ICCA_TALVA
ID ICCA_TALVA Reviewed; 4015 AA.
AC A0A482N9V7;
DT 26-FEB-2020, integrated into UniProtKB/Swiss-Prot.
DT 05-JUN-2019, sequence version 1.
DT 03-AUG-2022, entry version 16.
DE RecName: Full=Hybrid PKS-NRPS synthetase iccA {ECO:0000303|PubMed:30905148};
DE Short=PKS-NRPS iccA {ECO:0000303|PubMed:30905148};
DE EC=2.3.1.- {ECO:0000269|PubMed:30905148};
DE EC=6.3.2.- {ECO:0000269|PubMed:30905148};
DE AltName: Full=Ilicicolin H biosynthesis cluster protein A {ECO:0000303|PubMed:30905148};
GN Name=iccA {ECO:0000303|PubMed:30905148};
OS Talaromyces variabilis (Penicillium variabile).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Trichocomaceae; Talaromyces.
OX NCBI_TaxID=28576;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, CATALYTIC ACTIVITY, AND
RP PATHWAY.
RC STRAIN=HXQ-H-1;
RX PubMed=30905148; DOI=10.1021/jacs.9b02204;
RA Zhang Z., Jamieson C.S., Zhao Y.L., Li D., Ohashi M., Houk K.N., Tang Y.;
RT "Enzyme-catalyzed inverse-electron demand Diels-Alder reaction in the
RT biosynthesis of antifungal ilicicolin H.";
RL J. Am. Chem. Soc. 141:5659-5663(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:30905148). IccA
CC assembles the backbone of ilicicolin H (PubMed:30905148). The PKS
CC portion and trans-acting enoyl reductase iccB work together to
CC construct an octaketide, and two methyl groups are introduced by the MT
CC domain during the chain assembly (PubMed:30905148). 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:30905148). The biosynthesis
CC of ilicicolin H starts with formation of the tetramic acid by the
CC hybrid PKS-NRPS synthetase iccA with the partnering trans-enoyl
CC reductase iccB since iccA lacks a designated enoylreductase (ER)
CC domain. The cytochrome P450 monooxygenase iccC then catalyzes the ring
CC expansion of the tetramate to the acyclic 2-pyridone. The pericyclase
CC iccD further converts the acyclic 2-pyridone into 8-epi-ilicicolin H.
CC Finally, the epimerase iccE converts 8-epi-ilicicolin H into ilicicolin
CC H via epimerization. IccA to iccE are sufficient for ilicicolin H
CC biosynthesis and the roles of the remaining enzymes, iccF, iccG and
CC iccH within the pathway have still to be determined (PubMed:30905148)
CC (Probable). {ECO:0000269|PubMed:30905148, ECO:0000305|PubMed:30905148}.
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:30905148};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64545;
CC Evidence={ECO:0000269|PubMed:30905148};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:30905148}.
CC -!- DOMAIN: IccA 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:0000250|UniProtKB:Q5ATG8}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the NRP synthetase
CC family. {ECO:0000305}.
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DR EMBL; MK539848; QBQ83704.1; -; Genomic_DNA.
DR SMR; A0A482N9V7; -.
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..4015
FT /note="Hybrid PKS-NRPS synthetase iccA"
FT /id="PRO_0000448981"
FT DOMAIN 2409..2488
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 3572..3651
