SQHKS_PHOSM
ID SQHKS_PHOSM Reviewed; 2561 AA.
AC A0A3G1DJF3;
DT 18-SEP-2019, integrated into UniProtKB/Swiss-Prot.
DT 13-FEB-2019, sequence version 1.
DT 03-AUG-2022, entry version 14.
DE RecName: Full=Squalestatin hexaketide synthase {ECO:0000303|PubMed:27056201};
DE Short=SQHKS {ECO:0000303|PubMed:27056201};
DE EC=2.3.1.- {ECO:0000269|PubMed:27056201};
DE AltName: Full=Highly reducing polyketide synthase 2 {ECO:0000303|PubMed:27056201};
DE Short=HR-PKS 2 {ECO:0000303|PubMed:27056201};
DE AltName: Full=Squalestatin S1 biosynthesis cluster protein pks2 {ECO:0000303|PubMed:27056201};
GN Name=pks2 {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, AND INDUCTION.
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.
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.
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.
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). 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:27056201). These
CC initial steps feature the priming of an unusual benzoic acid starter
CC unit onto the highly reducing polyketide synthase pks2, followed by
CC oxaloacetate extension and product release to generate a tricarboxylic
CC acid containing product (By similarity). The phenylalanine ammonia
CC lyase (PAL) M7 and the acyl-CoA ligase M9 are involved in transforming
CC phenylalanine into benzoyl-CoA (By similarity). The citrate synthase-
CC like protein R3 is involved in connecting the C-alpha-carbons of the
CC hexaketide chain and oxaloacetate to afford the tricarboxylic acid unit
CC (By similarity). The potential hydrolytic enzymes, M8 and M10, are in
CC close proximity to pks2 and may participate in product release (By
CC similarity). On the other side, the tetraketide arm is synthesized by a
CC the squalestatin tetraketide synthase pks1 and enzymatically esterified
CC to the core in 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:A0A345BJN0, ECO:0000269|PubMed:11251290,
CC ECO:0000269|PubMed:15489970, ECO:0000269|PubMed:27056201,
CC ECO:0000269|PubMed:28106181, ECO:0000305|PubMed:27056201}.
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:27056201}.
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DR EMBL; KU946987; AMY15068.1; -; Genomic_DNA.
DR AlphaFoldDB; A0A3G1DJF3; -.
DR SMR; A0A3G1DJF3; -.
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:UniProtKB-KW.
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; 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; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 1.
PE 2: Evidence at transcript level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Oxidoreductase; Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2561
FT /note="Squalestatin hexaketide synthase"
FT /id="PRO_0000447826"
FT DOMAIN 2472..2550
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 1..77
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 82..587
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 603..925
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 972..1253
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255"
FT REGION 1421..1599
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000255"
FT REGION 1826..2146
