FFSA_ASPFV
ID FFSA_ASPFV Reviewed; 4042 AA.
AC A0A7L8UVC9;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 07-APR-2021, sequence version 1.
DT 03-AUG-2022, entry version 6.
DE RecName: Full=Polyketide synthase-nonribosomal peptide synthetase ffsA {ECO:0000303|PubMed:32913332};
DE Short=PKS-NRPS ffsA {ECO:0000303|PubMed:32913332};
DE EC=2.3.1.- {ECO:0000305|PubMed:32913332};
DE EC=6.3.2.- {ECO:0000305|PubMed:32913332};
DE AltName: Full=Cytochalasans biosynthesis cluster protein ffsA {ECO:0000303|PubMed:32913332};
GN Name=ffsA {ECO:0000303|PubMed:32913332};
OS Aspergillus flavipes.
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=41900;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE, AND
RP PATHWAY.
RC STRAIN=CNL-338;
RX PubMed=32913332; DOI=10.1038/s41429-020-00368-0;
RA Heard S.C., Wu G., Winter J.M.;
RT "Discovery and characterization of a cytochalasan biosynthetic cluster from
RT the marine-derived fungus Aspergillus flavipes CNL-338.";
RL J. Antibiot. 73:803-807(2020).
CC -!- FUNCTION: Hybrid PKS-NRPS synthetase; part of the gene cluster that
CC mediates the biosynthesis of the cytotoxic leucine-containing
CC cytochalasans, including aspochalasin C, aspochalasin E, TMC-169,
CC flavichalasine F, aspergillin PZ, aspochalasin M and flavichalasine G
CC (PubMed:32913332). The first step in the pathway is catalyzed by the
CC hybrid PKS-NRPS ffsA that utilizes 8 units of malonyl-CoA to
CC iteratively assemble the octaketide chain before addition of L-leucine
CC by the C-terminal NRPS modules (PubMed:32913332). Because ffsA lacks a
CC designated enoylreductase (ER) domain, the required activity is
CC provided the enoyl reductase fssC (Probable). The methyltransferase
CC (MT) domain of ffsA catalyzes the alpha-methylation at C10 and C14
CC using S-adenosyl-L-methionine as the methyl-donating cosubstrate
CC (Probable). Reduction by the hydrolyase ffsE, followed by dehydration
CC and intra-molecular Diels-Alder cyclization by the Diels-Alderase ffsF
CC then yield the required isoindolone-fused macrocycle (By similarity). A
CC number of oxidative steps catalyzed by the tailoring cytochrome P450
CC monooxygenase ffsD, the FAD-linked oxidoreductase ffsJ and the short-
CC chain dehydrogenase/reductase ffsI, are further required to afford the
CC final products (Probable). {ECO:0000250|UniProtKB:Q0V6Q6,
CC ECO:0000269|PubMed:32913332, ECO:0000305|PubMed:32913332}.
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000305|PubMed:32913332}.
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. The ffsA A
CC domain specifically recognizes L-leucine. FfsA contains also a
CC polyketide synthase module (PKS) consisting of several catalytic
CC domains including a ketoacyl synthase domain (KS), an acyl transferase
CC domain (AT), a dehydratase domain (DH), a methyltransferase domain
CC (MT), and a ketoreductase domain (KR). Instead of a thioesterase domain
CC (TE), ffsA finishes with a reductase-like domain (R) for peptide
CC release. FssA has the following architecture: KS-MAT-DH-MT-KR-PCP-C-A-
CC T-R. {ECO:0000305|PubMed:32913332}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of leucine-containing
CC cytochalasans. {ECO:0000269|PubMed:32913332}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the NRP synthetase
CC family. {ECO:0000305}.
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DR EMBL; MT586757; QOG08944.1; -; Genomic_DNA.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0016853; F:isomerase activity; IEA:UniProtKB-KW.
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; -; 1.
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; 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; 1.
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 PROSITE; PS00455; AMP_BINDING; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 2.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 3: Inferred from homology;
KW Acyltransferase; Isomerase; Ligase; Methyltransferase;
KW Multifunctional enzyme; NADP; Oxidoreductase; Phosphopantetheine;
KW Phosphoprotein; Repeat; S-adenosyl-L-methionine; Transferase.
