ID   GSFA_PENAE              Reviewed;        1790 AA.
AC   D7PI15;
DT   06-JUL-2016, integrated into UniProtKB/Swiss-Prot.
DT   10-AUG-2010, sequence version 1.
DT   03-AUG-2022, entry version 45.
DE   RecName: Full=Non-reducing polyketide synthase gsfA {ECO:0000303|PubMed:20534346};
DE            EC=2.3.1.- {ECO:0000269|PubMed:23978092};
DE   AltName: Full=Griseofulvin synthesis protein A {ECO:0000303|PubMed:20534346};
DE   AltName: Full=Norlichexanthone synthase {ECO:0000303|PubMed:23978092};
GN   Name=gsfA {ECO:0000303|PubMed:20534346};
OS   Penicillium aethiopicum.
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX   NCBI_TaxID=36650;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND DISRUPTION PHENOTYPE.
RC   STRAIN=IBT 5753;
RX   PubMed=20534346; DOI=10.1016/j.chembiol.2010.03.015;
RA   Chooi Y.H., Cacho R., Tang Y.;
RT   "Identification of the viridicatumtoxin and griseofulvin gene clusters from
RT   Penicillium aethiopicum.";
RL   Chem. Biol. 17:483-494(2010).
RN   [2]
RP   BIOTECHNOLOGY.
RX   PubMed=13577889; DOI=10.1038/182476a0;
RA   Gentles J.C.;
RT   "Experimental ringworm in guinea pigs: oral treatment with griseofulvin.";
RL   Nature 182:476-477(1958).
RN   [3]
RP   BIOTECHNOLOGY.
RX   PubMed=4583105; DOI=10.1038/244292a0;
RA   Gull K., Trinci A.P.;
RT   "Griseofulvin inhibits fungal mitosis.";
RL   Nature 244:292-294(1973).
RN   [4]
RP   FUNCTION, DISRUPTION PHENOTYPE, AND CATALYTIC ACTIVITY.
RX   PubMed=23978092; DOI=10.1021/cb400541z;
RA   Cacho R.A., Chooi Y.H., Zhou H., Tang Y.;
RT   "Complexity generation in fungal polyketide biosynthesis: a spirocycle-
RT   forming P450 in the concise pathway to the antifungal drug griseofulvin.";
RL   ACS Chem. Biol. 8:2322-2330(2013).
CC   -!- FUNCTION: Norlichexanthone synthase; part of the gene cluster that
CC       mediates the biosynthesis of griseofulvin, an important antifungal drug
CC       that has been in use for a long time for treating dermatophyte
CC       infections (PubMed:20534346, PubMed:23978092). The first step of the
CC       pathway is the formation of the heptaketide backbone by gsfA which is
CC       initiated by priming with acetyl-CoA, followed by sequential
CC       condensations of 6 malonyl-CoA units (PubMed:20534346). O-methylation
CC       at 3-OH by gsfB leads to griseophenone D which is further methylated at
CC       9-OH by gsfC to yield griseophenone C (PubMed:23978092). Griseophenone
CC       C is then substrate of halogenase gsfI which is responsible for the
CC       regio-specific chlorination at the C13 position to form griseophenone B
CC       (PubMed:23978092). The cytochrome P450 gsfF catalyzes the coupling of
CC       orcinol and phloroglucinol rings in griseophenone B to form desmethyl-
CC       dehydrogriseofulvin A which is further methylated at 5-OH by gsfD to
CC       yield dehydrogriseofulvin (PubMed:23978092). Finally, gsfE performs
CC       stereospecific reduction of enone 18 of dehydrogriseofulvin to afford
CC       the final product griseofulvin (PubMed:23978092).
CC       {ECO:0000269|PubMed:20534346, ECO:0000269|PubMed:23978092}.
CC   -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC       {ECO:0000269|PubMed:20534346, ECO:0000269|PubMed:23978092}.
