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PKSA_DOTSE
ID   PKSA_DOTSE              Reviewed;        2399 AA.
AC   Q30DW5;
DT   28-FEB-2018, integrated into UniProtKB/Swiss-Prot.
DT   06-DEC-2005, sequence version 1.
DT   25-MAY-2022, entry version 88.
DE   RecName: Full=Norsolorinic acid synthase {ECO:0000250|UniProtKB:Q12053};
DE            Short=NSAS {ECO:0000250|UniProtKB:Q12053};
DE            EC=2.3.1.221 {ECO:0000250|UniProtKB:Q12053};
DE   AltName: Full=Dothistromin biosynthesis polyketide synthase {ECO:0000303|PubMed:16649078};
DE   AltName: Full=Polyketide synthase A {ECO:0000303|PubMed:16649078};
GN   Name=pksA {ECO:0000303|PubMed:16649078};
OS   Dothistroma septosporum (Red band needle blight fungus) (Mycosphaerella
OS   pini).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Dothideomycetes;
OC   Dothideomycetidae; Mycosphaerellales; Mycosphaerellaceae; Dothistroma.
OX   NCBI_TaxID=64363;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND DISRUPTION PHENOTYPE.
RC   STRAIN=NZE7;
RX   PubMed=16649078; DOI=10.1007/s11046-006-0240-5;
RA   Bradshaw R.E., Jin H., Morgan B.S., Schwelm A., Teddy O.R., Young C.A.,
RA   Zhang S.;
RT   "A polyketide synthase gene required for biosynthesis of the aflatoxin-like
RT   toxin, dothistromin.";
RL   Mycopathologia 161:283-294(2006).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND INDUCTION.
RC   STRAIN=NZE7;
RX   PubMed=17683963; DOI=10.1016/j.fgb.2007.06.005;
RA   Zhang S., Schwelm A., Jin H., Collins L.J., Bradshaw R.E.;
RT   "A fragmented aflatoxin-like gene cluster in the forest pathogen
RT   Dothistroma septosporum.";
RL   Fungal Genet. Biol. 44:1342-1354(2007).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RC   STRAIN=NZE1 / ATCC MYA-605;
RA   Zhang S., Bradshaw R.E.;
RL   Submitted (JUL-2010) to the EMBL/GenBank/DDBJ databases.
RN   [4]
RP   FUNCTION.
RC   STRAIN=ATCC MYA-605;
RX   PubMed=12039746; DOI=10.1128/aem.68.6.2885-2892.2002;
RA   Bradshaw R.E., Bhatnagar D., Ganley R.J., Gillman C.J., Monahan B.J.,
RA   Seconi J.M.;
RT   "Dothistroma pini, a forest pathogen, contains homologs of aflatoxin
RT   biosynthetic pathway genes.";
RL   Appl. Environ. Microbiol. 68:2885-2892(2002).
RN   [5]
RP   INDUCTION.
RX   PubMed=18262779; DOI=10.1016/j.mycres.2007.03.018;
RA   Schwelm A., Barron N.J., Zhang S., Bradshaw R.E.;
RT   "Early expression of aflatoxin-like dothistromin genes in the forest
RT   pathogen Dothistroma septosporum.";
RL   Mycol. Res. 112:138-146(2008).
RN   [6]
RP   REVIEW ON FUNCTION, AND PATHWAY.
RX   PubMed=22069571; DOI=10.3390/toxins2112680;
RA   Schwelm A., Bradshaw R.E.;
RT   "Genetics of dothistromin biosynthesis of Dothistroma septosporum: an
RT   update.";
RL   Toxins 2:2680-2698(2010).
RN   [7]
RP   FUNCTION, INDUCTION, AND PATHWAY.
RX   PubMed=23207690; DOI=10.1016/j.fgb.2012.11.006;
RA   Chettri P., Ehrlich K.C., Cary J.W., Collemare J., Cox M.P.,
RA   Griffiths S.A., Olson M.A., de Wit P.J., Bradshaw R.E.;
RT   "Dothistromin genes at multiple separate loci are regulated by AflR.";
RL   Fungal Genet. Biol. 51:12-20(2013).
RN   [8]
RP   FUNCTION.
