ID   CLA3_CLACD              Reviewed;        2073 AA.
AC   A0A125R003;
DT   07-SEP-2016, integrated into UniProtKB/Swiss-Prot.
DT   13-APR-2016, sequence version 1.
DT   25-MAY-2022, entry version 19.
DE   RecName: Full=Non-reducing polyketide synthase cla3 {ECO:0000303|PubMed:26783060};
DE            EC=2.3.1.- {ECO:0000269|PubMed:26783060};
DE   AltName: Full=Cladosporin biosynthesis cluster protein 3 {ECO:0000303|PubMed:26783060};
GN   Name=cla3 {ECO:0000303|PubMed:26783060};
OS   Cladosporium cladosporioides.
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Dothideomycetes;
OC   Dothideomycetidae; Cladosporiales; Cladosporiaceae; Cladosporium.
OX   NCBI_TaxID=29917;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, AND CATALYTIC ACTIVITY.
RX   PubMed=26783060; DOI=10.1002/anie.201509345;
RA   Cochrane R.V., Sanichar R., Lambkin G.R., Reiz B., Xu W., Tang Y.,
RA   Vederas J.C.;
RT   "Production of new cladosporin analogues by reconstitution of the
RT   polyketide synthases responsible for the biosynthesis of this antimalarial
RT   agent.";
RL   Angew. Chem. Int. Ed. 55:664-668(2016).
RN   [2]
RP   BIOTECHNOLOGY.
RX   PubMed=5169000; DOI=10.7164/antibiotics.24.747;
RA   Scott P.M., Van Walbeek W., MacLean W.M.;
RT   "Cladosporin, a new antifungal metabolite from Cladosporium
RT   cladosporioides.";
RL   J. Antibiot. 24:747-755(1971).
RN   [3]
RP   BIOTECHNOLOGY.
RX   PubMed=22704625; DOI=10.1016/j.chom.2012.04.015;
RA   Hoepfner D., McNamara C.W., Lim C.S., Studer C., Riedl R., Aust T.,
RA   McCormack S.L., Plouffe D.M., Meister S., Schuierer S., Plikat U.,
RA   Hartmann N., Staedtler F., Cotesta S., Schmitt E.K., Petersen F., Supek F.,
RA   Glynne R.J., Tallarico J.A., Porter J.A., Fishman M.C., Bodenreider C.,
RA   Diagana T.T., Movva N.R., Winzeler E.A.;
RT   "Selective and specific inhibition of the plasmodium falciparum lysyl-tRNA
RT   synthetase by the fungal secondary metabolite cladosporin.";
RL   Cell Host Microbe 11:654-663(2012).
RN   [4]
RP   BIOTECHNOLOGY.
RX   PubMed=24935905; DOI=10.1007/s10969-014-9182-1;
RA   Khan S., Sharma A., Belrhali H., Yogavel M., Sharma A.;
RT   "Structural basis of malaria parasite lysyl-tRNA synthetase inhibition by
RT   cladosporin.";
RL   J. Struct. Funct. Genomics 15:63-71(2014).
RN   [5]
RP   BIOTECHNOLOGY.
RX   PubMed=26074468; DOI=10.1016/j.chembiol.2015.05.007;
RA   Fang P., Han H., Wang J., Chen K., Chen X., Guo M.;
RT   "Structural Basis for Specific Inhibition of tRNA Synthetase by an ATP
RT   Competitive Inhibitor.";
RL   Chem. Biol. 22:734-744(2015).
CC   -!- FUNCTION: Highly reducing polyketide synthase; part of the gene cluster
CC       that mediates the biosynthesis of cladosporin, a tricyclic octaketide
CC       that acts as an antimalarial agent though inhibition of the Plasmodium
CC       falciparum lysyl-tRNA synthetase (PubMed:26783060). The highly reducing
CC       polyketide synthase cla2 is responsible for biosynthesis up to the
CC       pentaketide stage, including of the tetrahydropyran (THP) ring, whereas
CC       the three subsequent ketide extensions with no reduction are catalyzed
CC       by the non-reducing polyketide synthase cla3 (PubMed:26783060).
CC       {ECO:0000269|PubMed:26783060}.
CC   -!- PATHWAY: Secondary metabolite biosynthesis.
CC       {ECO:0000269|PubMed:26783060}.
CC   -!- DOMAIN: Multidomain protein; including a starter unit:ACP transacylase
CC       (SAT) that selects the starter unit; a ketosynthase (KS) that catalyzes
CC       repeated decarboxylative condensation to elongate the polyketide
CC       backbone; a malonyl-CoA:ACP transacylase (MAT) that selects and
CC       transfers the extender unit malonyl-CoA; a product template (PT) domain
CC       that controls the immediate cyclization regioselectivity of the
CC       reactive polyketide backbone; and an acyl-carrier protein (ACP) that
CC       serves as the tether of the growing and completed polyketide via its
CC       phosphopantetheinyl arm (By similarity).
