CLA2_CLACD
ID CLA2_CLACD Reviewed; 2368 AA.
AC A0A0Y0M151;
DT 07-SEP-2016, integrated into UniProtKB/Swiss-Prot.
DT 13-APR-2016, sequence version 1.
DT 03-AUG-2022, entry version 21.
DE RecName: Full=Highly reducing polyketide synthase cla2 {ECO:0000303|PubMed:26783060};
DE EC=2.3.1.- {ECO:0000269|PubMed:26783060};
DE AltName: Full=Cladosporin biosynthesis cluster protein 2 {ECO:0000303|PubMed:26783060};
GN Name=cla2 {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 -!- 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; KT037691; AMB51799.1; -; mRNA.
DR AlphaFoldDB; A0A0Y0M151; -.
DR SMR; A0A0Y0M151; -.
DR GO; GO:0016746; F:acyltransferase activity; IEA:InterPro.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:InterPro.
DR GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR GO; GO:0008270; F:zinc ion binding; IEA:InterPro.
DR GO; GO:0009058; P:biosynthetic process; IEA:UniProt.
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 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; IPR013154; ADH_N.
DR InterPro; IPR011032; GroES-like_sf.
DR InterPro; IPR014031; Ketoacyl_synth_C.
DR InterPro; IPR014030; Ketoacyl_synth_N.
DR InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
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; IPR020843; PKS_ER.
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; IPR002364; Quin_OxRdtase/zeta-crystal_CS.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF08240; ADH_N; 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; PF00550; PP-binding; 1.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00829; PKS_ER; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF50129; SSF50129; 1.
DR SUPFAM; SSF51735; SSF51735; 2.
DR SUPFAM; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
DR PROSITE; PS01162; QOR_ZETA_CRYSTAL; 1.
PE 1: Evidence at protein level;
KW Multifunctional enzyme; Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2368
FT /note="Highly reducing polyketide synthase cla2"
FT /id="PRO_0000437051"
FT DOMAIN 2283..2360
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 13..437
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 548..877
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 936..1175
FT /note="Dehydratase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1655..1967
FT /note="Enoylreductase (ER) domain"
FT /evidence="ECO:0000255"
FT REGION 1991..2170
FT /note="Catalytic ketoreductase (KRc) domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 182
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 182
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 638
FT /note="For malonyltransferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 968
FT /note="For beta-hydroxyacyl dehydratase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2320
