FSA1_FUSSF
ID FSA1_FUSSF Reviewed; 3948 AA.
AC A0A0E4AZP0;
DT 30-AUG-2017, integrated into UniProtKB/Swiss-Prot.
DT 24-JUN-2015, sequence version 1.
DT 03-AUG-2022, entry version 32.
DE RecName: Full=Hybrid PKS-NRPS synthetase fsa1 {ECO:0000303|PubMed:25770422};
DE EC=2.3.1.- {ECO:0000305|PubMed:25770422};
DE EC=6.3.2.- {ECO:0000305|PubMed:25770422};
DE AltName: Full=Fusarisetin A biosynthesis protein 1 {ECO:0000303|PubMed:25770422};
GN Name=fsa1 {ECO:0000303|PubMed:25770422};
OS Fusarium sp. (strain FN080326).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Nectriaceae; Fusarium.
OX NCBI_TaxID=1608308;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, DISRUPTION PHENOTYPE, DOMAIN,
RP AND PATHWAY.
RX PubMed=25770422; DOI=10.1016/j.bbrc.2015.03.011;
RA Kato N., Nogawa T., Hirota H., Jang J.H., Takahashi S., Ahn J.S., Osada H.;
RT "A new enzyme involved in the control of the stereochemistry in the decalin
RT formation during equisetin biosynthesis.";
RL Biochem. Biophys. Res. Commun. 460:210-215(2015).
RN [2]
RP FUNCTION.
RX PubMed=28401214; DOI=10.1039/c7cc01929g;
RA Li X., Zheng Q., Yin J., Liu W., Gao S.;
RT "Chemo-enzymatic synthesis of equisetin.";
RL Chem. Commun. (Camb.) 53:4695-4697(2017).
RN [3]
RP FUNCTION.
RX PubMed=29972614; DOI=10.1002/anie.201805050;
RA Kato N., Nogawa T., Takita R., Kinugasa K., Kanai M., Uchiyama M.,
RA Osada H., Takahashi S.;
RT "Control of the stereochemical course of [4+2] cycloaddition during trans-
RT decalin formation by Fsa2-family enzymes.";
RL Angew. Chem. Int. Ed. 57:9754-9758(2018).
RN [4]
RP FUNCTION.
RX PubMed=34121297; DOI=10.1002/anie.202106186;
RA Fujiyama K., Kato N., Re S., Kinugasa K., Watanabe K., Takita R.,
RA Nogawa T., Hino T., Osada H., Sugita Y., Takahashi S., Nagano S.;
RT "Molecular basis for two stereoselective Diels-Alderases that produce
RT decalin skeletons*.";
RL Angew. Chem. Int. Ed. 60:22401-22410(2021).
CC -!- FUNCTION: Hybrid PKS-NRPS synthetase; part of the gene cluster that
CC mediates the biosynthesis of HIV-1 integrase inhibitor equisetin and of
CC fusarisetin A, both trans-fused decalin-containing tetramic acids
CC showing also antimicrobial activity (PubMed:25770422). The PKS module
CC of fsa1 together with the enoylreductase fsa3 catalyze the formation of
CC the polyketide unit which is then conjugated to L-serine by the
CC condensation domain of the fsa1 NRPS module (PubMed:25770422). Activity
CC of the Dieckmann cyclase domain (RED) results in release of the
CC Dieckmann product intermediate (PubMed:25770422). Diels-Alderase fsa2
CC is involved in endo-selective Diels-Alder cycloaddition to form the
CC decalin ring, leading to the production of N-desmethylequisetin also
CC called trichosetin (PubMed:25770422, PubMed:28401214, PubMed:29972614,
CC PubMed:34121297). Subsequent N-methylation is carried out by fsa4 to
CC give equisetin (PubMed:25770422). The enzymatic gene responsible for
CC the conversion of equisetin to fusarisetin A has not been identified
CC yet and is probably located outside of the fsa cluster
CC (PubMed:28401214). {ECO:0000269|PubMed:25770422,
CC ECO:0000269|PubMed:28401214, ECO:0000269|PubMed:29972614,
CC ECO:0000269|PubMed:34121297}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + ATP + 11 H(+) + L-serine + 7 malonyl-CoA + 8
CC NADPH + 2 S-adenosyl-L-methionine = (5S)-3-[(2E,6R,8E,10E,12E)-2,6-
CC dimethyltetradeca-2,8,10,12-tetraenoyl]-5-(hydroxymethyl)pyrrolidine-
CC 2,4-dione + AMP + 7 CO2 + 8 CoA + diphosphate + 6 H2O + 8 NADP(+) + 2
CC S-adenosyl-L-homocysteine; Xref=Rhea:RHEA:67324, ChEBI:CHEBI:15377,
CC ChEBI:CHEBI:15378, ChEBI:CHEBI:16526, ChEBI:CHEBI:30616,
CC ChEBI:CHEBI:33019, ChEBI:CHEBI:33384, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57288, ChEBI:CHEBI:57384, ChEBI:CHEBI:57783,
CC ChEBI:CHEBI:57856, ChEBI:CHEBI:58349, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:169938, ChEBI:CHEBI:456215;
CC Evidence={ECO:0000305|PubMed:25770422};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:67325;
CC Evidence={ECO:0000305|PubMed:25770422};
CC -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000269|PubMed:25770422}.