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..20
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 19..448
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATG8, ECO:0000255"
FT REGION 560..885
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATG8, ECO:0000255"
FT REGION 954..1260
FT /note="Dehydratase (DH) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATG8, ECO:0000255"
FT REGION 1400..1598
FT /note="Methyltransferase (MT) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATG8, ECO:0000255"
FT REGION 2120..2261
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATG8, ECO:0000255"
FT REGION 2379..2405
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2498..2529
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2545..2597
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2598..3029
FT /note="Condensation (C) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATG8, ECO:0000255"
FT REGION 3063..3459
FT /note="Adenylation (A) (KR) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATG8, ECO:0000255"
FT REGION 3063..3459
FT /note="Reductase (RED) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATG8, ECO:0000255"
FT COMPBIAS 2379..2400
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2549..2576
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2577..2597
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 190
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2448
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3611
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 4015 AA; 438112 MW; 6FFAF899982E5CE4 CRC64;
MAANDSNNQT KPQLPEEPVA IVGSSCRFPG SSNSPSKLWD LLRQPRDVLK EFDPDRLNLK
RFYHPDGDTH GSTDVTNKSY LLEEDSRLFD ASFFTINPAE AAGMDPQQRI LLETVYEAFE
SAGMTLEQLR GSLTAVHVGT MTNDYAGIQL RDLETIAKYN ATGTANSIVS NRISYVFDLK
GPSETIDTAC SSSLVALHHA ARGLLNGDCE TAVVAGVNLI YDAASYIAES KLHMLSPDSQ
SRMWDKSANG YARGEGAAAL LLKPLSRALR DGDHIEGVIR ATGVNSDGQS PGITMPFAPT
QAALIRQTYR RAGLDPVKDR PQYFECHGTG TPAGDPVEAR AISEAFEPSA DNPIYVGSIK
TIIGHLEGCA GLAGVMKVIL ALKNRTIPPN MLFNELNPAI APFYGPLQIP KKAMPWPELP
ENTPIRASVN SFGFGGTNAH VIIESFESST PSSDSEKCEE GALGPLLFSA GSGASLLHTV
QAYVQYLDQN PSVDLRDLSW LLQTRRSTHR VRTHFSGTSS DAILESMIKF VNNNEKTPST
EVGHQPKLIN PKEVPGILGV FTGQGAQWPQ MGKELIGKSP IFRRTLEDCD ATLQALPSSD
IPKWSLVKEL MANASSSRVA EAAISQPLCT AVQLGLVNML KASGLNFDAV VGHSSGEIAA
TYASGIINLQ AAIQIAYYRG FHAKLAKGEK GQQGGMLAAG LTLDKAKQLC LREEFVGRLQ
VAASNAPQTV TLSGDLDAIE EVKKYLDEEN VFARQLKVDT AYHSHHMKPC AEPYLKSLLA
CDIEVRKPTP GQCIWNSSVR GDTGLLKGDL SSLKGPYWVA NMVQTVLFSQ AVESSIWHGG
PWDLAIEVGP HPALKGPTEQ TLKAVYGVVP LYTGVLKRGA SDVEAFSTAI GVTWSQLGPS
FVDFAGYRKT FYESEPPTPK VIKDLPGYSW DHDKVYWRES RISKRYRTGR DQTHELLGRR
TPDDNEFELR WRNVLKLSEM PWLRGHEVLE EVLLPGAAYV SIAVEASKHI ATSKGKSIEL
LEVEDVDIQR PVVVPDNKEG VETLFTARLL PGSSSDKVLK ALFSYYICND QSTGTMVHTC
SGRLSVHLGE AKEDVLPQRD PVPQNLVNIN TDRAYGMFKD IGLNYTGVFR SIKESSRTLQ
YSAATGIWPE GSLSDKYLVH PAMLDVAFQT LFIARAHPAS RLITSALLPS HIERIQVSPS
VPILHARENS DEIKADFDCW VVHQTASSLT GDLNIYDKVS GKTFLQVEGL TTKMVGEQDA