FT CHAIN 1..4042
FT /note="Polyketide synthase-nonribosomal peptide synthetase
FT ffsA"
FT /id="PRO_0000454524"
FT DOMAIN 2399..2476
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 3607..3684
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 20..456
FT /note="Ketoacyl synthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32913332"
FT REGION 561..878
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32913332"
FT REGION 950..1249
FT /note="Dehydratase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32913332"
FT REGION 1390..1613
FT /note="Methyltransferase (MT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32913332"
FT REGION 2116..2289
FT /note="Ketoreductase (KR)domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32913332"
FT REGION 2515..2601
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2629..3061
FT /note="Condensation"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32913332"
FT REGION 3089..3486
FT /note="Adenylation"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32913332"
FT REGION 3750..3971
FT /note="Reductase-like domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:32913332"
FT COMPBIAS 2520..2534
FT /note="Acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2576..2601
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 2436
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3644
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 4042 AA; 443936 MW; BDED5A012290C7FE CRC64;
MATTTAPTTQ GHNQPSREPI AIVGSACRFP GGASSPSKLW KLLEHPRDVL KEIPPDRFSV
DGFYHPDNMH HGTSNVRHSY ILDDDIRVFD AQFFGIKPVE ANSIDPQQRL LMETVYEGIE
SAGLQLNKMK GSQTGVYVGL MSNDYADMLG NDQESFPTYF ATGTARSIVS NRVSYFFDWH
GPSMTIDTAC SSSLVAMHQA VQYLRSGDGS DVAIAAGTNI LLNPDQYIAE SKLKMLSPDG
RSQMWDEKAN GYARGDGIAV VVLKTLSQAL RDGDHIECIV RETHINQDGK TKGITMPSAT
AQTALIRSTY KNAGLDITKP SDRPQFFEAH GTGTPAGDPI EAEAIHTAFF GYKGLSKEIE
PLSVGSIKTI IGHTEGTAGL AAVLKASLAL QAGVIPPNLL FDKVNPKVKP FYGNLQIQTQ
AKSWPSLAPG AVRRASVNSF GFGGANAHAI LEAYEPSSTP TVGTPANVFT ALNVSAMSET
ALRGTLKKYV EYLKEEPSVD LRSLALTVNT RRSTFPVRTS VFGTSVEELS QRLSERSEAE
GKTLTPVAPT SLSSSPKILG VFTGQGAQWK QMGAVLLATS PRVVAILDQL EKSLAELPDG
PSWSIKGEIL ADEDSRVNEA VISQPLCTAV QIVLVDLLQS AGVQFHTVVG HSSGEIGAAY
AAGYLSASDA IRIAYYRGLH LYLAQGPNGQ QGAMMAVGTS FEDAQELCDL PAFRGRISIA
ASNSSASVTL SGDLNAIEWA KDVFDDEKKF ARLLKVDKAY HSHHMLACSD AYRKSMTDCG
ITVLQPARNG TTWISSVYGE DALDYRHEMN AEYWISNMVS PVLFSQAIEF AMADQGPFDI
GIECGPHPAL KGPALQVIQE MLGSSIPYTG LLSRGRPDTQ ALAEGISYLW QALGADVVNY
TSFDRFIAGP DASEPQVLAN LPSYAWDHDR AFWHESRQYW ANRTKEDPPH EILGTKCPDG
TDQQHRWRNM LRPREIPWIA GHQIQEQMVF PAAGYVSAAI EAVQMVTRGQ SLGAIEIEDF
VIGQAIAFND EYASVETQFT LTDISVEKDI WSASFFFYSA SPKSSRSLDL NASGKLKVTL
GEPKDDFLPP HLSPEFNMID VDSERFYDAL KKLGFGYTGP FKALGSLKRR MGVATGTITN
PTSTDPAHDL LLHPATFDNA IQSIILAYCY PNDGRLWSVQ LPTGIKKIKI NPVLCNRYAG
KKALLCFKAS TSDDRSAEIG GDVDIYDEQG NNALMQLEGL QTKPLANATA ANDSPLFLET
IWDIESPSRE AAVADRPDMQ PKTELSFDVE RVAFFYLRHL DSVATREERE KAESHHKIFF
EYIDHTVANV KSGTAQFAKR EWMYDTHDEI LDIISKYPDS LDMKLMHAVG EHLLPVIRGE
