TRAA_PENCR
ID TRAA_PENCR Reviewed; 3856 AA.
AC A0A481WNP4;
DT 23-FEB-2022, integrated into UniProtKB/Swiss-Prot.
DT 05-JUN-2019, sequence version 1.
DT 03-AUG-2022, entry version 17.
DE RecName: Full=Hybrid PKS-NRPS synthetase traA {ECO:0000303|PubMed:30811183};
DE EC=2.3.1.- {ECO:0000305|PubMed:30811183};
DE EC=6.3.2.- {ECO:0000305|PubMed:30811183};
DE AltName: Full=Terrestric acid biosynthesis cluster protein A {ECO:0000303|PubMed:30811183};
GN Name=traA {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, DOMAIN,
RP 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: Hybrid PKS-NRPS synthetase; part of the tra gene cluster that
CC produces terrestric acid (PubMed:30811183). The clavatol biosynthesis
CC cluster cla and the terrestric acid cluster tra are both involved in
CC the production of peniphenones and penilactones (PubMed:30811183). The
CC non-reducing PKS claF is responsible for the formation of clavatol from
CC successive condensations of 3 malonyl-CoA units, presumably with a
CC simple acetyl-CoA starter unit, and 2 methylation steps
CC (PubMed:30811183). The esterase claE probably collaborates with claF by
CC catalyzing the hydrolysis of ACP-bound acyl intermediates to free the
CC ACP from stalled intermediates (By similarity). The clavatol oxidase
CC claD then converts clavatol to hydroxyclavatol (PubMed:30811183).
CC Spontaneous dehydration of hydroxyclavatol leads to the accumulation of
CC the highly active ortho-quinone methide (PubMed:30811183,
CC PubMed:31860310). On the other hand, the PKS-NRPS hybrid traA is
CC involved in the formation of crustosic acid, with the help of traB and
CC traD (PubMed:30811183). The polyketide synthase module (PKS) of traA is
CC responsible for the synthesis of the polyketide backbone via the
CC condensation of an acetyl-CoA starter unit with 3 malonyl-CoA units
CC (PubMed:30811183). The downstream nonribosomal peptide synthetase
CC (NRPS) module then amidates the carboxyl end of the polyketide with L-
CC malic acid (PubMed:30811183). Because traA lacks a designated
CC enoylreductase (ER) domain, the required activity is provided the enoyl
CC reductase traG (By similarity). Crustosic acid undergoes
CC decarboxylation and isomerization to the terrestric acid, catalyzed by
CC the 2-oxoglutarate-dependent dioxygenase traH (PubMed:30811183). Both
CC acids are further converted to the 2 gamma-butyrolactones (R)-5-
CC methyltetronic acid and (S)-5-carboxylmethyltetronic acid, with
CC involvement of the cytochrome P450 monooxygenase claJ
CC (PubMed:30811183). Spontaneous addition of the methide to these gamma-
CC butyrolactones leads to peniphenone D and penilactone D, which undergo
CC again stereospecific attacking by methide to give penilactones A and B
CC (PubMed:30811183, PubMed:31860310). {ECO:0000250|UniProtKB:A0A0E0RXA7,
CC ECO:0000250|UniProtKB:A0A161CKG1, ECO:0000269|PubMed:30811183,
CC ECO:0000269|PubMed:31860310}.
CC -!- PATHWAY: Secondary metabolite biosynthesis.
CC {ECO:0000269|PubMed:30811183}.
CC -!- DOMAIN: NRP synthetases are composed of discrete domains (adenylation
CC (A), thiolation (T) or peptidyl carrier protein (PCP) and condensation
CC (C) domains) which when grouped together are referred to as a single
CC module. Each module is responsible for the recognition (via the A
CC domain) and incorporation of a single amino acid into the growing
CC peptide product. Thus, an NRP synthetase is generally composed of one
CC or more modules and can terminate in a thioesterase domain (TE) that
CC releases the newly synthesized peptide from the enzyme (Probable). TraA
CC contains also a polyketide synthase module (PKS) consisting of several
CC catalytic domains including a ketoacyl synthase domain (KS), an acyl
CC transferase domain (AT), a dehydratase domain (DH), a methyltransferase
CC domain (MT), and a ketoreductase domain (KR) (Probable). Instead of a
CC thioesterase domain (TE), traA finishes with a reductase-like domain
CC (R) for peptide release. TraA has the following architecture: KS-AT-DH-
CC KR-PCP-C-A-T-R (Probable). {ECO:0000305|PubMed:30811183}.
