SQTKS_PHOSM
ID SQTKS_PHOSM Reviewed; 2605 AA.
AC A0A3G1DJH7;
DT 18-SEP-2019, integrated into UniProtKB/Swiss-Prot.
DT 13-FEB-2019, sequence version 1.
DT 03-AUG-2022, entry version 16.
DE RecName: Full=Squalestatin tetraketide synthase {ECO:0000303|PubMed:27056201};
DE Short=SQTKS {ECO:0000303|PubMed:27056201};
DE EC=2.3.1.- {ECO:0000269|PubMed:27056201};
DE AltName: Full=Highly reducing polyketide synthase 1 {ECO:0000303|PubMed:27056201};
DE Short=HR-PKS 1 {ECO:0000303|PubMed:27056201};
DE AltName: Full=Squalestatin S1 biosynthesis cluster protein pks1 {ECO:0000303|PubMed:27056201};
GN Name=pks1 {ECO:0000303|PubMed:27056201};
OS Phoma sp. (strain ATCC 20986 / MF5453).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Dothideomycetes;
OC Pleosporomycetidae; Pleosporales; Pleosporineae; Didymellaceae; Phoma.
OX NCBI_TaxID=1828523;
RN [1]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, INDUCTION, DOMAIN, DISRUPTION
RP PHENOTYPE, AND PATHWAY.
RX PubMed=27056201; DOI=10.1039/c6cc02130a;
RA Bonsch B., Belt V., Bartel C., Duensing N., Koziol M., Lazarus C.M.,
RA Bailey A.M., Simpson T.J., Cox R.J.;
RT "Identification of genes encoding squalestatin S1 biosynthesis and in vitro
RT production of new squalestatin analogues.";
RL Chem. Commun. (Camb.) 52:6777-6780(2016).
RN [2]
RP FUNCTION, AND DOMAIN.
RX PubMed=11251290; DOI=10.1016/s1074-5521(00)90064-4;
RA Nicholson T.P., Rudd B.A., Dawson M., Lazarus C.M., Simpson T.J., Cox R.J.;
RT "Design and utility of oligonucleotide gene probes for fungal polyketide
RT synthases.";
RL Chem. Biol. 8:157-178(2001).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, AND PATHWAY.
RX PubMed=15489970; DOI=10.1039/b411973h;
RA Cox R.J., Glod F., Hurley D., Lazarus C.M., Nicholson T.P., Rudd B.A.,
RA Simpson T.J., Wilkinson B., Zhang Y.;
RT "Rapid cloning and expression of a fungal polyketide synthase gene involved
RT in squalestatin biosynthesis.";
RL Chem. Commun. (Camb.) 2004:2260-2261(2004).
RN [4]
RP FUNCTION, DOMAIN, CATALYTIC ACTIVITY, AND BIOPHYSICOCHEMICAL PROPERTIES.
RX PubMed=28106181; DOI=10.1039/c6cc10172k;
RA Liddle E., Scott A., Han L.C., Ivison D., Simpson T.J., Willis C.L.,
RA Cox R.J.;
RT "In vitro kinetic study of the squalestatin tetraketide synthase
RT dehydratase reveals the stereochemical course of a fungal highly reducing
RT polyketide synthase.";
RL Chem. Commun. (Camb.) 53:1727-1730(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:27056201, PubMed:11251290, PubMed:15489970,
CC PubMed:28106181). SQS1 is composed of a 2,8-dioxobicyclic[3.2.1]octane-
CC 3,4,5-tricarboxyclic acid core that is connected to two lipophilic
CC polyketide arms (PubMed:27056201). These initial steps feature the
CC priming of an unusual benzoic acid starter unit onto the highly
CC reducing polyketide synthase pks2, followed by oxaloacetate extension
CC and product release to generate a tricarboxylic acid containing product
CC (By similarity). The phenylalanine ammonia lyase (PAL) M7 and the acyl-
CC CoA ligase M9 are involved in transforming phenylalanine into benzoyl-
CC CoA (By similarity). The citrate synthase-like protein R3 is involved
CC in connecting the C-alpha-carbons of the hexaketide chain and
CC oxaloacetate to afford the tricarboxylic acid unit (By similarity). The
CC potential hydrolytic enzymes, M8 and M10, are in close proximity to
CC pks2 and may participate in product release (By similarity). On the
CC other side, the tetraketide arm is synthesized by a the squalestatin
CC tetraketide synthase pks1 and enzymatically esterified to the core in
CC the last biosynthetic step, by the acetyltransferase M4
CC (PubMed:11251290, PubMed:15489970, PubMed:28106181). The biosynthesis
CC of the tetraketide must involve 3 rounds of chain extension
CC (PubMed:11251290, PubMed:15489970, PubMed:28106181). After the first
CC and second rounds methyl-transfer occurs, and in all rounds of
CC extension the ketoreductase and dehydratase are active
CC (PubMed:11251290, PubMed:15489970, PubMed:28106181). The enoyl
CC reductase and C-MeT of pks1 are not active in the final round of
CC extension (PubMed:11251290, PubMed:15489970, PubMed:28106181). The
CC acetyltransferase M4 appears to have a broad substrate selectivity for
CC its acyl CoA substrate, allowing the in vitro synthesis of novel
CC squalestatins (Probable). The biosynthesis of SQS1 requires several
CC oxidative steps likely performed by oxidoreductases M1, R1 and R2
CC (Probable). Finally, in support of the identification of the cluster as
CC being responsible for SQS1 production, the cluster contains a gene
CC encoding a putative squalene synthase (SS) R6, suggesting a likely
CC mechanism for self-resistance (Probable).
