CLAF_PENCR
ID CLAF_PENCR Reviewed; 2587 AA.
AC A0A481WQB6;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 05-JUN-2019, sequence version 1.
DT 03-AUG-2022, entry version 15.
DE RecName: Full=Clavatol synthase claF {ECO:0000303|PubMed:30811183};
DE EC=2.3.1.- {ECO:0000269|PubMed:30811183};
DE AltName: Full=Clavatol biosynthesis cluster protein F {ECO:0000303|PubMed:30811183};
DE AltName: Full=Non-reducing polyketide synthase claF {ECO:0000303|PubMed:30811183};
GN Name=claF {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, DISRUPTION PHENOTYPE,
RP CATALYTIC ACTIVITY, DOMAIN, AND PATHWAY.
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: Non-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).
CC {ECO:0000250|UniProtKB:A0A0E0RXA7, ECO:0000250|UniProtKB:A0A161CKG1,
CC ECO:0000269|PubMed:30811183, ECO:0000269|PubMed:31860310}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + AH2 + H(+) + 3 malonyl-CoA + 2 S-adenosyl-L-
CC methionine = A + clavatol + 3 CO2 + 4 CoA + H2O + 2 S-adenosyl-L-
CC homocysteine; Xref=Rhea:RHEA:70075, ChEBI:CHEBI:13193,
CC ChEBI:CHEBI:15377, ChEBI:CHEBI:15378, ChEBI:CHEBI:16526,
CC ChEBI:CHEBI:17499, ChEBI:CHEBI:57287, ChEBI:CHEBI:57288,
CC ChEBI:CHEBI:57384, ChEBI:CHEBI:57856, ChEBI:CHEBI:59789,
CC ChEBI:CHEBI:188925; Evidence={ECO:0000269|PubMed:30811183};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:70076;
CC Evidence={ECO:0000269|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:0000269|PubMed:30811183}.
CC -!- DOMAIN: Multidomain protein; including an N-terminal starter unit:ACP
CC transacylase (SAT) domain, a beta-ketoacyl synthase (KS) domain, a
CC malonyl-CoA:ACP transacylase (MAT) domain, a product template domain, a
CC acyl carrier protein (ACP) domain, a methyltransferase domain (CMeT)
CC and a reductive NADPH-binding domain that is required for NADPH-
CC dependent product release. {ECO:0000305|PubMed:30811183}.
CC -!- DISRUPTION PHENOTYPE: Completely abolishes the production of clavatol,
CC as well as of the clavatol-derived compounds peniphenone D, penilactone
CC D, penilactone A and penilactone B (PubMed:30811183). Leads to the
CC accumulation of the 2 tetronic acids terrestric acid and crustosic acid
CC (PubMed:30811183). {ECO:0000269|PubMed:30811183}.
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DR EMBL; MK360918; QBK15044.1; -; Genomic_DNA.
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: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; -; 2.
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; IPR013120; Far_NAD-bd.
DR InterPro; IPR041068; HTH_51.
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; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR020806; PKS_PP-bd.
DR InterPro; IPR009081; PP-bd_ACP.
DR InterPro; IPR006162; Ppantetheine_attach_site.
DR InterPro; IPR029063; SAM-dependent_MTases_sf.
DR InterPro; IPR032088; SAT.
DR InterPro; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF18558; HTH_51; 1.
DR Pfam; PF00109; ketoacyl-synt; 1.
DR Pfam; PF02801; Ketoacyl-synt_C; 1.
DR Pfam; PF08242; Methyltransf_12; 1.
DR Pfam; PF07993; NAD_binding_4; 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 SMART; SM00823; PKS_PP; 1.
DR SUPFAM; SSF47336; SSF47336; 1.
DR SUPFAM; SSF51735; SSF51735; 1.
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.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 1: Evidence at protein level;
KW Acyltransferase; Methyltransferase; Multifunctional enzyme; NADP;
KW Phosphopantetheine; Phosphoprotein; Transferase.
