ID   CLAI_PENCR              Reviewed;        2346 AA.
AC   A0A481WR96;
DT   23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT   05-JUN-2019, sequence version 1.
DT   03-AUG-2022, entry version 12.
DE   RecName: Full=Highly reducing polyketide synthase claI {ECO:0000303|PubMed:30811183};
DE            EC=2.3.1.- {ECO:0000305|PubMed:30811183};
DE   AltName: Full=Clavatol biosynthesis cluster protein I {ECO:0000303|PubMed:30811183};
GN   Name=claI {ECO:0000303|PubMed:30811183};
OS   Penicillium crustosum (Blue mold fungus).
OC   Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC   Eurotiomycetidae; Eurotiales; Aspergillaceae; Penicillium.
OX   NCBI_TaxID=36656;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA], FUNCTION, AND DOMAIN.
RC   STRAIN=PRB-2;
RX   PubMed=30811183; DOI=10.1021/jacs.9b00110;
RA   Fan J., Liao G., Kindinger F., Ludwig-Radtke L., Yin W.B., Li S.M.;
RT   "Peniphenone and penilactone formation in Penicillium crustosum via 1,4-
RT   Michael additions of ortho-quinone methide from hydroxyclavatol to gamma-
RT   butyrolactones from Crustosic Acid.";
RL   J. Am. Chem. Soc. 141:4225-4229(2019).
RN   [2]
RP   FUNCTION.
RX   PubMed=31860310; DOI=10.1021/acs.joc.9b02971;
RA   Liao G., Fan J., Ludwig-Radtke L., Backhaus K., Li S.M.;
RT   "Increasing Structural Diversity of Natural Products by Michael Addition
RT   with ortho-Quinone Methide as the Acceptor.";
RL   J. Org. Chem. 85:1298-1307(2020).
CC   -!- FUNCTION: Highly reducing polyketide synthase; part of the cla gene
CC       cluster that produces clavatol and ortho-quinone methide
CC       (PubMed:30811183). The clavatol biosynthesis cluster cla and the
CC       terrestric acid cluster tra are both involved in the production of
CC       peniphenones and penilactones (PubMed:30811183). The non-reducing PKS
CC       claF is responsible for the formation of clavatol from successive
CC       condensations of 3 malonyl-CoA units, presumably with a simple acetyl-
CC       CoA starter unit, and 2 methylation steps (PubMed:30811183). The
CC       esterase claE probably collaborates with claF by catalyzing the
CC       hydrolysis of ACP-bound acyl intermediates to free the ACP from stalled
CC       intermediates (By similarity). The clavatol oxidase claD then converts
CC       clavatol to hydroxyclavatol (PubMed:30811183). Spontaneous dehydration
CC       of hydroxyclavatol leads to the accumulation of the highly active
CC       ortho-quinone methide (PubMed:30811183, PubMed:31860310). On the other
CC       hand, the PKS-NRPS hybrid traA is involved in the formation of
CC       crustosic acid, with the help of traB and traD (PubMed:30811183). The
CC       polyketide synthase module (PKS) of traA is responsible for the
CC       synthesis of the polyketide backbone via the condensation of an acetyl-
CC       CoA starter unit with 3 malonyl-CoA units (PubMed:30811183). The
CC       downstream nonribosomal peptide synthetase (NRPS) module then amidates
CC       the carboxyl end of the polyketide with L-malic acid (PubMed:30811183).
CC       Because traA lacks a designated enoylreductase (ER) domain, the
CC       required activity is provided the enoyl reductase traG (By similarity).
CC       Crustosic acid undergoes decarboxylation and isomerization to the
CC       terrestric acid, catalyzed by the 2-oxoglutarate-dependent dioxygenase
CC       traH (PubMed:30811183). Both acids are further converted to the 2
CC       gamma-butyrolactones (R)-5-methyltetronic acid and (S)-5-
CC       carboxylmethyltetronic acid, with involvement of the cytochrome P450
CC       monooxygenase claJ (PubMed:30811183). Spontaneous addition of the
CC       methide to these gamma-butyrolactones leads to peniphenone D and
CC       penilactone D, which undergo again stereospecific attacking by methide
CC       to give penilactones A and B (PubMed:30811183, PubMed:31860310). The
CC       function of the highly reducing polyketide synthase claI has not been
CC       investigated yet (Probable). {ECO:0000250|UniProtKB:A0A0E0RXA7,
CC       ECO:0000250|UniProtKB:A0A161CKG1, ECO:0000269|PubMed:30811183,
CC       ECO:0000269|PubMed:31860310, ECO:0000305|PubMed:30811183}.