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 (By similarity). Thus, an NRP synthetase is generally
CC composed of one or more modules and can terminate in a thioesterase
CC domain (TE) that releases the newly synthesized peptide from the enzyme
CC (By similarity). Occasionally, epimerase (E) domains (responsible for
CC l- to d-amino acid conversion) are present within the NRP synthetase
CC (By similarity). Fsa1 contains also a polyketide synthase module (PKS)
CC consisting of several catalytic domains including a ketoacyl synthase
CC domain (KS), an acyl transferase domain (AT), a dehydratase domain
CC (DH), a methyltransferase domain (MT), and a ketoreductase domain
CC (KR)(PubMed:25770422). Instead of a thioesterase domain (TE), fsa1
CC finishes with a reductase-like domain (R) for peptide release
CC (PubMed:25770422). Fsa1 has the following architecture: KS-AT-DH-KR-
CC PCP-C-A-T-R (PubMed:25770422). {ECO:0000250|UniProtKB:Q4WAZ9,
CC ECO:0000305|PubMed:25770422}.
CC -!- DISRUPTION PHENOTYPE: Results in the loss of production of equisetin
CC and fusarisetin A (PubMed:25770422). {ECO:0000269|PubMed:25770422}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the NRP synthetase
CC family. {ECO:0000305}.
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DR EMBL; LC025956; BAR40283.1; -; Genomic_DNA.
DR SMR; A0A0E4AZP0; -.
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; 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; 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; 1.
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.
PE 3: Inferred from homology;
KW Ligase; Methyltransferase; Multifunctional enzyme; Oxidoreductase;
KW Phosphopantetheine; Phosphoprotein; Repeat; Transferase.
FT CHAIN 1..3948
FT /note="Hybrid PKS-NRPS synthetase fsa1"
FT /id="PRO_0000441288"
FT DOMAIN 2389..2464
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 3540..3617
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 7..441
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25770422"
FT REGION 543..846
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25770422"
FT REGION 931..1233
FT /note="Dehydratase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25770422"
FT REGION 1381..1578
FT /note="Methyltransferase (MT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25770422"
FT REGION 2105..2277
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25770422"
FT REGION 2475..2555
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2547..2976