TTMLEYMRED NLLNDFYVHA IGFDEYTENL AQQVSQFSHR YPHMNILEIG AGTGGATKRI
FSKLGKRFGS YTYTDISAGF FEKTRETFRE YEHMMTFKAL NIEKDPVEQG FTEQSYDLVV
ASLVLHATHE METTMRNVRR LLKPGGYLIM LELGDYIEMR TGLIFGSLPG WWMGYDDGRK
LSPCMSEEDW SVCMQKTGFS GVDAIVPRQS ELPISLAVLT GQAVDDHVNF LRDPLTPGSI
DFVESNLTII GGTTSKVSAM VEEAAKSLGR FYEKIVTATS LAELDTTEVP FMGSVLFLTD
LDEPIFENVT EDALTALKQL FKQSRTCLWV TQGARDDNPF QNMSVGLGRV VKLEMTHLRL
QSLDFDVETE PSAPTIMQRL LQFEAMAQWE QSGESKDLLW SVEPEIGYDH GKAIIPRLMP
NPVRNARYNS SRRLITKYME PTSANLSLRW SGKSYDIHEG EPSGATSLVM DGRVQLEVSH
STLDAIGVTA TDYAYLVLGK NVKSQQQVIA LTPKSDSIVR VFDSWTVPYS MAEDDALRLL
PVVYTNLMAL SVISRLSSGE TLVLVEPEEA FAQTLSRLAT ERAISVVTLT SRMDVKNSDW
IYLHVNSPKR LVRSTVPRNA SWVIADRDQG GLAANVLQCL PANCKILATE SLTSKQPKLD
TFSSMAFIPS ILRTAFVRAH DIKATLELPS VVAAADISSD NQPSTEATFF SWTASPSVPV
QVTPVDHGTL FSSEKTYWLV GLSGGLGLSL CDWMVKHGAK YIVITSRNPQ VDARWEQHMK
AQGAVVRVYA NDITDRESVS SVCKKIRDEL PPVGGIAQGA MVLADTMFVD MDLPRVQKVV
GPKVNGSIHL HEMFVEVDLE FFVFFSSMAY VTGNQGQSIY AAANAYMTAL AAQRRKRGLA
GSAINIGTII GNGYVTRQLT IAQQEYLTHM GNVFMSEQDF HQIFAEAVVA GRPTSKDIPE
IMTGLRLAHL DDSDKVTWFH NPKFSHCVLW PEEQGGKAVM SKQNVTVRAQ LLLATTADEA
REIIEESLAA KLRSSLQIDA TVSVINMNAD QLGLDSLVAV DIRSWFIKEL NVEMPVLKIL
GGYTVAEMVA AAQEKLSPSL IPNLGKEVDP SLKAVVKAQV EKPVAAAEEK PIVTEKAEYA
DFDDENEEEG IPTEDSLPEI TVSDESSELS DREPAKFNFN GPGFKKVGFS PGPQTPLSED
DRSKWSSYGS PFDSDSDNAS IRKSRTSAAT SVTALDEYFS KPDHTIFERT LPMSFGQTRF
WFLKFYMEDQ TTFNITTSIS LAGKLDVGRF SRAVHHLGRR HEALRTAFFT DSNNQPMQAV
LKEPVLRLEH ARGEANVASE YRRIKNHQYD IGRGETMKIT LLSLSEKLHQ LIIGYHHINM
DGISLEVIIR DLQQLYDGKS LAPVSIQYPD FSIMQYKEHS SGQWDDELTF WKSEFADIPE
PLPILPPSTK AVRTPLSIYS SNTVKFEVGA ELSSQIENAC KRTKTSPFNF YLATFKVLLY
RLAEGKATDI CIGMADGGRN NDLVSQSVGF FLNLLPLRFK QQSSQMFSDA LKEARSKVIT
ALANSKVPFD VLLNEVNAPR TATLSPLFQA FINYRQGVQE KRQFCGCESE ATKFDGSQTA
YDLSLDILGN PGSGIVYLAG QSSLYSQSDV ETIAQSYYAL LKAFAKNPAL RISRPSLYDP
QAVDHALAKG KGPTNVGTWP ETLVHRVDEI VKAHGSKVAL KSATAKLTYT QMAERVNAIA
STLQSNGINK CSRVGVFQDP STDFFCTILA VLRIGAVFVP LEPRLTAPRL ATMVQDSDLN
AIVYDKANQK TLAELGSNSK KINVSLVLAK SSAVVSNQAT PGATAIILYT SGSTGKPKGI
LLSHSAWRNQ IESSSRAWEV PTGTGVHLQQ SSWSFDISIS QTFVALANGA SLIITPKTMR
GDSSAITKTI VSDQVTHVQA TPSELSSWLR FGDLAALRAS KWQFAMTGGE RMTPALIDGF
RKLAKNDLKL FNAYGPAETT LAVGSSEVDY MTSDDLDTPF TLFPNYSVYI LDGQKQPVPA
GIPGEVYIGG AGVAQGYLNQ DSLTAKRFLP DTFGTTEYTH FGWTKMHRSG DRGHLSEDGH
LVLEGRIDGD TQVKLRGIRI DLQDIESAMV QQANGALTEA VVSVCKLQET EYLVAHVVIS
PTFTGNTESF LDQLRASLPV PQYMQPAIAV TLDALPVNHS GKVDRKAIAA LPILPKATQP
GATSQPRDST EKLKDIWTQV LGQGMTSLHH IDAQSDFFHV GGSSLALVEV QAKIKTIFQV
EVSLVQLFEN PTLGAMARMV DPTAFSAPVN ANLTIPAEVA TAISAPTTSI NTAPKEIDWE
EETALTDDFY DIEIDPTPKD QGLPYKTVVI TGATGFLGKA LLRRMLDDNH IDKIHAITLR
RSRSDLPGIF SDPKVHLHRG DLNAPRLGLS ETAAAEIFAE TDAVIHNGAD VSFMKTYRTL
SKTNVGSTRE LVKLCLPHRI PIHYISSASV VHLSGLESYG EASVSSFEPP QDGTDGYTAS
KWASERFLER VSEKFSVPIW IHRPSSITGE DAPTLDLMTN MLSFSKKLRK APTSPAWQGT
LDFVDVEKVA TEIVEEVKND SAHPGGLVKY MYESGDLEIA VDDMKGSLER ETGQAFQTLS
LEEWTKAAAE EVTNELGICC SK