CC -!- DISRUPTION PHENOTYPE: Completely abolishes the production of
CC peniphenone D, penilactone D, penilactone A and penilactone B, as well
CC as of crustosic acid and tarrestric acid (PubMed:30811183). Leads to
CC the accumulation of clavatol, hydroxyclavatol and hydroxyclavatol
CC methyl ether (PubMed:30811183). {ECO:0000269|PubMed:30811183}.
CC -!- SIMILARITY: In the C-terminal section; belongs to the NRP synthetase
CC family. {ECO:0000305}.
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DR EMBL; MK360919; QBK15049.1; -; Genomic_DNA.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0016874; F:ligase activity; IEA:UniProtKB-KW.
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; -; 2.
DR Gene3D; 3.10.129.110; -; 1.
DR Gene3D; 3.30.300.30; -; 1.
DR Gene3D; 3.30.559.10; -; 1.
DR Gene3D; 3.40.366.10; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.12780; -; 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; IPR045851; AMP-bd_C_sf.
DR InterPro; IPR020845; AMP-binding_CS.
DR InterPro; IPR000873; AMP-dep_Synth/Lig.
DR InterPro; IPR042099; ANL_N_sf.
DR InterPro; IPR023213; CAT-like_dom_sf.
DR InterPro; IPR001242; Condensatn.
DR InterPro; IPR013120; Far_NAD-bd.
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; IPR032821; PKS_assoc.
DR InterPro; IPR020841; PKS_Beta-ketoAc_synthase_dom.
DR InterPro; IPR020807; PKS_dehydratase.
DR InterPro; IPR042104; PKS_dehydratase_sf.
DR InterPro; IPR013968; PKS_KR.
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; IPR016039; Thiolase-like.
DR Pfam; PF00698; Acyl_transf_1; 1.
DR Pfam; PF00501; AMP-binding; 1.
DR Pfam; PF00668; Condensation; 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; PF08242; Methyltransf_12; 1.
DR Pfam; PF07993; NAD_binding_4; 1.
DR Pfam; PF00550; PP-binding; 2.
DR Pfam; PF14765; PS-DH; 1.
DR SMART; SM00827; PKS_AT; 1.
DR SMART; SM00826; PKS_DH; 1.
DR SMART; SM00825; PKS_KS; 1.
DR SMART; SM00823; PKS_PP; 2.
DR SUPFAM; SSF47336; SSF47336; 2.
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; PS00455; AMP_BINDING; 1.
DR PROSITE; PS00606; B_KETOACYL_SYNTHASE; 1.
DR PROSITE; PS50075; CARRIER; 2.
DR PROSITE; PS00012; PHOSPHOPANTETHEINE; 1.
PE 3: Inferred from homology;
KW Ligase; Methyltransferase; Multifunctional enzyme; Oxidoreductase;
KW Phosphopantetheine; Phosphoprotein; Repeat; Transferase.
FT CHAIN 1..3856
FT /note="Hybrid PKS-NRPS synthetase traA"
FT /id="PRO_0000455070"
FT DOMAIN 2266..2347
FT /note="Carrier 1"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT DOMAIN 3428..3507
FT /note="Carrier 2"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 9..441
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT REGION 554..885