FT /note="Enoyl reductase (ER) (ER) domain"
FT /evidence="ECO:0000255"
FT REGION 2170..2343
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255"
FT COMPBIAS 9..77
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 253
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT MOD_RES 2509
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2561 AA; 280052 MW; 09344402469A1016 CRC64;
MDVSKEEGQR ANGFTNGNIN ETTNGHTNGY TNGHTNGHTN GTTNATTNGT TNGTMNGTTN
GTTNRTTNGT TNITPEFEGK LPQVPVAICG IGVRLPGGVR SDSDLFQMLV DKRDARGIVP
ADRYNVKAYY DPRGRPGSIL TEYGYYIDED LAQMDASMFS MSNVELSMMD PAQRLLLEVT
REAFEGAGEG DFRGKNIGTF VGDFTTDWQE LQYADLIHTA PYQVIGGSDF VLSNRLAYEY
NLTGPSASIK TACSATAEAL HEALLAIRAG SCPSAIVAGA NLILTPRGGI GMTAMGVLSP
DGSCKTFDSS ANGFARGDSV CAIYIKRLDL ALRDGNPIRA VIRACDSNAD GGGSGRTFGT
PNPITHEALI RKTYADAGLD LHSTSVIECH GTGTPIGDPL EAEAVANCFA DGVRPVYIGS
VKPNLGHGEG GSAMASIIKA VVALENRTII PNVKFNNPNP KIAWDKNLKV PTEPLPWPQD
CQERMSINSF GLGGSNTHII IDSAASFGIP SPENSLRETA NSPNEAQTSI LLMSANSPSS
ITAMSQRYSE YIQAHPDRVE DMAFTLATRR ERLKQASYCI VDHGISSNPP PPMASSGVLQ
TAFIFTGQGA QWMGMGKELM QQQPAFAHSI REMDTVIKSL EYAPQWSLEG ILLSDNDADK
SALAQTDRAQ PISTALQVAL VDLLATWHVY PAAVVGHSSG EVAAAYAAGI LTRREAIITA
FYRGHACARC EIPGGMAAVG LGRTKVEPSL KTGVVIACEN SNASVTISGD RSALEEVMAD
LREKYPTALV RKLQVPMGYH SHHMATVADL YKELVSPHLD PKAPQVPYFS TVYGRQVQEG
KAFGPSYWQL NMESPVLFRT AVSEMLKEMG PNTAHLEVGP HSALAGPLRQ IYEETGNSAP
YASTMVRGQN SCTAFLEAIG KLFCFGLSPQ IPSTKTRTVL PDIPTYPWDY KDKFWSETRV
MSNWRFKKHR THELLGERSL ESSDIEPCWR NLLRTGTVPW LADHCVGSDI VFPAAGFIAM
AGAAASQLAG SDGHYTVREV NIFSALVLHE TTATELITTL RKQPLTSSLQ SKWFEFSISS
ESNGVWTKYC SGLVTASVVI SAGLPEMPDT KTFPRKVDTS RWYTTMSRIG LNYGRRFVGL
EEISCSPVHQ VASVQITDVQ DDYEPYPLHP STLDKFLQSW TLAFTKGEYR LLTQLYLPTF
IEELSVSPAP RKKISGRTLA SGIPGTTVGT SLGMVDDELV FSLRGFKCKR TDESFIQNVS
KPRSMTLEWH LDTDFTDLHQ LIRPTRDTAP ENEILERLYL LYALENWDQL KDSTSSHPHL
NIYLSWLAEE VKSFTEPGHP LISDSKELVS MDVPHRRREI AFLRQRSKHY PMAAAVEVYA
RTCARMVEIM EGKDNLLNVL LEDDLLAKFY NYYNDASDLS SFFQAAGLNK PHMRVLEIGA
GTGGWTSHAL RGLTSELGDR LYEEYTITDV SHGFLNQCKE RFAAHSNIKY ALLDISSDPL
EQGFEEGYYD IVIASNVLHA TPKLVETLSR CRKVLNPAGR LLIQEACAPG SRHGYIMGLF
EGWWAGREDG RVRSPLMPVE EWDARLKLAG FEGAGTVVLD GQVPFYNYAN IIAQPAPTTN
VQPESRLTLM TSRPELDDFS ATTKTMLEEA GYQLDVCSWG AELPSDQDVV FLVDTEASVP
SLADENPENL ATFLRYMKDI STSTVLWVTK PAQTACPDPR NGLITGMART LRAELDMYIA
TLELDKLDRS AASAVLQVLR KLQDAARLEE TQEKDEKSSD IKVDFEYALS DGELLIPRFH
PFVVDQALLK DVPRADSRHL EIGQRGMLNT LHWVGDTLSA LGSNEVELNM TAVGMNFLDL
AVAMNIVDMS QSLGKGYNAL GSEGSGIVTR VGSNVTNLKI GDRVATMGVD TSVFATKLQR
PAGSCVRLPS GLSDEDAAGI LVPYATVLWS FIEKARLKKG QTVLIHSAAG GVGIAAIHVA
RWIGAEIYTT VGAQAKVDFL VNELGVARDH IFHSRDDSFV KDVLSATKGK GIDVVLNSLS
GELLHATWQC VAPGGCMLEI GKRDFLGRAQ LAMHLFEENR AYFGIDLSRL ALSEPEALQD
LLQKTMDLLE KQQLQPLWPT NTFDAVAVED AFRYMQRGVH MGRIVVRMPE DDSILPIAPM
LPKPQFKADS TYLLTGGMGG LGRSIIRWMV SYGAKDITVV SRSAGNRDVD RALITEIGEL
GCTLRCFAAD ISDMDSLQNV LSSLTKPVAG VLHMAMVLRD VGTLNMDFDS WTAALRPKVQ
GTWNLHDKLS GSLDFFVLFS SISGTLGSYG QANYAAGNTF LDSFVRFRHG LGQPASVIDI
AAIGDVGYVA ETKDVAERIG RAFGSLGTEQ EFLDTLQLAI ARSTEVPEQQ KLSSKTTKYS
EPSQIVMHNK MIPPLSDPRN TTPWKSDARM AIYRNTEEAP QSANSQSKER LGLFLVSLST
DPDQLDEPET PVLFAQEIAK RVAAFLMKGD KDDDALDTSL TLSQMGADSL VAIEIRNWWK
QTFGMEISTL ELNSPGQTFD SLGRLATKRL KEAYLLKNSG S
