LCSC_PURLI
ID LCSC_PURLI Reviewed; 2332 AA.
AC A0A179H0J7;
DT 10-APR-2019, integrated into UniProtKB/Swiss-Prot.
DT 07-SEP-2016, sequence version 1.
DT 03-AUG-2022, entry version 27.
DE RecName: Full=Highly reducing polyketide synthase lcsC {ECO:0000303|PubMed:27416025};
DE Short=HR-PKS lcsC {ECO:0000305|PubMed:27416025};
DE EC=2.3.1.- {ECO:0000305|PubMed:27416025};
DE AltName: Full=Leucinostatins biosynthesis cluster protein C {ECO:0000303|PubMed:27416025};
GN Name=lcsC {ECO:0000303|PubMed:27416025}; ORFNames=VFPBJ_02532, VFPFJ_04704;
OS Purpureocillium lilacinum (Paecilomyces lilacinus).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Sordariomycetes;
OC Hypocreomycetidae; Hypocreales; Ophiocordycipitaceae; Purpureocillium.
OX NCBI_TaxID=33203;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA], IDENTIFICATION, FUNCTION,
RP DOMAIN, DISRUPTION PHENOTYPE, INDUCTION, AND PATHWAY.
RC STRAIN=PLBJ-1;
RX PubMed=27416025; DOI=10.1371/journal.ppat.1005685;
RA Wang G., Liu Z., Lin R., Li E., Mao Z., Ling J., Yang Y., Yin W.B., Xie B.;
RT "Biosynthesis of antibiotic leucinostatins in bio-control fungus
RT Purpureocillium lilacinum and their inhibition on phytophthora revealed by
RT genome mining.";
RL PLoS Pathog. 12:E1005685-E1005685(2016).
CC -!- FUNCTION: Highly reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of the lipopeptide antibiotics
CC leucinostatins that show extensive biological activities, including
CC antimalarial, antiviral, antibacterial, antifungal, and antitumor
CC activities, as well as phytotoxic (PubMed:27416025). Leucinostatin A
CC contains nine amino acid residues, including the unusual amino acid 4-
CC methyl-L-proline (MePro), 2-amino-6-hydroxy-4-methyl-8-oxodecanoic acid
CC (AHyMeOA), 3-hydroxyleucine (HyLeu), alpha-aminoisobutyric acid (AIB),
CC beta-Ala, a 4-methylhex-2-enoic acid at the N-terminus as well as a
CC N1,N1-dimethylpropane-1,2-diamine (DPD) at the C-terminus (Probable).
CC The biosynthesis of leucinostatins is probably initiated with the
CC assembly of 4-methylhex-2-enoic acid by a reducing PKS. Two reducing
CC polyketide synthases, lcsB and lcsC, have been identified in the
CC cluster and it is not clear which is the one that assembles 4-
CC methylhex-2-enoic acid since both contain KS, AT, DH, cMT, ER, KR and
CC ACP domains (Probable). The polyketide residue might be transferred to
CC the NRPS lcsA, mediated by two additional enzymes, the acyl-CoA ligase
CC lcsD and the thioesterase lcsE. The linear polyketide carboxylic acid,
CC which is released from PKS, is converted to a CoA thioester by lcsD,
CC and then lcsE hydrolyzes the thiol bond and shuttles the polyketide
CC intermediate to lcsA (Probable). The C domain of the first module
CC catalyzed the condensation of 4-methylhex-2-enoic acid and MePro
CC carried by domain A1, followed by successive condensations of nine
CC amino acids to trigger the elongation of the linear peptide. A5 and A6
CC domains of lcsA are proposed to incorporate leucine, A2 AHyMeOA, and A3
CC incorporates HyLeu. A4, A7 and A8 incorporate AIB (Probable). The
CC AHyMeOA in leucinostatin A activated by the A2 might be produced by the
CC second PKS (lcsB or lcsC) present within the cluster (Probable). The
CC MePro is probably produced via leucine cyclization and may originate
CC from a separate pathway, independent of the cluster. Another
CC nonproteinogenic amino acid, beta-Ala, could be produced by an aspartic
CC acid decarboxylase also localized outside of the cluster. Two
CC candidates are VFPBJ_01400 and VFPBJ_10476 (Probable). The final
CC peptide scaffold may be released by the NAD(P)H-dependent thioester
CC reductase (TE) at the C-terminal region of lcsA (Probable).