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2368 AA; 257782 MW; 78CFB5EDCD2BC244 CRC64;
MTSSGDSSPQ IPIAIVGLGC RFPGDADSPK KFWDILKEGR DAYSPRTDRW NPDAFYHPNK
DRANTQPTKG GHFLKQDPYV FDPSFFNITA TEAIALDPKQ RLALEVAYEA LENAGFPLQK
VAGSQTACYM GSAMADYRDS ISRDFGHAPK YFVLGTCEEM ISNRISHFFD MHGPSATVHT
ACSSSLVATH VACQSLRSGE ADMALAGGVG IMLTPDSSLQ LNNMSFLNPE GHSRSFDADA
GGYARGEGCG ILVMKRLDDA VRDGDNIRAV IRGSGVNSDG WTQGVTMPSP EAQAALIKQV
FGKNKLDYDT IQYVEAHGTG TKAGDPVETK AIYDTIGRGI NKSRKLWIGS VKPNIGHLEA
AAGVAGIIKG VLSLENSAIP PNIYFSKPNP AIKLDEWNMA VPTKLVNWPV AQTKRMTVSG
FGMGGTNGLV VLEAYVPERL LNGATKVTTA KDTAHSGKRL FVCSSQDQAG FKRIGEAFVD
HLDNLGPIAS SSGYLANLAH TLSTARAGLS WRTTFVADSK AELREHLTTT LGQDATRVSD
TQAQRIGFVF TGQGAQWAGM GVEMLERPVF GASVAESAKL LRSFGCTWDP ATELQKAAKE
SRLAVPEISQ PICTIIQIAL VDELKSWGVS PAKVVGHSSG EIAAAYTIGA LSHRDAMAVA
YFRGMASTAL KTSAPHLEGG MMAVGTSAEA AQTIIAETKN SISGDITIAC VNSPSSVTLS
GDAKALEELR KILDARSVFA RRLKVDVAYH SSHMNVAAPE YQQSIADIEP RLCSDEVEEG
SLPVMVSSVT TEQVSPELLG TYYWIRNLVS PVQFSDALRE LVAPGGSDKN DVDLLIEIGP
HSALGGPIEQ ILSFHNVQKV DYKSVLTRGQ NALDTSLSLA SDLFVRGIQL DMEKVNGDSD
CHLLNDLPSY PWNHSKAFRA DSRIQRELLQ SKHPRHSMIG LKQPMLDESQ HVWRNYVRLT
DEPWLRGHVV GGTALVPGAG MLSMIFEAVQ QLVDPGKPAH SLRVRDVKFS AALTLPEDTS
IEVVTTLRPH LVSTSGSTPA SWWEFTISSC PGTDQIQDNC RGLVAIEYTN KRSEQMIYED
VNEENSRIAD FHRVRDESPL MIRREKFYEH MQKSGYNYGE TFQGMETVHL GDGETAFHVK
LIDIGETFSK GQLDRPFLIP GSSLDAIFQS IFGSTFKNGA FEVEKPNFLA YIGELEISLD
IPGEVGYVMP GVCFSRKHGF NQQSADIFTF DKSLSRMHLA VRDFRMTEPE VGDDASDGFE
PWAFTSAPHW NYAFSLLKTE ELRSVLSKVT TQDAPVELLR TILHENPSAS VLELIPEIGD
LAIASSYQLP KGAIQPSQLR YAVAKDIPDS FIDENLVGEV FALDGVGEDD RKISADVLIV
PSSLDLLEDR DAILARFLKL AGPAALMITA SGLHSARSVF EAHGFQAFPG LNGIASLPGL
YSHAEEPSLR QTNRGTRDTS DTDITILEPS SPSFNTTEFS KTLSSRLEDQ NYSVTIRKWA
GGETEEFQNT TYISLLELEQ PFLDNLSDPD FQGIKNLVLG SNRLIWLTLG DDPSFGAVDG
LSRVMRSELG TPKFQVMHLS GEAGLLSGPE LTVRVLKSPT EDTEFRERDG LLQVIRIFES
PDVNQSLRGH LENSTRILPI KQLDYPVRLT VGKPGFLDSL QFIKDRRTEA PLPENEIEID
VHASGVNFRD VMASMGLIST PILGFEASGV VTKCGSQVSQ FRTGARVSFV GEHTHSTRIR
ADPRLVAPIP DDVSFEEAAS LPIVGATAYH TLTNLARLRK GQTILIHAAA GGVGQAMIQL
ASHFGLVIYA TVGTEDKRKL LGEKYNIPPE NILNSRDASF AKGIKRLTGG RGVDCVINSL
SGELLRASWG CVAPFGIFIE LGLRDITDNM RLDMRPFSNV TSFTFCNILA LMQQDPDAMG
LVLKETFKLV SQGILTSPFP TTVFPVEQTQ EAFRLMQQGK HRGKLVLSFA GDPQAPVHCE
AKESLRLDGN ATYLIIGGLG GLGRSMALEL VASGARHLAF ISRSGDSTPQ AKATLAELEQ
RNLDFRVYRG DVSNEESFLD AMKLCSSDLP PIKGVIQMAM VLKDIIFEKM THEQWTIPLR
PKIQGTWNIH QYFDESRPLD FMVFCSSTSG IHGYPSQSQY AAGNTYQDTL AAYRRAHGLK
AVAVNLTIIR EVGILAEQGT TGNIAVWEEA LGIKEPAFHA LMKTLIAGQQ GPAGSEFLPP
QVSTGLGTAD IMSSYNLALP DYFQDPRFGP LAVSTFSTNV AGESQSAAVS LSSKLIEATN
VDQASEIITE GLVTKVADML QIPVSEVDAS RPMYRYGVDS LVALEVRNWI VKEMKATIAL
LEILAAVPMN VLAKTIASRS KHLAATLD