RX   PubMed=23448391; DOI=10.1111/nph.12161;
RA   Bradshaw R.E., Slot J.C., Moore G.G., Chettri P., de Wit P.J.,
RA   Ehrlich K.C., Ganley A.R., Olson M.A., Rokas A., Carbone I., Cox M.P.;
RT   "Fragmentation of an aflatoxin-like gene cluster in a forest pathogen.";
RL   New Phytol. 198:525-535(2013).
RN   [9]
RP   INDUCTION.
RX   PubMed=25986547; DOI=10.1016/j.funbio.2015.01.007;
RA   Chettri P., Ehrlich K.C., Bradshaw R.E.;
RT   "Regulation of the aflatoxin-like toxin dothistromin by AflJ.";
RL   Fungal Biol. 119:503-508(2015).
CC   -!- FUNCTION: Polyketide synthase; part of the fragmented gene cluster that
CC       mediates the biosynthesis of dothistromin (DOTH), a polyketide toxin
CC       very similar in structure to the aflatoxin precursor, versicolorin B
CC       (PubMed:12039746, PubMed:17683963, PubMed:22069571, PubMed:23207690,
CC       PubMed:23448391). The first step of the pathway is the conversion of
CC       acetate to norsolorinic acid (NOR) and requires the fatty acid synthase
CC       subunits hexA and hexB, as well as the polyketide synthase pksA
CC       (PubMed:16649078, PubMed:23207690). PksA combines a hexanoyl starter
CC       unit and 7 malonyl-CoA extender units to synthesize the precursor NOR
CC       (By similarity). The hexanoyl starter unit is provided to the acyl-
CC       carrier protein (ACP) domain by the fungal fatty acid synthase
CC       hexA/hexB (By similarity). The second step is the conversion of NOR to
CC       averantin (AVN) and requires the norsolorinic acid ketoreductase nor1,
CC       which catalyzes the dehydration of norsolorinic acid to form (1'S)-
CC       averantin (PubMed:23207690). The cytochrome P450 monooxygenase avnA
CC       then catalyzes the hydroxylation of AVN to 5'hydroxyaverantin (HAVN)
CC       (PubMed:23207690). The next step is performed by adhA that transforms
CC       HAVN to averufin (AVF) (PubMed:23207690). Averufin might then be
CC       converted to hydroxyversicolorone by cypX and avfA (PubMed:23207690).
CC       Hydroxyversicolorone is further converted versiconal hemiacetal acetate
CC       (VHA) by moxY (PubMed:23207690). VHA is then the substrate for the
CC       versiconal hemiacetal acetate esterase est1 to yield versiconal (VAL)
CC       (PubMed:23207690). Versicolorin B synthase vbsA then converts VAL to
CC       versicolorin B (VERB) by closing the bisfuran ring (PubMed:16649078,
CC       PubMed:23207690). Then, the activity of the versicolorin B desaturase
CC       verB leads to versicolorin A (VERA) (PubMed:23207690). DotB, a
CC       predicted chloroperoxidase, may perform epoxidation of the A-ring of
CC       VERA (PubMed:23207690). Alternatively, a cytochrome P450, such as cypX
CC       or avnA could catalyze this step (PubMed:23207690). It is also possible
CC       that another, uncharacterized, cytochrome P450 enzyme is responsible
CC       for this step (PubMed:23207690). Opening of the epoxide could
CC       potentially be achieved by the epoxide hydrolase epoA
CC       (PubMed:23207690). However, epoA seems not to be required for DOTH
CC       biosynthesis, but other epoxide hydrolases may have the ability to
CC       complement this hydrolysis (PubMed:23207690). Alternatively, opening of
CC       the epoxide ring could be achieved non-enzymatically (PubMed:23207690).
CC       The next step is the deoxygenation of ring A to yield the 5,8-
CC       dihydroxyanthraquinone which is most likely catalyzed by the NADPH
CC       dehydrogenase encoded by ver1 (PubMed:23207690). The last stages of
CC       DOTH biosynthesis are proposed to involve hydroxylation of the bisfuran
CC       (PubMed:23207690). OrdB and norB might have oxidative roles here
CC       (PubMed:23207690). An alternative possibility is that cytochrome P450
CC       monoogenases such as avnA and cypX might perform these steps in
CC       addition to previously proposed steps (PubMed:23207690).
