CLZ14_COCLU
ID CLZ14_COCLU Reviewed; 2555 AA.
AC A0A345BJN0;
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 hexaketide synthase clz14 {ECO:0000303|PubMed:28605916};
DE Short=SQHKS clz14 {ECO:0000303|PubMed:28605916};
DE EC=2.3.1.- {ECO:0000269|PubMed:28605916};
DE AltName: Full=Highly reducing polyketide synthase clz14 {ECO:0000303|PubMed:28605916};
DE Short=HR-PKS clz14 {ECO:0000303|PubMed:28605916};
DE AltName: Full=Squalestatin S1 biosynthesis cluster protein clz14 {ECO:0000303|PubMed:28605916};
DE AltName: Full=Zaragozic acid A biosynthesis cluster protein 14 {ECO:0000303|PubMed:28605916};
DE AltName: Full=Zaragozic acid A hexaketide synthase clz14 {ECO:0000303|PubMed:28605916};
GN Name=clz14 {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, CATALYTIC ACTIVITY, AND
RP 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:A0A3G1DJF3, ECO:0000269|PubMed:28605916,
CC ECO:0000305|PubMed:28605916}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|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; MF806528; AXF50643.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A345BJN0; -.
DR SMR; A0A345BJN0; -.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
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: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; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 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; IPR013149; ADH-like_C.
DR InterPro; IPR013154; ADH_N.
DR InterPro; IPR011032; GroES-like_sf.
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; IPR020843; PKS_ER.
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; PF08240; ADH_N; 1.
DR Pfam; PF00107; ADH_zinc_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; PF08242; Methyltransf_12; 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; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2555
FT /note="Squalestatin hexaketide synthase clz14"
FT /id="PRO_0000452626"
FT DOMAIN 2468..2546
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..84
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 90..595
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 611..928
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 975..1256
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1424..1595
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000255"
FT REGION 1821..2141
FT /note="Enoyl reductase (ER) (ER) domain"
FT /evidence="ECO:0000255"
FT REGION 2165..2338
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255"
FT COMPBIAS 13..84
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 261
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2505
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2555 AA; 279382 MW; D0AB78B2EF328810 CRC64;
MDVSKEAGHH ANGFANGNTN GTTNGHTNGH TNAHTNVHTN VHTNGHANGH TKVHTNGNTN