CC {ECO:0000250|UniProtKB:A0A345BJP0, ECO:0000269|PubMed:11251290,
CC ECO:0000269|PubMed:15489970, ECO:0000269|PubMed:27056201,
CC ECO:0000269|PubMed:28106181, ECO:0000305|PubMed:27056201}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=4.5 mM for 2R,3R-3-hydroxy-2-methylbutyric acid N-acetylcysteamine
CC thioester (for the DH domain) {ECO:0000269|PubMed:28106181};
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:27056201}.
CC -!- INDUCTION: Expression is induced on squalestatin S1-producing YMG
CC medium. {ECO:0000269|PubMed:27056201}.
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:11251290}.
CC -!- DISRUPTION PHENOTYPE: Impairs the production of SQS1 and accumulates a
CC compound corresponding to the squalestatin core and in which the
CC tetraketide sidechain is missing. {ECO:0000269|PubMed:27056201}.
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DR EMBL; KU946987; AMY15057.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A3G1DJH7; -.
DR SMR; A0A3G1DJH7; -.
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:UniProtKB-KW.
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; -; 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; 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; 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; 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 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Oxidoreductase; Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2605
FT /note="Squalestatin tetraketide synthase"
FT /id="PRO_0000447825"
FT DOMAIN 2518..2595
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 32..458
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 471..508
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 610..933
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1002..1316
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1467..1667
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000255"
FT REGION 1894..2207
FT /note="Enoyl reductase (ER) (ER) domain"
FT /evidence="ECO:0000255"
FT REGION 2230..2408
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255"
FT ACT_SITE 202
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2555
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2605 AA; 284477 MW; 3E263C74A3A52B5D CRC64;
MVPHYQQASS CESNTMTAMD EYQHHEDATI PIAIIGMSCR FPGNATSPEK LWELCAEGRS
AWSKIPKSRF RQEGFYNPNA ERVGTSHVVG GHFLEEDPSL FDASFFNLSA EAAKTMDPQF
RLQLESVYEA MESAGITLEH IAGSDTSVYA GACFRDYHDS LVRDPDLVPR FLLTGNGAAM
SSNRISYFYD LHGASMTVDT GCSTTLTALH LACQGLRNRE SKTSIVTGAN VILNPDMFVT