FT CHAIN 1..2587
FT /note="Clavatol synthase claF"
FT /id="PRO_0000455054"
FT DOMAIN 1654..1728
FT /note="Carrier"
FT /evidence="ECO:0000255, ECO:0000255|PROSITE-
FT ProRule:PRU00258, ECO:0000305|PubMed:30811183"
FT REGION 93..256
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT REGION 386..802
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT REGION 912..1222
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT REGION 1315..1593
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1609..1635
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1952..2126
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT REGION 2208..2452
FT /note="NADPH-binding (R) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT ACT_SITE 137
FT /note="Nucleophile; for transacylase activity"
FT /evidence="ECO:0000250|UniProtKB:A0A0K0MCJ4"
FT ACT_SITE 256
FT /note="Proton donor/acceptor; for transacylase activity"
FT /evidence="ECO:0000250|UniProtKB:A0A0K0MCJ4"
FT ACT_SITE 548
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 1947
FT /note="For methyltransferase activity"
FT /evidence="ECO:0000250|UniProtKB:Q65Z23"
FT ACT_SITE 2059
FT /note="For methyltransferase activity"
FT /evidence="ECO:0000250|UniProtKB:Q65Z23"
FT ACT_SITE 2085
FT /note="For methyltransferase activity"
FT /evidence="ECO:0000250|UniProtKB:Q65Z23"
FT MOD_RES 1688
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2587 AA; 284308 MW; 7B4DE6323DE60454 CRC64;
MPSESYPRVN PKVFLFGPQA LAFDAKLFTT LQSHLYDSWA LDALSDLPII WESLVKQVPK
LQHVEGERLL RELHQGLQTG SLPDSLFPLP NILLSPLVVI VQLTQYLAFV RSGLPGLGDT
DEIPQSVMQT SESLGLCTGI LSAFAVSCAS SIAKVQQYGA VAVRLSMLVG ALVDAEEASP
DTGSPAMSFS MSWNALESRT SVDEVLAEFP EAYISVFVDE KRATVTAPKE SAPALLDKLR
LSGAHVTEVA LSGRFHWPKH REDAKQLIAF CDHDPRFQFP DASEIVLPTR LSTGGRLHEI
ALQEILLKPS EWLSLFGLVQ SSHIDAGGAN FVCFGSERCV PPTMIRKLGP LLIHISDVDL
STSALPSELL RSTSASPFDN LPDDQIAVIG MACHVPGAED LDEYWRILTS GQSQHTRVPL
ERFSMKTAFR ELEENRKWYG NFLRDYDTFD HKFFKKSARE MSSADPQHRL VLKLAYQAIE
QSGYFGASHN SKHVGCYIGI GNNDYERNIA CHPANAYSAT GNLRSFAAGK VSHYFGWTGP
SLTIDTACSS SGVAIHQACR AILHGECTSA LAGGVNVLTS PEWFQNLAGA SFLSPTGQCK
PFDARGDGYC RGEGAGVVFL KRLSSAIADG DQVLGVIAST KVYQNQNCTA ITVPNSISLA
