CLZ2_COCLU
ID CLZ2_COCLU Reviewed; 2528 AA.
AC A0A345BJP0;
DT 02-JUN-2021, integrated into UniProtKB/Swiss-Prot.
DT 07-NOV-2018, sequence version 1.
DT 03-AUG-2022, entry version 20.
DE RecName: Full=Squalestatin tetraketide synthase clz2 {ECO:0000303|PubMed:28605916};
DE Short=SQTKS {ECO:0000303|PubMed:28605916};
DE EC=2.3.1.-;
DE AltName: Full=Highly reducing polyketide synthase clz2 {ECO:0000303|PubMed:28605916};
DE Short=HR-PKS clz2 {ECO:0000303|PubMed:28605916};
DE AltName: Full=Squalestatin S1 biosynthesis cluster protein clz2 {ECO:0000303|PubMed:28605916};
DE AltName: Full=Zaragozic acid A biosynthesis cluster protein 2 {ECO:0000303|PubMed:28605916};
DE AltName: Full=Zaragozic acid A tetraketide synthase clz2 {ECO:0000303|PubMed:28605916};
GN Name=clz2 {ECO:0000303|PubMed:28605916};
OS Cochliobolus lunatus (Filamentous fungus) (Curvularia lunata).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Dothideomycetes;
OC Pleosporomycetidae; Pleosporales; Pleosporineae; Pleosporaceae; Curvularia.
OX NCBI_TaxID=5503;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND PATHWAY.
RC STRAIN=ATCC 74067;
RX PubMed=28605916; DOI=10.1021/acs.orglett.7b01534;
RA Liu N., Hung Y.S., Gao S.S., Hang L., Zou Y., Chooi Y.H., Tang Y.;
RT "Identification and heterologous production of a benzoyl-primed
RT tricarboxylic acid polyketide intermediate from the zaragozic acid A
RT biosynthetic pathway.";
RL Org. Lett. 19:3560-3563(2017).
CC -!- FUNCTION: Highly reducing polyketide synthase (HR-PKS); part of the
CC gene cluster that mediates the biosynthesis of squalestatin S1 (SQS1,
CC also known as zaragozic acid A), a heavily oxidized fungal polyketide
CC that offers potent cholesterol lowering activity by targeting squalene
CC synthase (SS) (PubMed:28605916). SQS1 is composed of a 2,8-
CC dioxobicyclic[3.2.1]octane-3,4,5-tricarboxyclic acid core that is
CC connected to two lipophilic polyketide arms (PubMed:28605916). These
CC initial steps feature the priming of an unusual benzoic acid starter
CC unit onto the highly reducing polyketide synthase clz14, followed by
CC oxaloacetate extension and product release to generate a tricarboxylic
CC acid containing product (PubMed:28605916). The phenylalanine ammonia
CC lyase (PAL) clz10 and the acyl-CoA ligase clz12 are involved in
CC transforming phenylalanine into benzoyl-CoA (PubMed:28605916). The
CC citrate synthase-like protein clz17 is involved in connecting the C-
CC alpha-carbons of the hexaketide chain and oxaloacetate to afford the
CC tricarboxylic acid unit (PubMed:28605916). The potential hydrolytic
CC enzymes, clz11 and clz13, are in close proximity to pks2 and may
CC participate in product release (PubMed:28605916). On the other side,
CC the tetraketide arm is synthesized by a the squalestatin tetraketide
CC synthase clz2 and enzymatically esterified to the core in the last
CC biosynthetic step, by the acetyltransferase clz6 (By similarity). The
CC biosynthesis of the tetraketide must involve 3 rounds of chain
CC extension (By similarity). After the first and second rounds methyl-
CC transfer occurs, and in all rounds of extension the ketoreductase and
CC dehydratase are active (By similarity). The enoyl reductase and C-MeT
CC of clz2 are not active in the final round of extension (By similarity).
CC The acetyltransferase clz6 appears to have a broad substrate
CC selectivity for its acyl CoA substrate, allowing the in vitro synthesis
CC of novel squalestatins (By similarity). The biosynthesis of SQS1
CC requires several oxidative steps likely performed by oxidoreductases
CC clz3, clz15 and clz16 (Probable). Finally, in support of the
CC identification of the cluster as being responsible for SQS1 production,
CC the cluster contains a gene encoding a putative squalene synthase (SS)
CC clz20, suggesting a likely mechanism for self-resistance (Probable).