CC   -!- DOMAIN: Multidomain protein; including a starter unit:ACP transacylase
CC       (SAT) that selects the starter unit; a ketosynthase (KS) that catalyzes
CC       repeated decarboxylative condensation to elongate the polyketide
CC       backbone; a malonyl-CoA:ACP transacylase (MAT) that selects and
CC       transfers the extender unit malonyl-CoA; a product template (PT) domain
CC       that controls the immediate cyclization regioselectivity of the
CC       reactive polyketide backbone; and an acyl-carrier protein (ACP) that
CC       serves as the tether of the growing and completed polyketide via its
CC       phosphopantetheinyl arm (By similarity).
CC       {ECO:0000250|UniProtKB:Q5B0D0}.
CC   -!- DISRUPTION PHENOTYPE: Impairs the production of griseofulvin
CC       (PubMed:20534346, PubMed:23978092). {ECO:0000269|PubMed:20534346,
CC       ECO:0000269|PubMed:23978092}.
CC   -!- BIOTECHNOLOGY: Griseofulvin is a spirocyclic fungal natural product
CC       used in treatment of fungal dermatophytes (PubMed:13577889,
CC       PubMed:4583105). {ECO:0000269|PubMed:13577889,
CC       ECO:0000269|PubMed:4583105}.
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DR   EMBL; GU574478; ADI24953.1; -; Genomic_DNA.
DR   AlphaFoldDB; D7PI15; -.
DR   SMR; D7PI15; -.
DR   PRIDE; D7PI15; -.
DR   BioCyc; MetaCyc:MON-19267; -.
DR   UniPathway; UPA00213; -.
DR   GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR   GO; GO:0006633; P:fatty acid biosynthetic process; IEA:InterPro.
DR   GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR   Gene3D; 1.10.1200.10; -; 1.
DR   Gene3D; 3.10.129.110; -; 1.
DR   Gene3D; 3.40.366.10; -; 2.
DR   Gene3D; 3.40.47.10; -; 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; 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; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR   InterPro; IPR042104; PKS_dehydratase_sf.
DR   InterPro; IPR009081; PP-bd_ACP.
DR   InterPro; IPR030918; PT_fungal_PKS.
DR   InterPro; IPR032088; SAT.
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; 1.
DR   Pfam; PF16073; SAT; 1.
DR   SMART; SM00827; PKS_AT; 1.
DR   SMART; SM00825; PKS_KS; 1.
DR   SUPFAM; SSF47336; SSF47336; 1.
DR   SUPFAM; SSF52151; SSF52151; 1.
DR   SUPFAM; SSF53901; SSF53901; 1.
DR   SUPFAM; SSF55048; SSF55048; 1.
DR   TIGRFAMs; TIGR04532; PT_fungal_PKS; 1.
DR   PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR   PROSITE; PS50075; CARRIER; 1.
PE   1: Evidence at protein level;
KW   Acyltransferase; Phosphopantetheine; Phosphoprotein; Transferase.
FT   CHAIN           1..1790
FT                   /note="Non-reducing polyketide synthase gsfA"
FT                   /id="PRO_0000436720"
FT   DOMAIN          1716..1790
FT                   /note="Carrier"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   REGION          20..263
FT                   /note="N-terminal acylcarrier protein transacylase domain
FT                   (SAT)"
FT                   /evidence="ECO:0000255"