CC Transamination of the lcsA product by the transaminase lcsP may produce
CC DPD at the C-terminus (Probable). Further hydroxylation steps performed
CC alternatively by the cytochrome P450 monooxygenases lcsI, lcsK and lcsN
CC then yield the non-methylated leucinostatins precursor. It is also
CC possible that leucines can be hydroxylated prior to their incorporation
CC into the peptide (Probable). Varying extents of methylation then lead
CC to the formation of leucinostatins A and B (Probable).
CC {ECO:0000269|PubMed:27416025, ECO:0000305|PubMed:27416025}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000305|PubMed:27416025}.
CC -!- INDUCTION: Expression is positively regulated by the leucinostatins
CC biosynthesis cluster-specific transcription regulator lcsF.
CC {ECO:0000269|PubMed:27416025}.
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:27416025}.
CC -!- DISRUPTION PHENOTYPE: Abolishes the production of leucinostatins A and
CC B. {ECO:0000269|PubMed:27416025}.
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DR EMBL; LSBH01000002; OAQ83765.1; -; Genomic_DNA.
DR EMBL; LSBI01000004; OAQ90545.1; -; Genomic_DNA.
DR RefSeq; XP_018179264.1; XM_018321784.1.
DR AlphaFoldDB; A0A179H0J7; -.
DR SMR; A0A179H0J7; -.
DR EnsemblFungi; OAQ83765; OAQ83765; VFPBJ_02532.
DR EnsemblFungi; OAQ90545; OAQ90545; VFPFJ_04704.
DR GeneID; 28886833; -.
DR KEGG; plj:VFPFJ_04704; -.
DR OrthoDB; 19161at2759; -.
DR Proteomes; UP000078240; Unassembled WGS sequence.
DR Proteomes; UP000078340; Unassembled WGS sequence.
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; 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; 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; 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; Reference proteome;
KW Transferase.
FT CHAIN 1..2332
FT /note="Highly reducing polyketide synthase lcsC"
FT /id="PRO_0000446601"
FT DOMAIN 2246..2322
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258,
FT ECO:0000305|PubMed:27416025"
FT REGION 1..32
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 50..455
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 446..708
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 714..1011
FT /note="Dehydrogenase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 1193..1369
FT /note="Methyltransferase (CMet) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 1603..1916
FT /note="Enoyl reductase (ER) (ER) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT REGION 1945..2122
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:27416025"
FT MOD_RES 2282