CC       {ECO:0000250|UniProtKB:Q5B0D0}.
CC   -!- DOMAIN: The release of the polyketide chain from the non-reducing
CC       polyketide synthase is mediated by the thioesterase (TE) domain
CC       localized at the C-ter of the protein (By similarity).
CC       {ECO:0000250|UniProtKB:Q5ATJ7}.
CC   -!- BIOTECHNOLOGY: Cladosporin has been intensely studied for its
CC       antimalarial activity though inhibition of the Plasmodium falciparum
CC       lysyl-tRNA synthetase (PubMed:22704625, PubMed:24935905,
CC       PubMed:26074468). Cladosporin has also antifungal activity against
CC       dermatophytes, as well as Penicillium and Aspergillus species
CC       (PubMed:5169000). {ECO:0000269|PubMed:22704625,
CC       ECO:0000269|PubMed:24935905, ECO:0000269|PubMed:26074468,
CC       ECO:0000269|PubMed:5169000}.
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DR   EMBL; KT037692; AMB51800.1; -; mRNA.
DR   AlphaFoldDB; A0A125R003; -.
DR   SMR; A0A125R003; -.
DR   GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR   GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR   GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR   Gene3D; 1.10.1200.10; -; 1.
DR   Gene3D; 3.10.129.110; -; 1.
DR   Gene3D; 3.40.366.10; -; 1.
DR   Gene3D; 3.40.47.10; -; 1.
DR   Gene3D; 3.40.50.1820; -; 1.
DR   InterPro; IPR029058; AB_hydrolase.
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; 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; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR   InterPro; IPR020807; PKS_dehydratase.
DR   InterPro; IPR042104; PKS_dehydratase_sf.
DR   InterPro; IPR020806; PKS_PP-bd.
DR   InterPro; IPR009081; PP-bd_ACP.
DR   InterPro; IPR006162; Ppantetheine_attach_site.
DR   InterPro; IPR030918; PT_fungal_PKS.
DR   InterPro; IPR032088; SAT.
DR   InterPro; IPR001031; Thioesterase.
DR   InterPro; IPR016039; Thiolase-like.
DR   Pfam; PF00698; Acyl_transf_1; 1.
DR   Pfam; PF00109; ketoacyl-synt; 1.
DR   Pfam; PF02801; Ketoacyl-synt_C; 1.
DR   Pfam; PF00550; PP-binding; 1.
DR   Pfam; PF14765; PS-DH; 1.
DR   Pfam; PF16073; SAT; 1.
DR   Pfam; PF00975; Thioesterase; 1.
DR   SMART; SM00827; PKS_AT; 1.
DR   SMART; SM00825; PKS_KS; 1.
DR   SMART; SM00823; PKS_PP; 1.
DR   SUPFAM; SSF47336; SSF47336; 1.
DR   SUPFAM; SSF52151; SSF52151; 1.
DR   SUPFAM; SSF53474; SSF53474; 1.
DR   SUPFAM; SSF53901; SSF53901; 1.
DR   SUPFAM; SSF55048; SSF55048; 1.
DR   TIGRFAMs; TIGR04532; PT_fungal_PKS; 1.
DR   PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR   PROSITE; PS50075; CARRIER; 1.
DR   PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE   1: Evidence at protein level;
KW   Multifunctional enzyme; Phosphopantetheine; Phosphoprotein; Transferase.
