ILIA_NEOS2
ID ILIA_NEOS2 Reviewed; 4036 AA.
AC P0DO30;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 02-JUN-2021, sequence version 1.
DT 03-AUG-2022, entry version 5.
DE RecName: Full=Hybrid PKS-NRPS synthetase iliA {ECO:0000303|PubMed:31216742};
DE Short=PKS-NRPS iliA {ECO:0000303|PubMed:31216742};
DE EC=2.3.1.- {ECO:0000269|PubMed:31216742};
DE EC=6.3.2.- {ECO:0000269|PubMed:31216742};
DE AltName: Full=Ilicicolin H biosynthesis cluster protein A {ECO:0000303|PubMed:31216742};
GN Name=iliA {ECO:0000303|PubMed:31216742};
OS Neonectria sp. (strain DH2).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Nectriaceae; Neonectria;
OC unclassified Neonectria.
OX NCBI_TaxID=1735992;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], FUNCTION, CATALYTIC
RP ACTIVITY, AND PATHWAY.
RX PubMed=31216742; DOI=10.3390/molecules24122267;
RA Lin X., Yuan S., Chen S., Chen B., Xu H., Liu L., Li H., Gao Z.;
RT "Heterologous expression of ilicicolin H biosynthetic gene cluster and
RT production of a new potent antifungal reagent, ilicicolin J.";
RL Molecules 24:0-0(2019).
CC -!- FUNCTION: Hybrid PKS-NRPS synthetase; part of the gene cluster that
CC mediates the biosynthesis of ilicicolin H, a 4-hydroxy-2-
CC pyridonealkaloid that has potent and broad antifungal activities by
CC inhibiting the mitochondrial respiration chain (PubMed:31216742). IliA
CC assembles the backbone of ilicicolin H (PubMed:31216742). The PKS
CC portion and trans-acting enoyl reductase iliB work together to
CC construct an octaketide, and two methyl groups are introduced by the MT
CC domain during the chain assembly (PubMed:31216742). The nascent chain
CC is then condensed with tyrosine, catalyzed by the C domain, and the
CC resulting PKS-NRPS hybrid is offloaded by the RED domain to form an
CC advanced tetramic acid intermediate (PubMed:31216742). The biosynthesis
CC of ilicicolin H starts with formation of the tetramic acid by the
CC hybrid PKS-NRPS synthetase iliA with the partnering trans-enoyl
CC reductase iliB since iliA lacks a designated enoylreductase (ER)
CC domain. The cytochrome P450 monooxygenase iliC then catalyzes the ring
CC expansion of the tetramate to the acyclic 2-pyridone. The pericyclase
CC iliD further converts the acyclic 2-pyridone into 8-epi-ilicicolin H.
CC 8-epi-ilicicolin H might then spontaneously convert to ilicicolin H,
CC since ilicicolin H is produced in the absence of the epimerase iliE, in
CC contrast to what was observed for the Talaromyces variabilis ilicolin H
CC biosynthetic pathway (PubMed:31216742) (Probable).
CC {ECO:0000269|PubMed:31216742, ECO:0000305|PubMed:31216742}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + 8 AH2 + ATP + 4 H(+) + holo-[ACP] + L-tyrosine +
CC 7 malonyl-CoA + 2 S-adenosyl-L-methionine = 8 A + AMP + 7 CO2 + 8 CoA
CC + diphosphate + 6 H2O + N-[(4E,6E,10S,12Z,14E)-6,10-dimethyl-3-
CC oxohexadeca-4,6,12,14-tetraenoyl]-L-tyrosyl-[ACP] + 2 S-adenosyl-L-
CC homocysteine; Xref=Rhea:RHEA:64544, Rhea:RHEA-COMP:9685, Rhea:RHEA-
CC COMP:16623, ChEBI:CHEBI:13193, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC ChEBI:CHEBI:16526, ChEBI:CHEBI:17499, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:57384, ChEBI:CHEBI:57856, ChEBI:CHEBI:58315,
CC ChEBI:CHEBI:59789, ChEBI:CHEBI:64479, ChEBI:CHEBI:155893,
CC ChEBI:CHEBI:456215; Evidence={ECO:0000269|PubMed:31216742};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64545;
CC Evidence={ECO:0000269|PubMed:31216742};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:31216742}.