FT /note="Condensation (C) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25770422"
FT REGION 3000..3402
FT /note="Adenylation (A) (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25770422"
FT REGION 3653..3870
FT /note="Reductase (RED) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:25770422"
FT COMPBIAS 2484..2555
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 177
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2424
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3577
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 3948 AA; 435000 MW; C979ED9853F542D8 CRC64;
MDASEPIAVI GSACRFPGGS DSPSKLWELL KEPRDLLSKV PPERYNADAF YHADATHHGT
TNVRHSYFLS EDPSSFDNNF FNIQPGEAEA IDPQQRLLME VVYQGLCSAG QTIEGLRGSP
TAVYVGVMCD DWSGIITRDL EVFPRYGATG MARSIMSNRI SYFFDWHGPS MTIDTACSSS
LVAVHQAIQT LRSGESEVAI AAGANLILTP GMYVAESKLS MLSPSGRSKM WDQDVDGYAR
GEGIAAVVLK PLSAAIRDND HIDCIIRATG INQDGRTPGL TMPSATAQAD LIRSTYARAG
LDINKAEDRP QFFHAHGTGT PAGDPREAEA ISRAFYSPDN LSKDDKLYVG SIKTIIGHTE
GTAGLASLIG TSLAIQNKVI PPNMHLDVLN PKVAPFYNNL EVPTSALEWP ETRSGQPRRA
SINSFGFGGT NAHAIIEAYE PNATAHVSGA LFSPLTFSAS SEPSLRSLLM SYSEYLKLNP
QISLKDLAYS LQTRRSTLAY RVAITASTAE NASKQLDAIV DGEQSSSIST RQLSKSSPKI
LGIFTGQGTQ WPRMGARLLE ESPFASKRLA ELDDALSSLP ADDRPTWTLR EMILADSESS
RVAEAAISQP LCTAVQVVLV DLLRHAGIEL SAVVGHSSGE IGAAYAAGLL TARDAIRVAY
YRGLYAKLAQ SPNGHKGAMM AVGTTFEDAA DFCELEAFQG RIQIAAKNSP SSITLSGDED
AIIEAIEIFK DEGKFARQLK VDTAYHSSHV IPCAKPYLEA MNRCGIETAT ATKTQWYSSV
HGGQIMSADS LTTSYWVDNM TSAVLFSPAV AQAWEEGGPY DLAIEVGPHP ALKTPALDTI
EAISEGRPPY TGVIARGKDD IQQFSNALGF IWTHLGPGSI AFENFESVVS GSKDRPSFIQ
DLPNYPFDHA KQFMSMSRVS GWFNSIQEAP HPLLGRRCHD RETSHSVQWR NVLSHKEIPW
LQGHQLQGQI IFPATGYISM AVEAIKILAE PSSLGLITIE DLSITRALAF ADEDASIETL
FELRILSRSE TEIQAEFCCY SGIPHTHTAT MGLNATAQIK ASLGTPTSDQ LSNIAVDDYD
LRPVSVDRFY DFLARLGYNY SWPFRGTTSI RRKANFATGT LEDQSGSNWE DQLMVHPGML
DSSLQTTFAA FCCPGDERLW ALHLPTSFRS IAINPYFTSA GIGKQNSFTY QSVAIEERKT
SKVLVELNLL SEETGDTFLQ IEGMELVPFS PATPANDAVL FSRFDYRLAG PDGELTAAEY
SFKPEDYKMA LDCERIAFYY LRRLVETITP EEKANTLVHY RHLVDWAAYV VPQVANGGNP
HIPASAQQDT HDDIQQLLKK HYERVDIRLL ESVGENLPQV IRDSGNILEH MTKDGMLQDV
YEQGFGLNLV NQYIAHMTAQ IAHRYPRMNI LEIGAGTGGS TREILPRLGS AFSTYTYTDV
SGGFFDMAQD RFKDYADRMI FKTFDMNISP ASQGFTEGAY DLVIASNVLH ATLELEDMMK
HVRSFLKPGG FLIILETVNN DCLRVGLPMG SLPGWWLGAE HGRRWGPTLT LPQWDSLLSK
CGFGGIDTTT PPVHKILPGH VFCAQALDER IEILRSPMEH LATLPETKST QLAVIGGQTL
KVHRMCDQIS RRLSSRYSSI SRFNSIEELN DTGLPESCTV LSLTELDEPL FANMTYGKLE