CC       {ECO:0000250|UniProtKB:Q12053, ECO:0000269|PubMed:12039746,
CC       ECO:0000269|PubMed:16649078, ECO:0000303|PubMed:22069571,
CC       ECO:0000305|PubMed:17683963, ECO:0000305|PubMed:23207690,
CC       ECO:0000305|PubMed:23448391}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=6 H(+) + hexanoyl-[ACP] + 7 malonyl-CoA = 7 CO2 + 7 CoA + 2
CC         H2O + holo-[ACP] + noranthrone; Xref=Rhea:RHEA:35179, Rhea:RHEA-
CC         COMP:9632, Rhea:RHEA-COMP:9685, ChEBI:CHEBI:15377, ChEBI:CHEBI:15378,
CC         ChEBI:CHEBI:16526, ChEBI:CHEBI:57287, ChEBI:CHEBI:57384,
CC         ChEBI:CHEBI:64479, ChEBI:CHEBI:77904, ChEBI:CHEBI:78459;
CC         EC=2.3.1.221; Evidence={ECO:0000250|UniProtKB:Q12053};
CC   -!- COFACTOR:
CC       Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC         Evidence={ECO:0000250|UniProtKB:Q12053};
CC       Note=Binds 1 phosphopantetheine covalently.
CC       {ECO:0000250|UniProtKB:Q12053};
CC   -!- PATHWAY: Mycotoxin biosynthesis. {ECO:0000303|PubMed:22069571,
CC       ECO:0000305|PubMed:23207690}.
CC   -!- INDUCTION: Expression is positively regulated by the dothistromin-
CC       specific transcription factors aflR and aflJ (PubMed:23207690,
CC       PubMed:25986547). Dothistromin biosynthetic proteins are co-regulated,
CC       showing a high level of expression at ealy exponential phase with a
CC       subsequent decline in older cultures (PubMed:17683963,
CC       PubMed:18262779). {ECO:0000269|PubMed:17683963,
CC       ECO:0000269|PubMed:18262779, ECO:0000269|PubMed:23207690,
CC       ECO:0000269|PubMed:25986547}.
CC   -!- DOMAIN: The domain architecture includes starter unit:ACP transacylase
CC       (SAT), beta-ketoacyl synthase (KS), malonyl-CoA:ACP transacylase (MAT),
CC       product template (PT), 3 acyl-carrier domain (ACP), and
CC       thioesterase/Claisen cyclase (TE/CLC) domains (PubMed:16649078).
CC       Although duplicated ACP domains are common, pksA is the only fungal PKS
CC       containing 3 ACP domains (PubMed:16649078). The third (C-terminal) ACP
CC       is less similar in sequence to the first two and to that of the
CC       aflatoxin biosynthetic enzyme aflC (PubMed:16649078). It is possible
CC       that the third ACP domain was acquired by unequal recombination and has
CC       since diverged into a slightly different form that may have less
CC       functionality or altered specificity (PubMed:16649078).
CC       {ECO:0000305|PubMed:16649078}.
CC   -!- DISRUPTION PHENOTYPE: Impairs the production of dothistromin but still
CC       enables the conversion of exogenous aflatoxin precursors, including
CC       norsolorinic acid, into dothistromin (PubMed:16649078).
CC       {ECO:0000269|PubMed:16649078}.
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DR   EMBL; DQ149246; AAZ95017.1; -; Genomic_DNA.
DR   AlphaFoldDB; Q30DW5; -.
DR   SMR; Q30DW5; -.
DR   ESTHER; mycpj-q30dw5; Thioesterase.
DR   OMA; KWGCWLD; -.
DR   GO; GO:0102973; F:norsolorinate anthrone synthase activity; IEA:UniProtKB-EC.
DR   GO; GO:0031177; F:phosphopantetheine binding; IEA:InterPro.
DR   GO; GO:0009058; P:biosynthetic process; IEA:InterPro.
DR   Gene3D; 1.10.1200.10; -; 3.
DR   Gene3D; 3.10.129.110; -; 1.
DR   Gene3D; 3.40.366.10; -; 2.
DR   Gene3D; 3.40.47.10; -; 1.
DR   Gene3D; 3.40.50.1820; -; 1.
DR   InterPro; IPR029058; AB_hydrolase.
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; IPR014031; Ketoacyl_synth_C.
DR   InterPro; IPR014030; Ketoacyl_synth_N.
DR   InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
DR   InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR   InterPro; IPR020807; PKS_dehydratase.
DR   InterPro; IPR042104; PKS_dehydratase_sf.
DR   InterPro; IPR020806; PKS_PP-bd.
DR   InterPro; IPR009081; PP-bd_ACP.