CC -!- DOMAIN: IliA has the following domain architecture: KS-MAT-DH-MT-KR-
CC ACP-C-A-T-R. The PKS module (domains KS to ACP) is responsible for the
CC biosynthesis of the polyketide chain and catalyzes three Claisen
CC condensations, as well as beta-keto processing and methylation. The
CC downstream NRPS module contains the condensation (C), adenylation (A),
CC and thiolation (T) domains and catalyzes the formation of the L-
CC tyrosinyl-thioester and the amide linkage between L-tyrosinyl-thioester
CC and the tetraketide. The bimodular assembly line is terminated with a
CC putative reductase (R) domain that facilitates formation and release of
CC the tetramic acid product. {ECO:0000305|PubMed:31216742}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the NRP synthetase
CC family. {ECO:0000305}.
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DR SMR; P0DO30; -.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:UniProtKB-KW.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR GO; GO:0032259; P:methylation; IEA:UniProtKB-KW.
DR GO; GO:0044550; P:secondary metabolite biosynthetic process; IEA:UniProt.
DR Gene3D; 1.10.1200.10; -; 2.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.30.300.30; -; 1.
DR Gene3D; 3.30.559.10; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.12780; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR InterPro; IPR010071; AA_adenyl_domain.
DR InterPro; IPR001227; Ac_transferase_dom_sf.
DR InterPro; IPR036736; ACP-like_sf.
DR InterPro; IPR014043; Acyl_transferase.
DR InterPro; IPR016035; Acyl_Trfase/lysoPLipase.
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; IPR018201; Ketoacyl_synth_AS.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR InterPro; IPR013217; Methyltransf_12.
DR InterPro; IPR036291; NAD(P)-bd_dom_sf.
DR InterPro; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR013968; PKS_KR.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00501; AMP-binding; 1.
DR Pfam; PF00668; Condensation; 1.
DR Pfam; PF16197; KAsynt_C_assoc; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08659; KR; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF07993; NAD_binding_4; 1.
DR Pfam; PF00550; PP-binding; 2.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 2.
DR SUPFAM; SSF47336; SSF47336; 2.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR TIGRFAMs; TIGR01733; AA-adenyl-dom; 1.
DR PROSITE; PS00455; AMP_BINDING; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 2.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Ligase; Methyltransferase; Multifunctional enzyme; Oxidoreductase;
KW Phosphopantetheine; Phosphoprotein; Repeat; Transferase.
FT CHAIN 1..4036
FT /note="Hybrid PKS-NRPS synthetase iliA"
FT /id="PRO_0000453067"
FT DOMAIN 2425..2502
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 3596..3675
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 10..442