GTANETANEA TNRTPNATST TTTTFEGQLP QVPVAICGIG VRLPGGVRSD SDLYQMLVEK
RDARAIVPAD RYNIKSYYDP RGRPGSILTE YGYYIDEDLA QMDASMFSMS NVELSMMDPA
QRLLLEVTRE AFEGAGEGDF RGKNIGTFVG DFTTDWQELQ YADLIHTAPY QVIGGSDFVL
SNRLAYEYNL TGPSASIKTA CSATAEALHE ALLAIRAGSC PSAIVAGANL ILTPRGGIGM
TAMGVLSPDG SCKTFDSSAN GFARGDSVCA IYIKRLDLAL RDGNPIRAVI RACDSNADGG
GTGRTFGTPN PITHEALIRK TYADAGLELH NTSVIECHGT GTPIGDPLEA EAVANCFADG
KRPVYIGSVK PNLGHGEGGS AMASIIKAVV ALENRTIIPN VKFKNPNPKI AWDKNLKVPT
EPLPWPQDCQ ERMSINSFGL GGSNTHIIID SAASFGIPSP HSSLHETADL SNEAQTSILL
MSANSLSSIT AMSQRYSEYV QAHPDRVEDM AYTLATRRER LKQASYCIFN DGVLSTPPPP
VVSSGIVQTA FIFTGQGAQW LGMGKELMQQ QRAFAHSIRE MDAVIKSLEY APDWSLEDSD
ADKSALAQTD RAQPISTALQ VALVDLLATW NVHPAAVVGH SSGEVAAAYA ARILTRREAI
ITAFYRGHAC ARCEIPGGMA AVGLGRTKVE PLLKSGVVIA CENSNASVTI SGDRDALEEA
MAGLREKYPT TLVRKLQVPM GYHSHHMATV ADLYHRLVSP HLDPKSPQVP YFSTVYGRQV
QEAKAFGPSY WQLNMESPVL FRTAVSEMLR EMGSNTAHLE VGPHSALAGP LRQIYEETGL
SAPYASTMVR GQNSCTAFLE GIGKLFCFGL SPQIPSSKTR TVLPDIPTYP WDYKDKFWSE
TRVMSNWRFK KHRTHELLGE RSLESSDIEP CWRNLLRTGT VPWLADHCVG SDIIFPAAGF
IAMAGAAASQ LAGSDGHYTV REVHIFSALV LHETTATELI TTLRKQPLTS SLQSKWFEFS
ISSESNGVWT KYCSGLVTAS VVTSAGLPEM PDTTAFSRKV DTSRWYTSMS RIGLNYGRRF
VGLEDISCSP VHQVASVQIN DVQDDYEPYP LHPSTIDKFL QSWTLAFTKG EYRLLTQLYL
PTFIEELSVA PAPGKKISGR TLASGIPGTT VGSSLGVVDD ELVLSLRGFK CKKTDDAFIQ
NVSKPRSMTL EWHLDTNFTD LHQLIKPTRD TAPENEILER LYVLYALENW DQLKNSTSSH
PHLNIYLSWL EEEVKGFTEP GHPLISDSKE LVSMDVPHRR REIAFLRQRS KHYPMAAAVE
VYARTCARMV EIMEGKDNLL NVLLEGDLLA KFYNYYNDAS DLSSFFQAAG LNKPHMRVLE
IGAGTGGWTA HALRGLTSEL GDRLYEEYTI TDVSHGFLNQ CKERFAAHSN IKYALLDISS
DPLEQGFEEG YYDIVIASNL VETLCRCRKV LNPAGCLLIQ EACAPGSRHG YIMGLFEGWW
AGREDGRVRS PLIPVEEWDA RLKLAGFEGA GTVVLDGQVP YYNYANIIAR PAPTTIAQPE
SRLTLMTSSP ELEDFSAILK TMLEEAGYLL DVCPWGADLP SDQDVVFLVD TEASVPVLAD
ENPDNLATFL RYMKDISTST VLWVTKPAQT ICPDPRHGLI TGMARTLRAE LDMYIATLEI
HKLDKPAASA VVQVLRKLQD AARLEESQGD EKSSDIKVDF EYAFSNGELL IPRFHPFVVD
QVLLKDVPCA DSRHLEIAQR GMLNTLHWVG DTLPELGPSE VELNMTAVGM NFLDLAVAMN
IVDMAQSLGK GYNALGSEGS GIVTRVGSSV TNLKVGDRVA TMGVDTSVFA SKLQRPAESC
VRLPPGLSDE DAAGILVPYA TVLWSFIEKA RLKKGQTVLI HSAAGGVGIA AIHVARWIGA
EIYTTVGAQA KVDFLVNELD VPRDRIFHSR DDSFVKDVLS ATNGKGIDVV LNSLSGELLH
ATWQCVAPGG CMLEIGKRDF LGRAQLAMHL FEENRAYFGI DLSRLALSEP EALQELLQKT
MVLLEKQQLQ PLWPTNTFDA VAVEDAFRYM QRGVHMGRIV VRMPEDDSVL PIAPVLPEPQ
FKADSTYLLT GGMGGLGRSI IRWMVSYGAK DITVMSRSAG NRDVDRALIA EIGELGCTLQ
CFAADIADMH SLQNVLSSLS KPVAGVLHMA MVLRDVGTLN MDFDSWTAAL RPKVQGTWNL
HDKLSENLDF FVLFSSISGT LGSYGQANYA AGNTFLDSFV RFRHGLGRPA SVIDIAAIGD
VGYVAETKDV AERIGRAFGS LGTEQEFLDT LQLAIARSTG PPEQQELSSK KTTKYAQPSQ
IVMHNRMIPP LSDPRNTTPW KNDARMAIYR NTEEAPQSTS SQSKERLGLF LVSLTTDPDQ
LDEPETPIIF AQEIAKRVAA FLMKGDKEDN ALDTSLTLSQ MGADSLVAIE IRNWWKQTFG
MEISTLELNS PGQTFDSLGR LATKRLKEAY ILKSS