GLFGDVVEQA RLEPQAISVV EAHGTGTPVG DPAEYDAVRR VFGGSIRSDT LSLMSVKGLL
GHTEFASGIV SLVKILLMIN EGFIPPQASF TSMSPALNAY HEDMINIATQ LTPWNVDFRA
ALINNYGASG SNASMIITQA PKPRSSTSNP SPLSSSATSF PFWLCGIDSQ SLRAYATKFR
RFIHDNADSV KDLTVRNLSF QISRQSNRNL PRALIFSAAS RNELEEKLLD YEQGGRSIAE
IEVPPPRPVI LCFGGQISTY VGLGKDVYNQ ATILRSHLDQ CNTVCLSLGL GSIYPAIFQR
SPILDTVELQ TVLFAAQYSC ARAWIDSGVK VTAVIGHSFG ELTALCIAGA YSLADALRLI
SGRARLIRDK WGSDKGSMLA LEADLAEVTA LLSTSNKPDV SIACYNGPRS FTLAGSTESV
QFIEELARSN QTFFGMKLKK LNVTNAFHSA NVDPLISDLE ALGREIQFNE PIIQVEAATE
TRSSPTRGSH FIAQHLRNPV YFNHAVQRLA EEYPAAIWLE AGSNSTITTM ISRALGNSSS
PHHFQSVHIT SEESLPLLAE ATTKLWKEGL NVSFWAHHPM EVSQHSLVIL PPYQFEKARH
WMDLKEVPEV KSSIDTTVQP PEPPKGLTTF IGFEDQAKQS ARFRVNTTCD KFQQLTSANV
ALNTTAVTPG MLQIEISLDA IMNLQPDFKT YQFQPEVQGV SYHNALIDSN STDLYLDAIA
KDDGGLAWRW RLYGTDLGDR VTEFSSGSIV FLPASDPALK ENFERLSRLS GKKRCASLLQ
GNGADDVLQG RNIYRAFEQV VNYAEPFRRV TKIAGKEDES AGYVSKAYTG ETWMDPVLTE
CFCQVAGIFI NLMTDASDLS KRGVYICDGI SRWMHYPGLG SMTSAPDAWE VFAVHHHESE
TKYVSDVFAF DPRDGSLIEA ILGISYRLVP MDSMRKLLTR GPQQESHFST AAVSSKSTPV
HAPTPTTTVS STPSSLNSFQ EKTIVKNVAK PPGPDISAKM CEIICNLSGL EPEEIEDDSD
LVELGIDSLM AMELVREVDS AFKCTLQNDQ LMELTDFASL VSCIRSTLGF DDEESGVGFE
RDSSVDTEAY ILLEPNEPAT NINGANGTVS FDHRDGNAVL SMSTLLDAFR EIKWDTDDDI
VKGQLGTYSK HVMPRSTELC IVYIVDAFEQ LGCPIRSAAP GQVLTRVPYH PKHEKFMNMI
IYGLLEKDAR LIDINGSIIT RTAVAPPTAS ADTLLSKLLH DEPVHAAEHK LAALIGQKFA
DLITDKEDGL KLIFGNPESR EIAADMYSNS PVNTVWIKQL ERFFERVLGR LPKDGQPICI
LEVGGGTGGT TSRIVPLLAK LGVPVKYTMT DISGSLIAAA RKRFKKYPFM DFKPLNMESE
PDAKFLQSQH IILATNCIHA TRNLSVSLKN LHRILRPDGA LIMLEMTEQV PWCDFIFGLL
EGWWLFEDGR DYVLQPATYW EKVLQSVGYG HVDWTEGELP EARIQRLIIA HASGSRYDRG
PKPPLASIPE LTLPDISERR ARIDAAVHKY TKDFVAPSQI LSPAKLPSLS SGQCVLVTGA
TGSLGAHIVA SLVQRPGIHT VVCLNRLSTT EATVRQQNSL QMRGISLDPT SLSKLKVIET
DTSKPNLGLS PENYQYLIQN VTEIVHSAWP MSLTRPMRTY EPQFKIARGL IDLAREVAQH
RPAPFKFGFQ FISSSAVIAN YPLLAGTPVV PEQSGTVESV PLTGYAEAKL ATERILAETL
YRFPDRFHVM AVRIAQITGS TSNGYWNPSE YMPFLIKSSQ VLKILPELDG TLSWYPVNDV
ASVLGELLLS QSTTDLIYHI DNPSRQTWRE MIAILARALD LGQKSIVPFG QWVNRVRGFR
GSIADNPALQ LIDFFEHYFV PMSCGGLVLD TTKSSQHSKT LQNQGPIDED LMMKYIARWK
ESGFLNP