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31216742"
FT REGION 561..886
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31216742"
FT REGION 955..1262
FT /note="Dehydratase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31216742"
FT REGION 1402..1601
FT /note="Methyltransferase (MT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31216742"
FT REGION 2136..2277
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31216742"
FT REGION 2520..2583
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2597..2621
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2627..3054
FT /note="Condensation (C) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31216742"
FT REGION 3088..3485
FT /note="Adenylation (A) (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31216742"
FT REGION 3088..3485
FT /note="Reductase (RED) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:31216742"
FT COMPBIAS 2547..2583
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2601..2616
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 181
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2462
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3635
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 4036 AA; 438607 MW; 2B0DD39E8D029DB9 CRC64;
MSQQRYPEPI AVIGSACRFP GASSSPSKLW SLLQEPRDVL KKFDPDRLNL KRFHHTNGDT
HGATDVNNKS YLLEENTRLF DASFFGISPL EAAGMDPQQR LLLETVYESF EAAGVTLDQL
KGSLTSVHVG VMTNDYSFIQ LRDPETLSKY NATGTANSIM SNRISYVFDL KGPSETIDTA
CSSSLVALHH AAQGLLSGDC ETAVVAGVNL IFDPSPYITE SKLHMLSPDS QSRMWDKSAN
GYARGEGAAA LLLKPLSRAL RDGDHIEGIV RGTGVNSDGQ SSGITMPFAP AQSALIRQTY
LRAGLDPIKD RPQYFECHGT GTPAGDPVEA RAISESLLDG ETSSDNPLYV GSVKTVIGHL
EGCAGLAGVI RAILALKHRT IPPNLHFKEL NPAIAQYYGP LQITTKALPW PEVPAGTPAR
ASVNSFGFGG TNAHAIIESY DNGSASSSIQ AQDEQPEESS EGGLGPLIFS AASGSSLLRT
VQAYLEHLRE HPSVDLQDLS WLLQTRRTTH RVRTHFSGAS RDTVLENMAT FVTTHEKASS
ATIGYQPQLV NPSEAPGVLG IFTGQGAQWP AMGRELIQKS PLFRKTIEEC EAILNALPEG
DVPEWSLMQE LTADASSSRL SEAMISQPLC TAVQLGLVNL LTAAGISFDA VVGHSSGEIA
ATYASGIITT KGAMQIAYYR GFHAKLATGP DGERGGMLAA GLSFEKATQF CSRPEFQGRI
QVAASNAPQS VTLSGDINAI KEAKEQLDAD NIFARQLKVD TAYHSHHMQP CAGPYLQSLL
ACDIELQAPK PGSCVWNSSV RGDAELLKRD LSSLKGTYWV ANMVQTVLFS QAIESSIWHG
GPFDLAIEVG PHPALKGPVE QTLKAAYGSV PMYTGALKRN GSDVEAFSAA LGVTWAQLGP
SFVDFSSFRE AFYESQAPAP KVIKDLPTYS WDHEKDYWRE SRISRRYRTG KDVGHELLGR
RTPDDNDHEL RWRNVLKLSE MPWVRGHEVL DEVLLPGAAY VSIAVEAGKH LATSTGKSVR
LIDVENVDIL RPVVVPDNQE GVETLFTAHI LSSSPSEGVL RARFSYYICN DQSSGSMVHT
CSGDLVVHLG ADSESGDLLP PRDAVPPNLV NIDGERVYKM FEGIDLKYSG VFRSIADSKR
CLNYATATGV WPEGSLSNDY GVHPAMLDVA FQTLFIARAH PASRQITSAL LPSHIDRVRV
SPSVQILQPE GGGDIKAAFE SWVVGQTATS LTGDLNVYDA ETGKTFLQVE GLATNMVGEQ
DASHDQPIFS KTVWGRYDSV GLADPVRDAV KDAEATRLAE DIERVALFYI KRIVNQIGAD
ERAGFQWYHQ RMFGAFEKHL ATIKNDEHPV LPSNWLADEP SVLEDISNAH PDSIDLQLLH
AVGENLADVV RGDTQLLEVM QEDDMLDRFY MDNCASAPIN QSIADVLQQI TFKFPRCNIL