FT   CHAIN           1..2073
FT                   /note="Non-reducing polyketide synthase cla3"
FT                   /id="PRO_0000437052"
FT   DOMAIN          1641..1718
FT                   /note="Carrier"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   REGION          9..242
FT                   /note="N-terminal acylcarrier protein transacylase domain
FT                   (SAT)"
FT                   /evidence="ECO:0000255"
FT   REGION          366..796
FT                   /note="Ketosynthase (KS) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          898..1198
FT                   /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          1276..1590
FT                   /note="Product template (PT) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          1594..1637
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1721..1786
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1805..1950
FT                   /note="Thioesterase (TE) domain"
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        1723..1741
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1743..1771
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        538
FT                   /note="For beta-ketoacyl synthase activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT   ACT_SITE        987
FT                   /note="For acyl/malonyl transferase activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT   ACT_SITE        2058
FT                   /note="For thioesterase activity"
FT                   /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT   MOD_RES         1678
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ   SEQUENCE   2073 AA;  225592 MW;  5EF5CA3E150078BC CRC64;
     MHNGSESVLL FGDYTEPWIE SIDSLCRQAV SEAWLQSFLD DTVTIIKEQK RSIERILQDS
     LGEFTDLKDL ADRHRGRTDE ISYVQGLMLF TVRAAYLLQW VKRDPSLLTA SHAIGFSGGL
     ANASVLAVAQ DFDTLYTACL EGLRIFSRSC RLAIVRSRAI EEGSGSWGWL VVGISSNDLR
     HALDHFQNSL GIPNSKRSKV GLTGDRWNTV IGPPSTLELV FKQCPAIKSL PKEKLNIHAL
     QHALDLSESD LDYIIGDSAL AQSHVNPEFS LWGMAQPKEP WGSWGELLKV VIVKMLSEPL
     DIVGVVDEFS GRLGSVPQVN ICNMAMEGPS SHAAYLLSTM KLSGKTVNFE NGFGSEKAQS
     ASSGRIAIVG MSGRGPGCED LEEFWNVISN AQDQHQEIPK DRFNLEDYLK QGHVTHCQSE
     SMAKHGCFIT KPGEFDARFF HISPREALLM DPGHRMFLMS AYEALETAGY SNGHTKATDP
     QKISIFFAQC NDDWRIASHD VKGCDSYTLP GTARAFGPGR LAFHLGWEGP AYSMDSACAS
     SVSSVHFACM SLKNKDTDMA VVGAANVIGY PHTFISLSQS GVLSRTGNCK PFRDDADGYC
     RADFSGAIVL KRLEDAIAAN DNILGVLAGT GRNQAGNATS ITTSDTATQT RLFHKVLRSA
     NVSPEDISYV EMHGTGTPIG DPAEMGAIAN VFGNRKGNTP LPLGAVKGNV GHSESSAGMA
     SLLKCLMMLQ KDAIPPQAGM PHALNPKFPS LSDINVVIPS KLGDFKKTLN MPRRILLNNF
     DAAGGNGCLL LEEYVPPTSK ELNIDEQDPR STHVVVLSAK TQASHHANKR NLLDWLKTNR
     STRIQDIAYT STARRVHWPL RYAIAASSTQ ELTTKLESSI ARENSESTNG RKSPIVFTFT
     GQGSQYAGMG AELYSTCFAF RDTIKLCARI CDDHQFPDFI DIITDKDIDI STKSPLQIQL
     ALLALEIGLA AFWKSIGVLP DMVVGHSLGE YAALYVAGVL SLGDVFYVVG RRAMLLLDRC
     EIGSCSMLAL NASVATVQAH LDTQPHLSCA VACINGPKAT VVSGPLGEIA DLQTLFHGNK
     IRSKLLPVPF AFHSLQMEPI LDEFTILAGI ATFMQPKIPV ASTLLATVVD KEGIFGTQYL
     AEQTRQRVDF VGALNAVKSK MDDPIWLEVG PSPVCSGLVQ ATISPSTTKI MSTLDATGSD
     WSSIAHCLSG LYQNGVDIDW LGLHAPYEGG LTLQALPSYQ WDLKDYWMPY VEPSGVDQTV
     IANTASGRGT MSSSISTCAQ YVITETKTPK PQVNLGAPTA DAGFKAFIDG HRLRGVPVCA
     GAVFIEAAET AARYLLKYLG RNDADTAVLS LQDMALIRPI TQKSVQANAE LQTTATLDSG
     SKDTVRITFG ESLAAGSSQH LGGCLLSICE AGLESQWEKS SFFIRSRMND IIANVKGGQG
     HRIQRDIYYA LFADTVEYDN PFRGVKEAYV SQDFEEAAAE VILKADPTGT QFTTSPYWTD
     SLSQLCGFVV NGNPSRPKDI TYMMASLGSY IQMGQIVPGK SYFTYSRISD RAQDLVYCDT
     FVFDNDRLVA QSTNCVFHRV QNVILERLLG KPASSSVPAQ ASDPLRSKRS PQEARSLPGE
     AKTEKPGSTI ATTSPVLESG KSEQGMFQAL IAAIVKTTGG ELSELNDDTE LADIGVDSIM
     AIEIVAHVKD ATNQDLPLSF VLEYPTIGNL RCAFDEDVSS EFTDSEVTSG TPNSSESVTS
     EEELPGPEEH AFKEPKDDSP LARRDMDNSN DRSLDGGVLD DGSPQPRVRI SLLQGRPVRG
     KPKFFLIADG SGSIATYIHL PPAKVKMPIY GVDSPFLHCP SRFTPEAGIP AAAKWIVEAL
     MKAQPEGPFF LGGFSGGAML SYEVARQLAA FDRKVDSMVL IDMCCPRPAV SSDLKESLWN
     DDIESFEEIA SHVGSNVASN MQQHLRAIFK AVSVYHPPSM TAKERPDRTI IIWAKKGMIT
     RCHDVPEIME RLSARGLTRT IPEGFMEDPS FGAIRWSFVS KGANDLGPNG WQKYIGHEPL
     CLSVDLDHLE MMEPGQVHIF RGAFEEAFRL IEA