modules and can terminate in a
CC       thioesterase domain (TE) that releases the newly synthesized peptide
CC       from the enzyme (By similarity). Occasionally, methyltransferase
CC       domains (responsible for amino acid methylation) are present within the
CC       NRP synthetase (By similarity). InpA has the following architecture: C-
CC       A-T-TE (PubMed:18804170). {ECO:0000250|UniProtKB:A0A144KPJ6,
CC       ECO:0000305|PubMed:18804170}.
CC   -!- DISRUPTION PHENOTYPE: Eliminates the production of fellutamides
CC       (PubMed:27294372). {ECO:0000269|PubMed:27294372}.
CC   -!- SIMILARITY: Belongs to the NRP synthetase family. {ECO:0000305}.
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DR   EMBL; BN001302; CBF76038.1; -; Genomic_DNA.
DR   RefSeq; XP_661099.1; XM_656007.1.
DR   AlphaFoldDB; Q5B7I5; -.
DR   SMR; Q5B7I5; -.
DR   STRING; 162425.CADANIAP00005262; -.
DR   EnsemblFungi; CBF76038; CBF76038; ANIA_03495.
DR   EnsemblFungi; EAA59056; EAA59056; AN3495.2.
DR   GeneID; 2872916; -.
DR   KEGG; ani:AN3495.2; -.
DR   eggNOG; KOG1178; Eukaryota.
DR   HOGENOM; CLU_000022_60_8_1; -.
DR   InParanoid; Q5B7I5; -.
DR   OMA; ADSWLFI; -.
DR   OrthoDB; 4243at2759; -.
DR   Proteomes; UP000000560; Chromosome II.
DR   GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR   GO; GO:0009058; P:biosynthetic process; IEA:UniProt.
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; IPR013120; Far_NAD-bd.
DR   InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR   InterPro; IPR009081; PP-bd_ACP.
DR   InterPro; IPR010080; Thioester_reductase-like_dom.
DR   Pfam; PF00501; AMP-binding; 1.
DR   Pfam; PF00668; Condensation; 1.
DR   Pfam; PF07993; NAD_binding_4; 1.
DR   SUPFAM; SSF47336; SSF47336; 1.
DR   SUPFAM; SSF51735; SSF51735; 1.
DR   TIGRFAMs; TIGR01733; AA-adenyl-dom; 1.
DR   TIGRFAMs; TIGR01746; Thioester-redct; 1.
DR   PROSITE; PS00455; AMP_BINDING; 1.
DR   PROSITE; PS50075; CARRIER; 1.
PE   2: Evidence at transcript level;
KW   Ligase; Phosphopantetheine; Phosphoprotein; Reference proteome.
FT   CHAIN           1..1480
FT                   /note="Nonribosomal peptide synthase inpA"
FT                   /id="PRO_0000444108"
FT   DOMAIN          1003..1082
FT                   /note="Carrier"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   REGION          1..24
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          44..458
FT                   /note="Condensation"
FT                   /evidence="ECO:0000255"
FT   REGION          479..871
FT                   /note="Adenylation"
FT                   /evidence="ECO:0000255"
FT   REGION          1117..1436
FT                   /note="Thioesterase (TE) domain"
FT                   /evidence="ECO:0000255"
FT   MOD_RES         1041
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ   SEQUENCE   1480 AA;  163417 MW;  91C8F603F06BF34C CRC64;
     MSHSMSSSSS SSSSSSSSRD EGQSRLNNVL SNIAKQCRTT SAQVQDVYPC TPLQQGLFAL
     SLTSPGAYMA QHVFRLQPFV DQGRMKQAWN VVLQKHAILR TRIVMLGENA MQVVLKQSPE
     WRNCSDLRAY LDADQSITLQ TGEPLTRWAI SDTHLVWSAH HSVYDGFSVE LILRDVATAY
     ADGEIPPRPS FRQFIQRMFQ QKQKSLTEAY WKKKTAHLDE VDTFPRLPAS TYRPRPNSVY
     KHESSLAIDG PSGVTLSTIA NAAWGLVQSS HLGSEQVSFG TTLSGRNANM PDIDKVVGPT
     LATVPVLLDV RSSQSVADFL QATQAYFTEL IPHQHIGLQN LRRLNRATEA VCNFQTLFAF
     QPGMTETQGQ SPYGHLLTAE NKDKVEAAFY SYALTFQCSL AGTGIIKVLA SYDDKIISSS
     QMKRLVFQFE HIVSQLISSN GSKRLSEIQL ISPQDLDQLD IWKRKMESYE QLLPLDAIQR
     HIDTRPDATA VAAWDGTLSY VELDAFATRL ATWLVHEQKV GPEIVIPICF DRSQWMIVSI
     FGVLKAGGAF LLLDPIYPEN RLRYMIKMVN ARTILVSESC RARFEGVPGA ILAVNAAWFE
     THTHASIPMR ELPVDRALYL VFTSGSTGQP KGVIVTHASY AASAAGHMPA LGMNENTRQL
     FFASPAFDLS IYEILGSLMC GGTVCVPTEE DRNGSVAPVI RDMNVNLISL TSSYARHLRP
     EDVPRLETLA LVGEPLARDV QRVWANRLTL INAYGPAECS VVSTVKRPVT LDSNPANIGT
     TVAGRAWVVH PKDHEILLPI GATGELLLEG DHLARGYLND EEKTAAAYIF GPYWAPSPTP
     RRFYKTGDLV HFDEDGSIVF EGRKDSQVKI RGQRVEIAEI EHHLARLFPN AAGAAVDVFK
     HEYHVHLVAF LFCDKESWNS SDTPADILQR LGDVNVSTMS HIKQQLEQVM PHHMVPTRYQ
     IWARMPTSLA GKLDRKALRK ELGNQSTTVI ELDETSTEFP VIDSTNKVAL RLNHKILDLA
     SEEKTTLDGR DFPLSILGLD SIQLITIVTF IRSEYGAKMT VETLYDLKLT VTGLAAMITS
     PHDRPAEAAP TLDLSKELQR VYRELTRRSE SIKHKRKVFL TGATGLLGSQ ILRQLLADPS
     VQRVIVHVRA NDAAKGMARV VSAATLAKWW SSSYANRVEC WPGDLGMPQL GLQPEQWRML
     CGTADAGAPI TSVIHNGAAV QWQAPYQALK AVNVDSTVEL LTAMAQWSEP GSFTFVSGGL
     KRSPGQDLES FMKSLEQANG YSQSKFVAEE LVSRFAGHQS THRVSIVRPG WVIGTEKDAV
     PNTDDFLWKL VQACIQIGAY PAEGGDLWLA VADAEEVATR ILATTFAASG ESPSVDNVEI
     GTTVSRFWEL IKVQTGMELT QMSAEDWKQA AQDFAASQES EQTFLPVLAM LQDPQMEFGV
     QRPANGGPPS NVNAAIRSNI KTLVETGFLS DSSEVVIVED