EIGAGTGGTT WSVLNSINNA YDSYTYTDIS SGFFPNAAEK FSDFSNKMAF KILDVEKDPT
TQGFVEESYD VIIAANVLHA TRSLETTLRN VRSLLKPGGF LVLMEVTGMQ SVRVTFILGG
LPGWWLGADD GRPLGPGVSV VDWDVLFDKT GFSGADTVMH DLEDDTKHCN SLIVTQAVDD
AFLRMREPLS FMAELPPLTE PLLVIGGKKL TTTKMMSEIQ KLLPRSWKRH VQTVGSIDEI
DTAKLIPRMD VICLQEADEP LFATPMTAKR IALLKSLLMS ARNMLWVTGA GKSHTPRTSI
FLGIARIVPS ELPQLNLQML GLESGASHSV AARNCVEAFL RLRATEEGNG SHMLWSQEPE
MEILADGQTM VPRVMPNKPL NELYNASRRA VTKTIDATDV PVRAVAGPGK MTLQAAELQD
ASAQRARVQV KYALHIPSVN GKQVYLVCGH RQGSESATPV MAISESNGTI VEVDLERLIT
IDEDGCTPGV LAATANHLLV RAIATLASGA RKVLLYQAEE SLAAMVATEI AAQGGEAHFA
SSSSDAPDSW IKIHVNSSKR ALSRVVPRDV QLYVDCSGYS QSAVSSVSSA SDTLRACVPA
DCVAQQLGGG LLQEAFQRMD AGGSTLFKDS YAKAKSSFSE NQEQILDCDL VKAADLAGAD
ASSLTRKRYV TDWQEKESLT LTIQPLDLQG IFKPDKTYFM VGMAGGLGLS ICQWMIRNGA
KHLVITSRNP KIDDSLLEDA RRANAKLHVM TMDVSKRDSV EKVVRLVQDT LPPIAGVCNA
AMVLSDKLFI DMDVDQLNNT LAAKVYGTEH LDSVFDDMPL DFFVLLSSVA TVIGNIGQAN
YHAANLFMTS LIAQRRARGL TGSVVHVGYI SDVGYVTRQD RDRQLDQHFR NVRLMPLSET
DVHHAFAEAI RGGKPGSVSG AHDIIMGLET FKEPLAPEKQ PLWLANPRFA HFMPPTMLQT
QQQHRGSGSA DNVRKQVEEA ETEDEAVAAV VKAFCSKLES ILQLQEDSVN IQRAIIDLGI
DSLVAVEIRT WFLKELGAEV AVVKILGGDT VIQVCTWATK KVMAINMKKK EAAQLDEAAA
EKTATAATPA PAPDAAPAPA APTKTASLTV PVENTSRTPE SNSASVSDAD DSESSGAVSK
LGTSISGSSY AKMEFGDADA RSESTGSSGM ADSDDSSNRP ETIREEIMSQ AQSRIWFLSK
HLEDPAAFNM TFHYRAQGPL SMARLRHALQ VTTHHHECLR MRFYPRLGDG QPMQGVMGSS
LYELEHIPDA NDSDVKNELA RFKTRVWDLE NGKTFGVTVL SHSAEEHDII YGYHHLVMDV
VGWHVFVHDL DKAYKMQSLD KSAGSYFDYT SLQLEQEKAG VLEEDLKYWQ AEFTTTPETL
PLLPMAHTIV RPAEPGNESH HEYQELTSGQ FTALKETCQR LRISPFHFHV AVMQVLLARY
ANTEDVCIGI VDANRNDARF AQTVGCFINM LPVRSHVSSH DSFANVARAA SKKALAAFAH
SAVPFDMILD KVKAPRSSAS TPLFQAAVNY RTGSVWELPL GDCQMKLAGA KDADNPYDIS
LGITDMGSGC MIEIHCQASL YTSEGCRTIL DSYVRLLESF AANPHLDITE CEIYDKSQVG
QALELGKGPE MEFGWPSTMS QRVLDMCSLH SDKSAVKDNT ITLSYSNLAS RVNAVADAIL
QAGCTAGSHV AVLCEPTVDA TVAMLAVLHV GAVYVPLDTS LPTARHAAMV QSSRPALLLS
HSATEGLVRD LGNELDSPIR QVRIDSISEE ARQEVPCAAE RGAPAVLLFT SGSTGTPKGI
FLSQANFVNH LALKIHVLGF GQECVLQQSS LGFDMSLIQT FCALANGGLL VIVPSEMRRD
PVELTGLLSR ERISLTIATP SEYLAWLRYG EASLTENTAW RHACMGGEQV SRQLKSELRR
VNLSGLRLTN CYGPTEITAA ATFQAIDLEE KQDEDERAKF AVGKALPNYS VCILDASGQP
QPAQHAGEIC IGGAGVALGY LNLADETARK FIADVTSTAD RRMYRTGDQG RLLSDGTLLC
LGRLDGDTQV KLRGLRIELQ EVESALLQAA DGLLSTAVVS QRGDVLVAHA TLSPGRDNAS
EEELTQVLGH LRLPQYFIPA AIIILAAMPT NSNGKLDRKA IGALSLPERG SNGTQEKMTI
REGEVRLLWE RVLPDTSTTG RLAPSSDFFL CGGNSLLMMK LQAAIRESIG VAISTRTLYQ
ASTLREMARR IDEHQTAEGD DTEREIDWAA ETTVPKALLR QIRELPAPVK SSKSDGIEVL
MTGATSFLGG HLLQALLRSP VVRKVHCVAV LADDQHQLPR DEKIECYTGS LLSSTLGLNA
DERDRLEQTV DVIIHAGSSG HCLNTYDSLR TPNLLSTHFL SSLALPRSIP LLLLSSNRVV
LLSGSTAPPP GSVAAFAPAT DGLEGYTASK WASESFLENL VAHMQQVSRS PLTVAVHRPC
VVVSEQAPNS DALNAILRYS VSMRCVPQLD NVEGYLDFGK VEKIVDEIAD SALQLAQAGS
QDQEIRFRHH SGGAKVPVRE FRAHMEDIYG GSFDEVDVTE WMRRAADAGI DPLITAYLEG
ILDSGSPMVF PYLGEE