CC   -!- COFACTOR:
CC       Name=pantetheine 4'-phosphate; Xref=ChEBI:CHEBI:47942;
CC         Evidence={ECO:0000255};
CC       Note=Binds 1 phosphopantetheine covalently. {ECO:0000255};
CC   -!- PATHWAY: Secondary metabolite biosynthesis.
CC       {ECO:0000305|PubMed:30811183}.
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; an enoylreductase (ER)
CC       domain that reduces enoyl groups to alkyl group; a ketoreductase (KR)
CC       domain that catalyzes beta-ketoreduction steps; and an acyl-carrier
CC       protein (ACP) that serves as the tether of the growing and completed
CC       polyketide via its phosphopantetheinyl arm.
CC       {ECO:0000305|PubMed:30811183}.
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DR   EMBL; MK360918; QBK15047.1; -; Genomic_DNA.
DR   GO; GO:0016746; F:acyltransferase 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:0009058; P: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; -; 2.
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; IPR014031; Ketoacyl_synth_C.
DR   InterPro; IPR014030; Ketoacyl_synth_N.
DR   InterPro; IPR016036; Malonyl_transacylase_ACP-bd.
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; IPR016039; Thiolase-like.
DR   Pfam; PF00698; Acyl_transf_1; 1.
DR   Pfam; PF08240; ADH_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; 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; SSF53901; SSF53901; 1.
DR   SUPFAM; SSF55048; SSF55048; 1.
DR   PROSITE; PS50075; CARRIER; 1.
PE   3: Inferred from homology;
KW   Acyltransferase; Multifunctional enzyme; NADP; Oxidoreductase;
KW   Phosphopantetheine; Phosphoprotein; Transferase.
FT   CHAIN           1..2346
FT                   /note="Highly reducing polyketide synthase claI"
FT                   /id="PRO_0000455055"
FT   DOMAIN          2258..2336
FT                   /note="Carrier"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT   REGION          13..415
FT                   /note="Ketosynthase (KS) domain"
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT   REGION          530..842
FT                   /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT   REGION          912..1213
FT                   /note="Dehydrogenase (DH) domain"
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT   REGION          1633..1946
FT                   /note="Enoyl reductase (ER) domain"
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT   REGION          1972..2151
FT                   /note="Ketoreductase (KR) domain"
FT                   /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT   ACT_SITE        183
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT   ACT_SITE        183
FT                   /note="For beta-ketoacyl synthase activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT   ACT_SITE        622
FT                   /note="For malonyltransferase activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT   ACT_SITE        944
FT                   /note="For beta-hydroxyacyl dehydratase activity"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT   MOD_RES         2296