DR   InterPro; IPR030918; PT_fungal_PKS.
DR   InterPro; IPR032088; SAT.
DR   InterPro; IPR001031; Thioesterase.
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; PF00550; PP-binding; 3.
DR   Pfam; PF14765; PS-DH; 1.
DR   Pfam; PF16073; SAT; 1.
DR   Pfam; PF00975; Thioesterase; 1.
DR   SMART; SM00827; PKS_AT; 1.
DR   SMART; SM00825; PKS_KS; 1.
DR   SMART; SM00823; PKS_PP; 3.
DR   SUPFAM; SSF47336; SSF47336; 3.
DR   SUPFAM; SSF52151; SSF52151; 1.
DR   SUPFAM; SSF53474; SSF53474; 1.
DR   SUPFAM; SSF53901; SSF53901; 1.
DR   SUPFAM; SSF55048; SSF55048; 1.
DR   TIGRFAMs; TIGR04532; PT_fungal_PKS; 1.
DR   PROSITE; PS50075; CARRIER; 3.
PE   2: Evidence at transcript level;
KW   Acyltransferase; Multifunctional enzyme; Phosphopantetheine;
KW   Phosphoprotein; Repeat; Transferase.
FT   CHAIN           1..2399
FT                   /note="Norsolorinic acid synthase"
FT                   /id="PRO_0000443456"
FT   DOMAIN          1733..1812
FT                   /note="Carrier 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   DOMAIN          1877..1953
FT                   /note="Carrier 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   DOMAIN          2020..2099
FT                   /note="Carrier 3"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   REGION          10..247
FT                   /note="Starter unit:ACP transacylase (SAT) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          375..808
FT                   /note="Ketoacyl synthase (KS)domain"
FT                   /evidence="ECO:0000250|UniProtKB:Q12053, ECO:0000255"
FT   REGION          905..1192
FT                   /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT                   /evidence="ECO:0000250|UniProtKB:Q12053, ECO:0000255"
FT   REGION          1307..1327
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1353..1658
FT                   /note="Product template (PT) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          1665..1734
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          2098..2149
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          2164..2393
FT                   /note="Thioesterase/Claisen cyclase (TE/CLC) domain"
FT                   /evidence="ECO:0000255"
FT   COMPBIAS        1711..1726
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        2098..2122
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        544
FT                   /note="For beta-ketoacyl synthase activity"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        995
FT                   /note="For acyl/malonyl transferase activity"
FT                   /evidence="ECO:0000250"
FT   ACT_SITE        2234
FT                   /note="For thioesterase activity"
FT                   /evidence="ECO:0000250|UniProtKB:Q12053"
FT   MOD_RES         1770
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   MOD_RES         1911
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   MOD_RES         2057