MSSLGLLGPE GKSHTFDARA NGYGRGEGIA TVIIKRLDEA LAAQDPIRCI IRGTALNQDG
KTATLTSPSQ TAQSDLIRAC YRAAALDPND TAFLAAHGTG TRTGDAVEIA AAAEVFGEKR
LPDRPLWIGS LKTNIGHSEA TSGLASVIQA ALALEKGLIP PNINFKEPNE KLSQVSSAVK
VPSTLEKWPL GSRVRRASVN NFGYGGANAH VILESGLTGS TQLANGNGHY ETNGTTNGHK
GANGTTNGHK GANGTTNGHN GTNGITNGHD ITRGTIDYEP LESFVISLSA KEEAGTRSMM
TNLGEYLRKN HVDDETKHFK SIAYTLGSHR STFKWTAAKP ITSLEELLAA AGGGQFQASR
ALERTRLGFV FTGQGAQWFA MGRELINTYP VFRKSLDRAN GYLKEFGCEW SILDELSRDA
ETSNVNDMTL SPPLCTAVQI SLVRLLESWG IVPTAVTGHS SGEIAAAYAA GALDFRSAMA
VTYFRGEVGL ACQDKIVGKG GMIAVGLGPE EAEDRIARVQ SGKIVIACIN SQSSVTVSGD
LAGIVELEEG LKAEGVFARR VKVQAAYHSH HMQVIANGYL TSLKDILKPG KKFGEIIYSS
PTTGKRETSA KLMASAQHWV NNMLSPVRFA ESFQNMCFPT QKVSRSGELE QDVDIILEVG
PHGMLQGPIQ QMMSLPRFES ARMPYLSCLL RGQSAVYTMQ SLAAGLMGWG YRVDMAAVNF
PQGTHGARIL HDLPSYPWNH DNSHWWEPRL NKAHRQRVHP PHDLLGSLIP GRDLREPTWR
HFIRVQDIPW IRDHVVQSQL VYPGAGFICM AIEAMVQLHD LKDSQSKKIA GYRLADVDIL
RAMLIPDTSE GLEAHISLRP CSTKLLLTNE WYDFCVSSVG EDDKFVDHCR GRIAVEFNTS
SLSDAPKTTS RERSRGAGLT RSVDPSNLYS FLRAQGIYHG SIFQNLKTIS SRKNYSESSF
VVADTASVMP DGFQSAHVVH PTTLDSIFQG AYTALPSAGL DQKTAMIPRS IQEIYLSSAL
TSEVGQCLVS DTSLIRYDGQ SFTVNVGISS KADSECTPVL EIKGLRNQSV GQMAPQQGDS
GNNDLCFKLE WALDISSVKQ ERLKEKFGFP LDPAEADIIM GLRQACLYYI RQALTSLTPS
ARDQLDWHQK RFYDWMMLQM HLAEEDRLAP NSSAWLQCTS SDEQKLLENV RAASVNGQMV
VHVGESILAI LRHEIAPLEL MLQDKLLYRY YTDAIKWDRS YQQIDQLVKL HAHKCPSAKI
IEIGAGTGGC TRAVLDALST HGAARCAQYD FTDVSSGFFE AAQQKFTAFA DVIRFQKLDI
EKDIETQGFE CGSYDLVIAS QVLHATGKIE DTMANVRRLL KPGGKLLLVE TTRDEMDLQL
VFGLLPGWWL SSEEERKMSP SLSTSSWEKV LKKTGFNGLD VELRDCDSDQ FYSFSVIMAT
ASPTVPMNPV DFIILHGKSS IPDQWMNDLR TATSPFTKSD PVVGHINNAD PTGKFCIFLE
DPEEDILFHP DEKSYASIKR VITQCKGLLW ISRGGSMHGT LPTSSLKTGL LRTLRLEYAE
KRFISLDLNP ARAPWAHESI STIREVLRGA LAQTAEIPIR DSEFAENDGQ LYVPRISSDI
ARNEALSSNS HSPAQTEPFH QPGKLLQMGI KTPGLIDTLQ FSKTDAPDHL PADYIEIEPK
AFGLNFRDVM VAMGQLEESI MGFECAGIVR RVGPSSAGHN IKVGDRVCAL LGGQWTNTVR
VHWHAVAPIP QAMGWETAAS IPIVFVTAYI SLVKIAKLQA KETVLIHAAS GGVGQAAIIL
AKYAGAEIFA TVGTEEKREL LIKEYKIPDD HIFSSRNALF AKSIRQRTNG KGVDVVLNCL
AGGLLQESFD CLADFGRFIE IGKRDIELNH CLNMGMFARS ATFTAVDLIA IGRDRSYMVA
EALPKVMALL QQKAVRPVTP ISIYKIGDIE TAFRLMQAGK HMGKIVITAP EDAMVPVVTQ
PPKLQLRSDA SYLIVGGLGG IGRSLCKNFV ENGARSLVLL SRNANVSRQS GEFLDELRST
GCVVSVVDCD ISNKTQVEST MLRLKEEKLP IRGIVHAGMV LQDSVFEHMT LEDYNTATRP
KVRGSWNLHS ALSDCDLDFF IMLSSLAGVS GSASQANYTA GGAYQDALAT YRRSRGLAAV
SIDLGMVQSV GYVAETKGVA ERLVRMGYSP ISEMEVLKIV EHAITNPPPE TSSGQIITGI
STKPGRHWTE SSWLQDARFA TLRERARDVK EQSNAQGGGQ DKQIGAGQEL SMATSLVEAI
DVVGRAITAK LATMFLIAAE SIIASKSLSE YGVDSLVAVE LRNWLAAQLS SDVSVFDVTQ
SQSLTALATT VATKSSRIDK SLLVA