SGDRPVFTKT VWGSDGSLGL DEPERDPVGD AEGLSLAEAA ERMALFYMKR VVKEISPEER
TKFQWYHQRM FEAFEQHLVN VGSGSHPMLK SEWLSDDSSI MDGLDRIHPT SIDLKLLRAC
GENMPDVVRE KTQLLEVMSK DDMLNRFYMD NCAARINNDI AKVVKQISFK FPRANILEIG
AGTGGTTWSI LKDINDAYDS YTFTDISSGF FPKAAEKFSD FAHKMIFKTL DVEKQPSEQG
FAENSYDVIV AANVLHATRS LETTLRNARS LLRPGGYLIL MEITNPESLR TTFIFGGFSG
WWLSEEPHRK LGPVVTAMDW DTVLNDTGYS GADMVVHDLA EESKHLTSLI VSQAVDDDFL
RLREPLSNLA DMSAPTESIL VIGGKKLLTS KMVNEINKLL PKSWKRHISS AGSIDDIDIN
ELKPGTEVIS LQELDDPLFS TPMTAERMST IQNLMMSAKT LLWVTTAGKS HAPRASMFHG
IARIVPSELQ HLQIQVLGLE AGSTPAIATR HCVEAFLRLR GTSDTTREML WAIEPEVEIM
ADGQVLIPRV VPDETLNQTY NASRRVVTKT VDATDLAVEA VAGPTKMMLQ TAELQAGERK
TRIQVKYALH LPAMDGKGIY VVYGQRQDDT SSFVLAVSKS NSSIVDVDSK HAVSVSDNCE
PATLNVLATY LIARAIATLS KQAGSVLLSE PEESLAAIVA TETAKQGTQA YFLSSKKVSP
VEWIKVHANA SKRAIQKAVP HDVQLLIDCS GIEASGNAVM ASMPLHCVER QLDAHLLFDA
LESTESKPES LLEEAYQYAT QLITQEQVQS ECEVFPASDL PLTNMLSLVH KKYVTDWQQR
DSLVVSVPPL DLEGIFKADK TYLMVGAAGG LGLSICEWMI RNGAKNLIIT SRKPQVDQNM
IEEASRVGAT VKVMAMDVSS KESVAEVVQQ AQEIMPPIAG VCNAAMVLSD KMFLDMDVDQ
LNGTLAAKVY GTEHLDAVFA DAPLDFFIVL SSTATTIGNI GQANYHVANL FMTSLVAQRR
ARGLAGSVIH IGYVADVGYV TRQDRERQLE QHFRNVRLMA LSETDVHHAF AEAVRGGRPG
NTVGSPDIIM GLEPASVPLE PERQTLWLSN PCFGHLVPST LQNDSSQTGG TGNGSSVRRQ
VEEAQTEDEA VDAVLDGFCA KLEAILQLRE GSVKENVQRA VIDLGIDSLV AVEIRTWFLK
ELGAEVPVVK ILGGDTVLQI CTTAAKKVMA NAMKKKEEDA VAEEGGREAA SKKEPAPAAS
APTPAPVAPS LLDVPARAFE PDSATISEVG DDSAFSNKGS SSSATGASSP KELSDSESVP
DTSKDQSHVR PETVRDERMS PAQARIWFLT KHLDDPSAYN MVFHYRVKGP LKTVRLRHAL
QVATGHHESL RTLFYSRLED GQPMQGVMPA SAYELKHVPG ADEADLKKEL ALLKAREWDL
ENGRTFSVSV LSRAADEHDV VFGYHHIIMD VVGWYFFVRD LDRAYRMQPF DKKISGSYVD
YSVMQLSQKN TAAASDDLAF WQKEFSTVPD PIPLLPIAAV SARPTDSGRK VSHHEYLELD
PAQNLAVKET CEKLRISPFH FHVAVLRALI GGYTNIDDMC IGVVDANRGD ERFAQTVGCF
VNMLPVRVEA PSDATFADIA RSASRKALMA FAHSSAPLDM ILDAVKAPRS SETTPLFQVA
VNYRTGGVWD LPMGDCQMKL SLTDGKDAEN PFDISLGIAE TGKGCVIEMH CQKTLYSSDA
TRTLLNTYLR LVDTFCKNTH VKLKDCVIHD QAKVSEALQI GKGPTTDFGW PSTLSHRVLE
TCLKSPKNAA IQFKGELLSY EQLASRIHLV AAAIVRAGAS KGSRVAVLCE PSADAIISML
ATLHIGGVYI PMDVSLPTAR HAAMMNGGQP TLLLSHAATK HRVEDLVNET GSTISVLQVD
TISSVEEKET VSCAAEPHNN AVLLFTSGST GTPKGIMLSQ ANFVNHLALK TDRLQLGQEN
VLQQSSMGFD MSLIQMFCAL ANGGCLVIAP SEMRRDPVEL TNLVHNSQIS LTIATPSEYL
AWLRYGTASL KDHTIWRHAC MGGEPVSRQL KTEFWRLDLA NLQLTNCYGP TEITAAATFE
TIRLDDQDDD NDRAQHAVGK ALPNYSVRIL DTAGRPQPVD HIGEICIGGA SVALGYLGLP
EQTKAKFTVD PVSGERLYLT GDKGKLLSDG TLLCLGRLDG DTQIKHRGLR IELQEVESAL
IQTANGLFSS AVVSARGSIL VAHATISQSQ AEPSESDLAK ILSRLKLPQY FIPATIGILP
TMPTTANGKL DRKAIASLPL PQKVTGEEGP QEKMNIREGE LRLLWERVLP DTATTTPLGP
SSDFFLCGGN SMLLMKLQAA IKESIGIEIS TRVLYQASTL REMALCVDEQ REEQADALEQ
HFDWQAETSL PKWLLDQIED LPKTTKQPPK PNGIDILMTG ATSFIGGRLL RSLVRSPSVR
KVHCVAVLAD EQDQLYQDEK VKCYTGSLLS STLGLNNGER DQLARNVDVV IHAGSSGHCL
NTYGSLRTPN LVSLQFLASL ALPRSIPLLL LSSNRVPLLS GNTALPPTSV AAFPPATDGR
EGYTATKWAS EVFLEKLVGA VQKKAPRPWV ASVHRPCVVV SEHAPNSDAL NAILRYSASM
KCVPHLESAT GYLDFASVES IVDSMAESAI EMATGNVTDQ PSIRFQHHSG GVKVPIGDFK
VHMENVYGGN FEEVHLEEWM HRAAAAGLDP LITAYMEGII EAGAPIVFPY LGETV