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ   SEQUENCE   2399 AA;  259252 MW;  C82F86A242F2AFE4 CRC64;
     MTHSNATRVL VFGDQTYDFV PKLRELFHVK DNPILTAFLE QSHYVVRAQM IQTLPPAEHK
     AARTFDLADM LKKYVAGKLN PAFQTALSCI TQLGVFMREF HDFTKPYPRH DSSYVLGICT
     GSLAAAAVSS SNSLSELLPI AVQTALIAFR LGLCVTDMRD RLESSEEDRT QPWSVVLFDT
     DEQTVTKAIK DFCTSNVLPK TKQPWITSAS SKTITISGAP RVLKKLSQEP ALKDKKTRQI
     PIYVPAHNSA LFTPEDVKSI LETTPVDTWS NYPTKLPFIS SVSGKMAWAD NYLAVIHLAL
     NQCLLESIGW GKVETELPRL LKSRGAENVL ITPITTSADR ALSAALSPTI SNIEVEKPTI
     NESFAHRPGS GKSKLAIVSM SGRFPEAQST DAFWDLLYKG LDVVKEVPKR RWDVETHVDP
     TGRARNKGAT KWGCWLDFAG EFDPRFFSIS PKEAPQMDPA QRMALMSTWE AMERGGIVPD
     TTPSTQRNRI GVFHGVTSND WMETNTAQNI DTYFITGGNR GFIPGRINFC FEFSGPSFTN
     DTACSSSLAA IHLACNSLWR GDCDTAVAGG TNMIFTPDGH AGLDKGFFLS RTGNCKPFDD
     KADGYCRAEG VGTVMVKRLE DALADGDPIL GTILDAKTNH SAMSDSMTRP FVPAQIDNME
     ACLSTAGVDP TSLDYIEMHG TGTQVGDAVE MESVLSVFAP NEQFRGKDQP LYVGSAKANI
     GHGEGVSGVT SLIKVLLMMQ NNTIPPHCGI KPGSKINHNY PDLAARNVHI AFEPKPFLRR
     EGKLRRVLIN NFSAAGGNTA LLIEDAPDRM PLSGQDPRTT QTVTISGHVG KSLSNNVANL
     LAHLKKNPTI DLSQLAYTVS ARRWHHLHRV AVAGTTVADI TAKLEKAIEN KEGVNRPKAK
     PSVFFAFTGQ GSQYLGMGKQ LYDSYPMFRS ELQGYDRLAQ SQGFPSFAHI FTETKGDVEQ
     NLPVVVQLAI TCLQMALFNL VTSFGIKASA VVGHSLGEYA ALYAAGVLSA SDTIYLVGKR
     AELLQDHCQR GTHAMLACKA SEWSLAEITA GKNVEVACVN GPEDTVLSGT VEEIGEVQKT
     LSAKSIKATL LKLPFAFHSA QVQPILEDFE ELAAGATFEK PKLAVISPLL GSVVEDEGVV
     GPNYLARHCR EAVGMVKALG VAKEKGIINE KTIVIEIGPK PLLCGMIKNI LGQNIVALPT
     LKDKGPDVWQ NLSNIFTTLY TGGLDINWTA FHAPFEPAKK VLQLPDYGWD LKDYFIQYEG
     DWVLHRHKIH CNCADAGKDV HNTSHYCPGK HTFAENVVVP GGAQKAVQEA PAAKTETKKM
     SKLDPTKEAY PGIPLTTTVH KVIEEKTEPL GAQFTVETDI SRKDVNSIAQ GHTVDSIPLC
     TPSFYADIAL QVGKYAMDRI RAGHPGAGAI DGRVDVTDLV VDKALIPHGK APQLLRTNVT
     MSWPPKMAAT TRSAKVTFKT YTADGKLDTD HAYCTVRFTT DSQQKSLQKK VPEYKAAIAK
     LRARDAKGEL THYNTKSGYK LMSSMAHFHP DYKLLDNLVL NEAENEAVSV MNFSSCTDAG
     IYAAHPAYVD AITQVGGFAM NAKDDTDIDK EVYVNHGWES FQVYKKMEKS VEYVVYSKMT
     KDPKGDMVHG DTIVLDGDEV VAFFRGLSLR SVPRKALRAV LQSAMDKGIR QRGGKPGAAK
     GAVAAPAPAK KMVEPVKAAS KKETPAAAAP PSPSKAAPPP APKPAALKAS VPKADPGKVD
     EALKIISEES GIALDELTDD SNFTDMGVDS LSSMVITSRL REDLELDLAP DFALFADCPT
     VASLRTFLAG AAGGPTDSPA AIATLEFGEP TPAKELEAGP ALKSTPISPG VQALQPVPAP
     TPAPKPVITS PAAPVSSKVF DDALQIISEE SGIALDELTD DSNFTDMGVD SLSSMVITSR
     LREDLELDLS PDWALFADCP TVASLRSFLG GSGPGSTAPA DADTPVDTTA AEIEAPVPNE
     AASYMPNSSQ ADVDDAVAAV IGNDPPRRPE PPKQAAAPAV ARTEALNAAL DIIAEESGVA
     AEDFTDDTIF SDIGIDSLCS MVISSRFREE LELDLDSQFS LFVDLPTVAQ LREFLTGSSA
     DSDSSSVASN PADPAATPPR SESSDTEPDD EAPSKPKSGP GSTDSCRSTN SVILQGKPKT
     AAKTLFLLPD GGGSASSYSV IPKLQSDVAV VGINCPYARD PENMTCTWQA MMQSFINEIK
     RRQPKGPYHL GGWSSGGAFA YVTAEKMIKQ GDEVGSLFIF DAPVPQVMEK LPREFYEAVN
     FTESTAVGTA EPPPYLIPHF MAVVDVMLDY KCKPLQTKKM PNVGLIWADS TVMKEDEAPK
     MKGMHFMIQK RTNFGPDGWD EVCPGAKFEI VKAVDTNHFT LMTKARVNYV SDLIDKVMG
 
 
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