FT                   /note="O-(pantetheine 4'-phosphoryl)serine"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ   SEQUENCE   2346 AA;  257702 MW;  825CE6D62D765BA1 CRC64;
     MGDAPIQPQT PAIAVVGMAC RLPGSNNSIH AFWNFLKQAR QASNTVPESR FNVGAHADGS
     GKPKTMTSVP GMFLEDIDIG AFDAGFFNIS PAEAMAMDPQ QRQLLEVAYE CLENSGISVD
     AIFGREMGCF VGSFVGDYAD MMARDPEERP TTAATGIGRA ILSNRISHFF NLKGPSMTID
     TGCSGSLVAV DLACRYLEAG DIESAFVAGS GILHGWADGY AKSEGVNCVM LKNLDSAIRD
     GDPIRAVIRG WATNSDGYTP GITHPSVDAQ VACIKRAYAK AGIEDYSQTG YLECHGTGTP
     IGDAVETTAI ANVFAQSRDD SRPLIIGSVK SNIGHSEAAS GLSGLIKSVM AIENGVIPGT
     PSFITPNPNI NFQALRLHVS QTSIPWPLNT IRRASINSFG YGGTNCHLIV EDARLHLGVE
     QNETYNSSLC SSTSLSLDED DPRDVVYPRP YIIVLSAVDD DSLTINCKKL LRHLADLHVH
     LKLPDLSYTL ATRRSHHSKR AFAVSNSLNL HARDFMRGQK QFENPRIGFI FTGQGSQWPQ
     MGKDLVRTFP RALEIISEMD AVLQGLPDAP TWSLLDMLVE PHDASRIRQP EISQPLVTAI
     QLTLVALLED WNIFPDNVIG HSSGEIAAAY AAGYISKEDA IINAFYRGHA AKVASDSNLS
     VGMMAVGLGK DEIRPHLEDL ADSVYVACVN SPRSITLSGV KTSLEMLRDR LSSVGIFVRI
     LQVDLAYHSP FMKTIGDRYE HSLGQNLPVV GEQPSNTRHT SMFSTVTGEV IKNNPDSQYW
     RKNMCSPVQF WQGLAAMLSD SEPDLLVEIG PSNTLAGPVR QTNDNLANSS KVEYFSALKR
     GEDPIGALFD LCGQLYLRGC PIKLERVNRG YEQTNTPPAI VDLPNYGWNH SFSYWNENES
     SKDWRFRRYL PHDLLGSKIL GTTWHTPSWK NTLRLRSLPW LEDHKIGSDV IFPAAGYISM
     AIEALYQATC AVNEQHAGFS ISQLHFSLRN VEFKRAMILD HTSDTRLVLT LESQKGINSW
     RLFRISSFDG KQWTEHCTGL IRTSEEDSLV QKDLVMPKMI HATPAQVWYR KFADIGYGYG
     PSFEKMLLVE ARVGAAQNRC VISMQAPAAA QSPSFYPIHP TCLDACLQSV FPSLWQGDHT
     AISTLLLPAR IDSLVIHPQP NSINSNVASA KSTYSGRGRL QDRTSWSSDC SLNREEDGKC
     VLRINGLRFS SVDLGSVQPA AQFWYRSVWC PDITKWSFMP QKHWIPRPNT VNELINWVVH
     KHGEVSIIEL NWDSDDASSL WLDRADHPMR DLTKKYRLLL SDHESLVKSQ NLFPNHASSM
     QMILDRDDPL SGPEWPKMQL VILKSSDCSV HDSSMGRLLG QISEIMSTDG MLVIVAQSLG
     SDSHSNDARS DSSVFMEHED RSKSYVPFSH LLSLDLPSSA KHVQLYSRAS PAPSCPPQPV
     ALYSFQKTSP ISKGLRESLT QNNISLSEVS IHGPETVEIG IGLVVDEIYA PLLCNISSQQ
     WESLKTLFER ETPVLWVTQG AQHQVTNPDS SLIYGYLRSL RAEGNASSRF VILDVENGDS
     PGSRTAITTL LSEMSSSPDR FDHEWEFCER SGIIHVNRIY QDRKLNNLDD IEPAQTSIAS
     CDEKVALHAT HLGSLEALQW TQEDTEDSIL APGDVEVKID VAGLNFKDVA LAMGIVHGDE
     YRLGHEGSGR IQRVGSQTAG YQVGDRVAVF SIGSFANRIQ VSTELIHHIP DNMSFEDAAT
     LPLVYSTALY SLLDVANLQA NQSVLIHSAT GGLGIACIQI AQYIGAKVYA TAGTQEKREL
     LCKEYSIPES QVFSSRDTRF VAGIRGATQG GGVDVIVNTL TGDLLHESWM LCADGGIFVE
     LGKKDIIERN SLSMEPFDRN CSFRAVDLSH KQITDTMKKG LLTRIFDMIK CGNIGPIRPQ
     TTFALNDIQS AFAHMRSARH IGKILILAKD DADTSVPVHS SRRPISIPGD RTYLIVGGLR
     GLCGSLAICL AQRGAKHITI ISRSGCNDER SKAIIADCEN LGCRIVDAVG DVTSLQHVKN
     VFQKADPPIR GVIHGAMVLR DKPIETMSAV DFHQTISSKV KGAWNIHHAA AEQDKSQSLE
     FFTMLSSISG VVGQKGQANY AAANVFLDSF AAYRCSLGLP AHSLDLGVVD AIGVAAEKGG
     MERYFNLEHW PRIKESKLHE ILCISIDEQK KARYSQLITG LPSGISQLPI LSQDARFSIL
     CAEDSQTEGH QPVSPSKDTS SKELYEFRLL VKAMKAKSQL VEKAVTLCGL QLSRLLYLKN
     QVIDANKSLA AYGLDSLIAI EFRNWLKKEL AVEMSTFEVI GASCLHALAE KMVSKVEAGV
     PVVEVV