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT REGION 943..1247
FT /note="Dehydratase (DH) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT REGION 1290..1456
FT /note="Methyltransferase (MT) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT REGION 1984..2158
FT /note="Ketoreductase (KR) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT REGION 2351..2422
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 2446..2884
FT /note="Condensation (C) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT REGION 2910..3310
FT /note="Adenylation (A) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT REGION 3403..3429
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 3544..3768
FT /note="Reductase (R) domain"
FT /evidence="ECO:0000255, ECO:0000305|PubMed:30811183"
FT COMPBIAS 2356..2372
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 2380..2422
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT MOD_RES 2307
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT MOD_RES 3467
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 3856 AA; 420817 MW; 9B9E28C5EC33162F CRC64;
MVLPQPEPIA IVGSGCRFPG SSSSPSSLWD LLEKPRDVSK EPTNERFELR GYYHPNGAHH
GTMNVQRAYM LDEDVGTFDA TFFNISPNEA ESIDPQQRLL MEVVYEALEA GGHRLDILRG
SDTAVYVGTM SVDYNDIMLR DINSIPTYFS TGTSRAILAN RISYFFDWHG PSMTIDTACS
SSMVALHQSV QALRSGESRV AIAGGTELLL GPEQFVGESK MNLLSPTGQS RMWDASANGY
ARGDGIAAIV LKKLSDAIAD GDHIECLIRQ TGINQDGKST GLTVPSSAAQ ADLIRSTYTK
GGLDIDNPRD WPQFFEAHGT GTKAGDPREA SAISQCFGSQ PIHGNPLYVG SIKTIIGHTE
GTAGLAGVFK ASLAIQHGII PPNMLLHQLN DEVAQYCDNL RVPNAPTAWP KLPDGVPRRA
SVNSFGFGGT NGHAILEEYQ PPTETRNTAT TGRDENNASV FRIFPFSAAS EESLTANLRA
YATSLKTRTT VDLVDLAWTL QSRRSALPFK TSLTAECIEG LITKIDSTLE KAKANSGLKV
GTRSAPTKPK VLGIFTGQGA QWATMAAGLI RTSETVRRKI EQLDGSLATL PEANRPTWRI
ADQLCADAED SRLNEAALSQ PLCTAIQVVL IDLLRSSGIT FEAVVGHSSG EIAAAYAADY
ISAHDAIRIA YYRGVYAKHA RGPKDQKGAM MAVGTTWEDA EELLNLPAFR GRVKIAAQNS
AASLTLSGDV EALSHAKRVF DEEKKFTRLL VVDTAYHSHH MLLCSERYIH SLRTCGIQVN
YNRNTSCTWY SSVKHGEPMH PEPSLGDLYW NDNMVNTVLF ADAVKGAAKG SQLNLAIEVG
PHPALKGPAL QTLSDFEMSL PYTGVLKRKG NDLEAFSDAL GFVWTHCGPG AVDFQTYEEL
IYPACKTPSL AIGLPAYQWD HKRVYWYQSR LAKKTQTRGE AFHELLGVPS PNNTDRDLRW
SNFLKTNEIP WLNGHQLQGQ TVFPAAGYVA MALEAGLKLA QGRSVKVLQI DDLTIDKAVT
FDDGANFAVE TLVALTGVTQ GQSRTKKQTA DFAVYSCANT GSSTELGVVS RGKVTVIYGT
PSFSTLHSSP HNEKNMVDIQ AEQFYSSLHE LGYGYNGPFK TLSSTKRTLN QASARVETYG
YGEDENTLIV HPTMLDVAFQ ASFLARMSPG DDQLWSLHVP TFIKCIRVNP ELCASIPSSP
TSLSLSAVLH ESDSLSMLSS VDVFTEDGQE TMIQVEGLSM KPFSPATADD DRSMFSTTVY
GSMSPDLAMD VGNGRPPSEG LAFSQCNVAL ACVAQQIVHR YPHAKILEIG AGEGHATRAV
LESIGSKLSY TFTDSSTEVI EKAAESFKDF KEKVLLKTFD PLGKPSSQGL DEHAYDLVIA
SNILASNSVS HTELENIRRL LKPGGYLLAS GLTGDAPTRT LGGGTVEGND ARKHGPVNTA