CC {ECO:0000250|UniProtKB:A0A3G1DJH7, ECO:0000269|PubMed:28605916,
CC ECO:0000305|PubMed:28605916}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:28605916}.
CC -!- DOMAIN: Multidomain protein; including a ketosynthase (KS) that
CC catalyzes repeated decarboxylative condensation to elongate the
CC polyketide backbone; a malonyl-CoA:ACP transacylase (MAT) that selects
CC and transfers the extender unit malonyl-CoA; a dehydratase (DH) domain
CC that reduces hydroxyl groups to enoyl groups; a methyltransferase
CC (CMeT) domain responsible for the incorporation of methyl groups; an
CC enoylreductase (ER) domain that reduces enoyl groups to alkyl group; a
CC ketoreductase (KR) domain that catalyzes beta-ketoreduction steps; and
CC an acyl-carrier protein (ACP) that serves as the tether of the growing
CC and completed polyketide via its phosphopantetheinyl arm.
CC {ECO:0000305|PubMed:28605916}.
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DR EMBL; MF806533; AXF50653.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A345BJP0; -.
DR SMR; A0A345BJP0; -.
DR GO; GO:0016746; F:acyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0008168; F:methyltransferase activity; IEA:UniProtKB-KW.
DR GO; GO:0016491; F:oxidoreductase activity; IEA:InterPro.
DR GO; GO:0031177; F:phosphopantetheine binding; 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; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 2.
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; 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; 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; 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; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 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; 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; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53901; SSF53901; 1.
DR SUPFAM; SSF55048; SSF55048; 1.
DR PROSITE; PS50075; CARRIER; 1.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 3: Inferred from homology;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2528
FT /note="Squalestatin tetraketide synthase clz2"
FT /id="PRO_0000452625"
FT DOMAIN 2441..2518
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 17..412
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 420..457
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 538..856
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 925..1239
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1390..1590
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000255"
FT REGION 1817..2130
FT /note="Enoyl reductase (ER) (ER) domain"
FT /evidence="ECO:0000255"
FT REGION 2153..2331
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255"
FT REGION 2408..2430
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2415..2430
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 187
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2478