ALKILWKQGG SILWITSGAR AENPHSYMTT GVGRCMRFEY PNITLQALDI KQISDRCPEL
IVDHLLRLEI LDKWSKELRS DELLWSLEPE IYIEEETAII PRLYPYESGN ARYNAERRKV
IKQADMETDR VVFAEFEGKW EIQHASPLHI AQELPSSSDI SARTIQITHL SPATVNIAPG
VSAMAWAGVD TASNEPVVAV THIAESPVSI PAGWCIPLDK LDPVKTLTGV SATLIASSIL
ERLVKGETLV VHDAPPHIRA ALDKLAKPVS IAIFYTSSDE AMSKLGARYI DRRSPLRVIR
ASLPKSASKF ISLSQDFGKD ETSKVISMCL PRDCETINTA HLFGPRNVAQ QSAFEKDVSS
SLKKAFEEVG SQVNTTASTD LISLKDTPNP IADQVRFAIL DCTDTPIQAS VHPIDDGRIF
RADKTFLLIG LTGELGQSLC KWMVEQGARS IVLTSRRPNV SEHFLGSFAE TGAIVKALPM
DVTDRTSIEA CLETIKKTLP PIAGVVNGAM VLRDALFENM PYEDFMKVLN PKVVGSQLLD
EMFYDTPLDF FIFFSSTTAV MGNSGQSNYI AGNMYMNALA AQRKKRGVAA SSIDISSIIG
LGYVERAEDL SEDTFIKMGY KPMSEQDLQK LFAEAIVLGR PDCHEVCELV TGVTPIYTDA
QASDQYLKDV KFGHFLMERL DTQTYTGKTS TVPVRVQLAD VKTRADAVAI IKESFIVRLR
RVLAVGPDEI INEKVTLVEQ GVDSLMAVEV RSWFIKELDV DIPVLKILGG MSVPDLVDES
LDLLSPSILD VSSLEAGNAH PAKPTTVIPQ TPTRVTPPES SQGTSDQDKP HTGSDSSRSP
IDTPLTSWDR QDLSPPDKSD DAPNSTDNLT PPRTFPNELP SIMSYGQAGF WFLNDYLVNK
KAFNMAVMLK LTGSIRTQPL ENAVQLVAER HEILRTRFFW SEDGDERTPM QGINPPTMKL
TIKTIADEKE AETELKRLHD EDWDLGSGEG VKIILLRLSD QVHFLLSGMH HIYLDGYSFS
VFFKDLESAY INHRLPPLPV ESQYRTFALQ QRKMYDDGDL LKSIEYYRQS FPKEFAPIRL
FPFATTASRQ LANEYSQHEA KLSITPDVSA KVRQLARANR STSFHVYLAA LKILLFSLLP
DTEELFIGIA DANRGDKKFM GSLGFFLNLL PLRFQRGKPR SRVSSAIQTA RDAAYGALQH
SQLPFDVLLR ELNVPRSDKH TPIFQVFMDY RQVVQERSSW GGCKLSDEKW CNAGTGYDVA
LEVTENINTD TLLSLRLQKQ LYSEEHTQVL LRSYLSVLEY MIRGSDKSVD AAPAWSSYDL
KVAVDAGKAP EFKSKWPPTV SHQIDQVIQN NPDKIALKDG NGNVLTYAQM GNRIDTISKA
LIDAGTVQGT VVGVFQEPSA DWICSLLAIF KAGAVYVPLD LRNSIPRLAS IVKASRPSVI
ITDITTDDKV DLIGAKFVTK LQLGSLDEST RQDSTEINHA KVGSLAVILF TSGSTGEPKG
LMMTHTNLLS YAEVSSKTFA RVDEDLVVLQ QSPFSFDFSL DQTMAALTNG GYLYVVPASK
RGDPDEISKI MVEESVTYTT ATPSEYDLWL RYSTETLQQC NSWKYAFSGG EAMSYKLARE
FGTLKLTNLH VFNGYGPAET TILSHRIDLK YADPDLPDPL PAGYPLPGFS VCIVDDKMRP
VPLGVQGEIV LGGPCIVSGY LNMPESTRDK FLPDTFFGTS GTVYRSGDRG RLCYDGLLFC
DGRLEGNTMI KLRGFRVELD EVEKTIVSHS AGALSHAVAT VRGTEEGRYL VAHIVFAPEF
PEQDREGVMK SLRQMLPLPP YMRPSVFQVL PDIPRTAHLK IDRKAIQDIP VQTTQSEISK
SLTASEKRLS ELWRRVLPLD PGTLTHESDF FLIGGNSILL VKLQALLREG LWMAPKLVTL
MGSSTLGAMA SVLEDCGPVN VIHWDEEIKF PNDLQLATPL RAAGKSTDIN VLLTGSSGYL
GRHLLLSLLK DHRVAQVHCL CRTSSDQQVV NDPGSKANIV QSDLAQHNLG IPESTYSQLA
TEVDVIIHCA ANRSFWDRYE ALKADNLDST KELVKFVVSS GRAIPLHFLS SGAVAKYNSG
LTPPADGGDG YVATKWASEV FMKQAADSTN LPVFSHRPVA CESAQQSEEE TISIVNELMQ
IVKLLGCRPS FDGVGGFVDV MPVNEIVEAI HETALNSQTG EGLCILEHKA HQRAYVRSFA
TVVESDDGLS KLPCIPILEW FGRAKKAGFS YFLASQDLIL GSQLFSRR