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2332 AA; 253547 MW; A638E44C0E2D32D6 CRC64;
MSPTAIRDVS SRSSDNTPSD AQSTGSPVST TLSTDQFLSD AESQGSFPPI AIVGIGLRLP
GGVNTTEAFW SSILNKQSFR SEVPRSRYNV DAFHSTSGRP GTVKSRHGYF LEDDISSMDA
AFFSMSKAEV ERLDPQQRLL LEVVWECMES AGQRDWRGRN IGCYVGVFGE DWLDLNAKDP
QHTGMYRITG TADFALANRV SYEFDMKGPS MTIETGCSSS LVGLHEACAA IHAGACESAV
VAGTNLLLSP TMTLALSEQG VLSPSGMCQS FDAKADGYVR GEAVNAVFVK KLEDAVRDGD
PIRAIIRGTA TNFDGKTAGI SNPSSDSHEA LIRQAYAAAG IDDFTSTAFV ECHGTGTPTG
DPIETTAVGR VFGEKGVYIG SVKPNVGHSE GASGLTSLIK TVLALEHSTI PPQANFADPN
PKSGDDLDIQ FSPITKARPG SSTVNFLFTG QGAQWAGMAL ELLHDFPDFL ASIRAMDKAL
QSLPHPPNWT MEEELQRPKE LNRINEPEFS QPICTALQVG LVNLLYTVGI RPAAVVGHSS
GEIAAAYAAG ALSQDAAITV AYYRGQVTKK QTRRGGMAAV GLGSEEVAQF LKATEHTAGI
VGVACVNSPN SVTLSGDDEA LDAAIGRIKS AMPDCFVRRL KVDKAYHSHH MEEIGDIYEM
LIAPYVSTKE LRIPLFSSVT SKRIISSEHL GAPYWRSNLE RPVLFSSARK FPPHELLGVR
TMDADDLEPA WRNMLRLDDA AWIRDHKIHD DVVFPAAGYV SMIGEAIRQI NSDDIPIADF
SLKQVDIRTA LVLREDETKE LVTRMRKVRL TTSLESSAWF EFCISSFNGE TWVKHCTGQA
RASSDAVIQG EPELGEDHPR PVSSPAAWYR TMKAVGLNYG PQFQGLTNIS AASATMTKDE
DRKAAATIRD RSHDEQDRMA ETKYQIHPTT IDYCLQTFMV AVASGLSREL NNLRMPTYID
QLYIRRGATS MRVGVSVGTS QGGLVRGTAT AVSDGQVVLW MRGVELSSLG DTNTPTEGGS
SPDDGVAAAQ LVWKPDLDFA DPSTLIESHG RVRDACVKVE RLSLLCSLET LRRVRDLPVG
TSLSHLEKFR TWLVAQRQRA VDGTYDHVPD APTLASLGPE HLGAEMLAAQ VAVDGTSGSE
VGKVMVRSVE FAEAIFRGEI DSIEVLIQQS GLENVYIYMQ SLCEYERYFE LLGHSNPCLR
ILEIGAGTGG TTEGVLKGLT RPDSNGQPLR RYSQYDYTDV SVGFFGNAQQ RFKDYENIQY
RVLDITREPE AQGFEEGSYD LVLASNVLHA TPSLQETLSN VRRLLKPGGK LFLQELSPVY
RAINYIMGFL PGWWLGDMDG RPTEPYVVPS RWDSELRKTG FSGVDSAIFD DEAPYHLNAN
IIATAVLESP SQGTAPNGHV SILCTTRDSS IATQLHNTLA DQGHDVTFTS LNDGPPENGC
IISLLDLEEP FFYRMTSEKL SKLQSYLGGI APSSALLWVT GLGQVGCKDP VYASTLGAAR
TIRSELAIDF ATLELDLSRL PLRLYVDTII GVCGKIERTC HLKGSGELDP DWEFASVDGE
VLIPRYNWIG IDQDVQYIPG GSEAPADTSG DEEALQLSVG RPGQLQSLTW VAGEALPPLG
PDQIEIEPRA VGLNFKDVLV AMGIVQGLKP GLGLECAGII RRVGSEVQDL KVGDRVVAFD
HGFFASRTIT SSKLAAKIPD ALTFEEAATM PCVYSTAMHA LVQVGGLQSG QSVLIHSACG
GVGIAAINIC RMKGAEIFAT VGNPEKAYFL MKEFGIRQDH IFHSRDGSFY TDLMEVTQGR
GVDLVLNSLS GELLHTSWKC VAEFGKMLEI GKRDFVGRGQ LAMDTFEANR MFVGVDMSQM
AIGRPDMFKR VLGDCMRCFS QGLIDPIRPI KSFPASQVVD AFRYMQKGQH IGKIVVTMPG
EGHASSASNL EIVRRAKSAH FRPDASYLLV GGLGGLGRAV STWMIENGAR SLVYLSRSGG
ESLQDKAFVR ELSAQGCTAQ VFKGDAACQQ DVEKAIRDAD RPIAGVLLMS MVLQDRAFLK
LTLNDWHAAV APKVNAAWAV HNALESTQTN LDFMVLFSSL SAVMGQIGQA NYASGNTFLA
AFAQYRHALS LPASVLDIGV MEDVGYVSEN QGILEQFRSL GYYTLKEQGL LDALTFSIKN
QEPRTVDTSQ LLNSAEIVIG LRSLQPVSDP TTRVLWKRDR RMALAHLKRA SSSAGDTATA
ASGSQDLAVF VSKVADQPHL IEQEETQEFL TKQIGARLYA FMFQPEEDLD VNLSLTALGI
DSLVAIEIRN WWRQTFGLEL SVLEIMSASS IKALGKLAID GLRKEHRRDT GS