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2528 AA; 276615 MW; CDC97BEC8FD17B1A CRC64;
MPAMEETQFH DDATVPIAIV GMSCRFPGNA TSPEKLWELC SEGRSAWSKI PKSRFRQEGF
YNPNAERVGT SNVIGGHFLE EDPSLFDASF FNLSAEAAKT MDPQFRLQLE SVYEAMESAG
ITLEHFAGSD TSVYAGACFR DYQDSLVRDP DLVPRFLLTG NGAAMSSNRI SYFYDLHGAS
MTVDTGCSTT LTALHLACQG LRNRESKTSI VTGANVILNP DMFVTMSSLG LDDALRENDT
IRCIIRGTAL NQDGKTATLT SPSQTAQSDL IRACYKAAAL DPSDTAFLAA HGTGTRTGDA
VEISAAADVF GENRLPDRPL WIGSLKTNIG HSEAISGLAS VIQAALALEK GLIPPNINFK
EPNEKLDQVS AVVKVPSTLE KWPVGSGVRR ASVNNFGYGG ANAHVILESV TTGSTHRADV
NGHHQKNGTT NGHKGANGTT NELNGTNGTA NGHDITTGTK DYEQLESFVI ALSAKEEAST
SSMVTNIGDY VRKLHVEDET KHLKSIAHTL GNHRSMFKWT AAKSIKSLGD LLGTAEEGAQ
WFAMGRELIN TYPVFRQSLD RADRYLKEFG CEWSIIEELS RDAETTNVND MMLSPPLCTA
VQISLVLLLE SWGIVSTAVT GHSSGEIAAA YAAGALDFRS AMAVTYFRGE VGLACQDKIV
GQGGMIAVGL GPEDAEIRIA HVQSGKIVIA CINSQSSVTV SGDLTGIVEL EELLKAEGVF
ARRVKVQAAY HSHHMQVIAK GYLTSLKDIL KPGKNFGEII YSSPTTGKRE TNVKLMASPQ
HWVNNMLSPV RFAESFQNMC FSNQKSSQSG EESRDVDIVL EVGPHGMLQG PIQQMMSLPR
FETARIPYLS CLLRGQSAVH TMQTLAAGLM GLGYRVDLAA VNFPQGTSGV KVLHDLPSYP
WNHKNSHWWE PRLNKAHRQR VHPPHDLLGS LIPGRDLREP TWRHFIRVHD IPWIRDHVVQ
SQLVYPGAGF ICMAIEAMSQ FHDLKDSQSK KIAGYRLADI DILRAMIVPD TLEGLEAHIS
LRPCSTKLLL TNDWYEFCVS SVGDDDRFLD HCRGRIAIEL DTSNMADAAM TSSRGYSHTT
GLTRSVDPSN LYRFLRAQGI YHGPIFQNLE TISSRKNHSK SSFVVANTAS VMPNGFQNPH
IIHPTTLDSI FQGAYTALPG AGLDRNTAMI PRSIQELYLS SALTSEVGQC LVSDTSLIRY
DGQSFTVNVD VSSKADNKHK PILEIKGLRN QSVGQIALQK GDSSNNDLCF KLDWALDISS
VKQERLKEKF GFPLDPAEAH IIMGLRQACL YFIRQTLQSL TSSDRDQLDW HQKRFYDWMM
YQIQLAKEDR LGPNSSAWLQ CSSSDEQKLL ENVRAASVNG EMVVHVGGSI PAILRHEIAP
LELMLQDKQL YRYYTDAIKW DRSYQQIDQL VKLHAHKCPT AKIIEIGGGT GGCTRAVLDA
LSNHGAARCE QYDFTDVSSG FFEAAQQKFA AFADVIRFQK LDIEKDIEMQ GFESGSYDLV
IASQVLHATG VMENTMSNVQ KLLKPGGKLL LVETTRDEMD LQLVFGLLPG WWLSSEEERK
MSPSLSVNSW EKVLKKTGFN GLDVELRDCD SDEFYSFSVM MATASSTIAS NSIEAAIVHG
EVPLPDQFLD DLKAAISSFA GLHPVVGPLK SIDVTGKFCI FIEDPETNIL SSPDENSYAS
IKELVTRCKG LIWVSRGGAM HGTRPDSSLK TGLLRTLRLE YTEKRLISLD LDPARPQWDY
DSITTISEVL RQALVQQADS PIKDSEFAEQ DGQLFVPRIS SDISRNDNLS SDSARAAQME
PFHQLGKLLQ MGIKTPGLID TLQFSKTDAP DNLANDYIEI EPKAFGLNFR DVMVAMGQLE
ESIMGFECAG IVRRVGPSSA DHGIKVGDRV CALLGGQWTN TVRVHWHSVA PIPETMNWET
AASIPIVHVT AYISLVKIAK MQAGETVLIH AASGGVGQAA IILAKHAGAE IFATVGTDEK
RELLVKVYKI PEDHIFLSRN ALFAKNIRRK TNGKGVDVVL NCLAGGLLQE SFDCLADFGR
FIEIGKRDIE LNHCLNMGMF ARSTTFTAVD LIAIGRDRSY MVAEALPKIM ALLQEKAIRP
VTPISIYKIG DIETAFRLMQ AGKHMGKIVI TAPEDAMVPV VTQPPKLQLH PDASYLIVGG
LGGIGRSLCR NFIENGARSL VLLSRNANVS QQSGEFLDEL RSTSCIVHVV DCDISNKTQV
ESTMLRLKQE LLPIRGIVHA GMVLQDSVFE RMTLEDYNTA IRPKVQGSWN LHSGLSDRDL
DFFIMLSSLA GVSGSASQAN YTAGGAYQDA LAKHRRVQGL PAVSIDLGMV QSVGYVAETK
GVAERLVRMG YSPISELEVL KIVEHAITNP PPEISSGQII TGISTKPGRH WTESSWLQDA
RFATLRERAR DAKEQSNSQG GGTDSKISPG QELSMATSLV EAIDVVGRAI TAKLATMFLI
AAESIIASKS LSEYGVDSLV AVELRNWLAA QLSSDVSVFD VTQSQSLTAL ATTVATKSAR
INKSLLVA