QWHGALRKAG FSGIDSITPQ TSGMASPFSA IVTQAVDKRI NFLRKPLSTP SFVRLDELVI
VGNQSLKAAQ LTEEIYDHLI QFCGKITVLD GLPTDDDDIS SMATFINLAD IHEPIFRDIS
AEQFEGLKCL FELASNILWV TEGARADEPY HNASIGFGRS IAYEMPHLSL QFLDLNDTGS
TASRVISEAV LRLVALREWE ETEHNFKDKT LWSREPELYV EKERLMVPRL LQVDDQNDRI
NSLRRVVTKM VDPDNSSVLI SKAVDGSFVL REEVLRQSGQ NFVQIKHSVL SAINVAPEAF
LFLGAGFSQV TDEVVITLSD ANASMSTPLA HVPAQWHTGG LSTLISAVAR QLLARRLISM
VVAHSHLLVH GLDENESFVS ILKQHAGLKD IDIKFSAANP AANSEWIQVT PWTSSHVTRQ
SIPATTTHFL DLSADDKNQD AAVIIREALP VICKHIGVSD LFRPESFVPA GSKDSILRAL
QDAVREAKTT ASSEIPSASI RPTELIDATV LKSPLSVVDW TVDGEVPVQV QPIDATQLFS
QHKTYVLVGL SGRLGQSISQ WMSQNGAGCI CLTSRTPKAD PEWQAEMEKK GTTVKLIPMD
VTNRADVERV FADLRANSPP IAGVASGAAV FHDATFSEMT HEILEKVMNP KVVGTKNLDE
VLGDTKLDFF IVFSSLTSVV GNSGQSNYTA ANAYMTGLVG QRRKRGLAAT SLDIGSIVGI
GYLERASDTA REQLIRNGFM AVSETDLHQL LAEAIRAGAT NSSASPMVTT GCRNVQEGEE
FPVPWIDDPR MQHKVILGEH SSKAEMAGKK SALPVRDQLA VSKSTADALE ILKELSECFA
AKLAMISRLA DGQVGHDIPL VELGIDSLVA VEVRGWFLKE LKTDIPVLKV LGGGTVATLC
QQALEKLPES ILPNVESGGP SKTGSSKPTA KPSVAKPRSP PSPSGSETGS PGRWSENNTT
SPQSTLSSDQ SPSSTPATVL SNVPSNVDLT TVAKSEMALI PSSDFVKTEL VSFQQSRFWF
LGLLIDDQAT FNVTFYLRIT GNLRTGDLER AVRLVTNRHE SLRTCFVAHE QEADLAYQKV
LPNSLVRLKR KNINRVEDVD IEYAAMKQVP FDLASGNLMR LVLLTLSASE HYLLFNYHHI
LMDGVSLQNF LADLEKAYQR QPLGPPPCQV PEFSRVQRAA FESGVFNEDI AYWKNEFPNG
HPVLPLLPMS HITSRMALNS FNVHQVECRV DSELMAKVRE AARVNGCTTF HFYLATFKAM
LFRFTDAGDL TIGIADANRI SPDVEGTIGL LLNLLTLRFQ RNPSQTFAQS VGEARGKALE
ALKHSNVPFD ILLKELNVPR SSAYSPFFQA FFDYRQGHQE KLSFGSTEFE FLQVHPGRTA
YDMTLDVTDG ADSARILFRT QASLYDKTAA QLLLNTFIHL LDTFATNTSL KLDDFALFSD
KELKLALNVG HGPNFESSWP GGTIPHRIDQ IAKENDDKVA LKDGHGTILT YGAMINRTQA
IAAALQQVGV GESSRVLVFE DATVDWPCSM LAIMRLGAVY VPLDLRNPLP RLADVAGSCK
PVAILVDSTT LDHVAQVNVT FAEVVNVSEV GVNSIKVANV SRSDAVAALL YTSGSTGKPK
GIVVTHSGLR NEIEGYTSQW VLKAERVLQQ SAFTFNHSSD QIYTGLVNGG FVYIVPWDKR
GDPIEVTKII KEENITYTKA TPAEYSLWLD YGSGNLKQAS SWRFAFGGGE SLTGTITRSL
ATLQLPNLRF FNSYGPTEIS ISSTKMEVAY RDSPPDGRIP CGFMLPNYAA YILDDQRKPV
PVGMPGELYI GGAGVSLGYL DNEELTEQHF LPNPYAIPEY VAQGWTRMYR TGDIAHLQGD
GAMVFHNRIA GDTQVKIRGL RIELGDIESN IIKAAEGALK EVAVTLRDGD PPILVAHVVF
APHHHIVDTE AFLVQLLKNL DVPQYMVPVM AIPLERMPLS NHSKTDRKAL KELPLPQRSN
HDTGDNTESL TETMLELRRL WVDVLNTGEL GLDIGPSTSF FTVGGNSLLI VRLQSRIRQT
FNVTVRLFDL IDANTLSDMT QKIEESLNVD LIDWDKETAL LSDFTMPEAT KHQPLKTTDK
VILVTGSGGF LGKHILTELI ARPDVSKIHC IGLRDKPGNT PRRLALNSTK IITHSGDLTE
PWLGLGEEKF ASLTLEVDVI LHMAATRSFW DNYSLLRPIN VTPTKLLVQM ATGRKIPIHY
VSSAGVVSAE GVEILAGSAA KYQPRVDGSN GYVASRWASE QILEHAVSAL DVPVSIHRFV
PAKEPANQTV VVDALQHFVS FVDELSIMPD FSGTTGHFEM TPIHSAASQL AENLVKTPTQ
QSSLLEFVHH DCPIRIDIAE MVAFLEEQRG GKGLEKVPGL KFVGDMKRAG LAYFVTSQTL
LMGGTNGTSV VLESRR