FT   REGION          392..765
FT                   /note="Ketosynthase (KS) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          922..1223
FT                   /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT                   /evidence="ECO:0000255"
FT   REGION          1298..1615
FT                   /note="Product template (PT) domain"
FT                   /evidence="ECO:0000250|UniProtKB:Q5B0D0, ECO:0000255"
FT   REGION          1621..1648
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          1686..1718
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        1698..1712
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        563
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT   MOD_RES         1753
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ   SEQUENCE   1790 AA;  196166 MW;  1D91BA36BF35B1E5 CRC64;
     MTSAKVLYFS GEIPQGDPEG DQRTLFRKLH LLSKERDHVV LASLLECVTL TLKDECSKLS
     PQYRDLLPPF ESVLDLTDHV VQLRKTPLGG AIERVLVLVF QLGSLVAYHE AHPLEYNFTP
     ASTVIIGRGS GLLSAAAIGL SPSIVMVPSI AKEIARISFR FGLVVDKVCR SLEVSSDEIN
     SDGAWVYCVH GIGEKEARDA VNQFNEIKAY PSTNGASVFN VDDAGNSVSI GGPPKTLEAL
     FSESNIFKKT KNVAMRKIQG MWHTDRVYGP EHVEQIVPKI ESARELHVPL ISPVSGDPFR
     ETEAGPLLEQ IMEEILMERV RWDMIIETVS KQLKQLMPKS VQLVSIQPSH YNQNMLERWK
     SELPDAAVSG LTMMPAILEL ALEQSPPKDT RSSKIAVVGM SCRFPGSDTT EEFWERLMLG
     EDMHRHIPPD RFDVETHVDP TGKRHNTSKT SYGCFVDNPG LFDAMFFGMS PREAEQTDPM
     QRLALVTAYE ALEKAGYVDG RGVIHRKRVG TFYGQASDDY REVNSGQEVG TYFIPGGCRA
     FGPGRINYFL NFWGPSFSVD TACSSSLAAI QAACSSLWSG DIDMAITGGM NILSNSDVYA
     GLSQGHFLSP TGGCKTWDEG ADGYCRSDGV GSVVLKRLED AEADNDNILA VVLSAATSHS
     AEAVSITHPH DAAQALLYNQ IVRRAGIDPL EVGYVEMHGT GTQAGDPTEM RSVTSVFAPP
     HIQGSRPIPL HVGSVKANMG HGEAAAGIMA FVKTMLVFQN GIIPPHIGVK TGLNPALPDL
     DKAGVVIPFR AANWRPTGTK KRLAMVNNFG AAGGNTAMII EEAKARPRLC EDIREAHAIT
     ISAKTAVSLS LNIKRLVEYI ESAQDLSLAD VAYTVSARRR HYEYRKSVVV RSLAEAIKHL
     QPHIETAKSQ TPTLVKRPPV AFAFAGQGTF YVGIAAQIYR DSPFFRAQID QFDNLARRQN
     FPSFLPAINK TCAHEDLPAS SIHLAIVCVE VALARMCMTF GIKPCAVIGH SLGEYAALAV
     AEVLSDSDTV FLVGTRATIL ESNCSPYTHG MISVRASVDD ISREADGLPF EVSCINGPNE
     TVIGGTVENL EAVADRLSKV GYRKTRLDVP HAYHTAQMDN VVNELIRQSQ GIAYNTPKIP
     IMSPRDSSVI ETGANIDSSY LPTSLKKAVD FAGALNAAWE AGVVSKSTVW LELSHHPVCS
     GFINRTLPNT SLTCSTLHRD SDNWTSLLKT LSSLYEVGLN IDWNEYHRPF EHALRLVSAP
     TYAWNNKDYW IQYRGDWNLT KGQVLPEAEL PAVSGFRTSS IHRLYSENYD SSTAHLLGEC
     NMTDLSLKGV IEGHAMNGYG VASSFLHAEM AFTLARRIQE KASLSTFTGM GINVTNFEYH
     DPVVKDASSL DPYPIVVDAE ANLEMGEVQI KWFNPAIEKW YCHAIAYYED PSTWLSNWSR
     TTRLVTSRID ALVAMSNKGM ANKLTTSLAY TLFGKLVDYS SMYHTMQWVI LNEDEAVAEV
     VFPADTQGDW AVPPHFIDGV VSLSGFILNG GTHFDNVNNF FITPSWKSMR FAKPLAPGGR
     YLTYVRMIPE GVDDKGRLGS YVGDVYILQD GEIVGVVEAI LFRQWPRIML NRFFQPVGMA
     PPAPRVEKKR DAGRGTLPSS SSLQEKTTAT AVTAKITARF PGSVITPSRS APISKSGSSP
     KIVPQLDYSL LTPRTSPNSD ERIEKTDSDS GFEEADGAND VTSRAVEILA EELAVDKGLL
     TDECEIADIG VDSLMSLVIS QKLREDLGIE VRDAFYLEVT TIGDLKKLLS