TRT4_ASPTN
ID TRT4_ASPTN Reviewed; 2422 AA.
AC Q0C8A4;
DT 06-JUL-2016, integrated into UniProtKB/Swiss-Prot.
DT 06-JUL-2016, sequence version 2.
DT 03-AUG-2022, entry version 87.
DE RecName: Full=Non-reducing polyketide synthase trt4 {ECO:0000303|PubMed:23116177};
DE EC=2.3.1.- {ECO:0000269|PubMed:22549923, ECO:0000269|PubMed:22782788};
DE AltName: Full=Terretonin synthesis protein 4 {ECO:0000303|PubMed:23116177};
GN Name=trt4 {ECO:0000303|PubMed:23116177}; ORFNames=ATEG_10080;
OS Aspergillus terreus (strain NIH 2624 / FGSC A1156).
OC Eukaryota; Fungi; Dikarya; Ascomycota; Pezizomycotina; Eurotiomycetes;
OC Eurotiomycetidae; Eurotiales; Aspergillaceae; Aspergillus;
OC Aspergillus subgen. Circumdati.
OX NCBI_TaxID=341663;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=NIH 2624 / FGSC A1156;
RA Birren B.W., Lander E.S., Galagan J.E., Nusbaum C., Devon K., Henn M.,
RA Ma L.-J., Jaffe D.B., Butler J., Alvarez P., Gnerre S., Grabherr M.,
RA Kleber M., Mauceli E.W., Brockman W., Rounsley S., Young S.K., LaButti K.,
RA Pushparaj V., DeCaprio D., Crawford M., Koehrsen M., Engels R.,
RA Montgomery P., Pearson M., Howarth C., Larson L., Luoma S., White J.,
RA Alvarado L., Kodira C.D., Zeng Q., Oleary S., Yandava C., Denning D.W.,
RA Nierman W.C., Milne T., Madden K.;
RT "Annotation of the Aspergillus terreus NIH2624 genome.";
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [2]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=22549923; DOI=10.1002/cbic.201200124;
RA Itoh T., Tokunaga K., Radhakrishnan E.K., Fujii I., Abe I., Ebizuka Y.,
RA Kushiro T.;
RT "Identification of a key prenyltransferase involved in biosynthesis of the
RT most abundant fungal meroterpenoids derived from 3,5-dimethylorsellinic
RT acid.";
RL ChemBioChem 13:1132-1135(2012).
RN [3]
RP FUNCTION, AND CATALYTIC ACTIVITY.
RX PubMed=22782788; DOI=10.1002/cbic.201200369;
RA Matsuda Y., Awakawa T., Itoh T., Wakimoto T., Kushiro T., Fujii I.,
RA Ebizuka Y., Abe I.;
RT "Terretonin biosynthesis requires methylation as essential step for
RT cyclization.";
RL ChemBioChem 13:1738-1741(2012).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=23116177; DOI=10.1021/ol302682z;
RA Guo C.J., Knox B.P., Chiang Y.M., Lo H.C., Sanchez J.F., Lee K.H.,
RA Oakley B.R., Bruno K.S., Wang C.C.;
RT "Molecular genetic characterization of a cluster in A. terreus for
RT biosynthesis of the meroterpenoid terretonin.";
RL Org. Lett. 14:5684-5687(2012).
RN [5]
RP FUNCTION.
RX PubMed=25671343; DOI=10.1021/jacs.5b00570;
RA Matsuda Y., Iwabuchi T., Wakimoto T., Awakawa T., Abe I.;
RT "Uncovering the unusual D-ring construction in terretonin biosynthesis by
RT collaboration of a multifunctional cytochrome P450 and a unique
RT isomerase.";
RL J. Am. Chem. Soc. 137:3393-3401(2015).
RN [6]
RP FUNCTION.
RX PubMed=28759016; DOI=10.1038/nchembio.2443;
RA Mori T., Iwabuchi T., Hoshino S., Wang H., Matsuda Y., Abe I.;
RT "Molecular basis for the unusual ring reconstruction in fungal
RT meroterpenoid biogenesis.";
RL Nat. Chem. Biol. 13:1066-1073(2017).
CC -!- FUNCTION: Non-reducing polyketide synthase; part of the gene cluster
CC that mediates the biosynthesis of terretonin, a fungal meroterpenoid
CC that acts as a mycotoxin (PubMed:22549923, PubMed:23116177,
CC PubMed:25671343). The first step of the pathway is the synthesis of
CC 3,5-dimethylorsellinic acid (DMOA) by the polyketide synthase trt4
CC (PubMed:22549923, PubMed:23116177). DMOA is then prenylated into
CC farnesyl-DMOA by the polyprenyl transferase trt2 (PubMed:22549923,
CC PubMed:22782788, PubMed:23116177). Methylation by the methyltransferase
CC trt5 then leads to farnesyl-DMOA methyl ester which is further subject
CC to epoxidation by the FAD-dependent monooxygenase trt8 to yield
CC epoxyfarnesyl-DMOA methyl ester (PubMed:22549923, PubMed:22782788,
CC PubMed:23116177). Cyclization of epoxyfarnesyl-DMOA methyl ester by the
CC terpene cyclase trt1 leads to a tetracycle intermediate which is in
CC turn converted to preterretonin (PubMed:22549923, PubMed:22782788,
CC PubMed:23116177). Dehydrogenase trt9 comes next to transform
CC preterretonin to preterrenoid (PubMed:22549923, PubMed:23116177). The
CC FAD-dependent monooxygenase trt3 is then required for the C-
CC hydroxylation at C16 of preterrenoid to yield terrenoid
CC (PubMed:22549923, PubMed:23116177). The cytochrome P450 trt6 catalyzes
CC three successive oxidations to transform terrenoid into an unstable
CC intermediate, which then undergoes the D-ring expansion and unusual
CC rearrangement of the methoxy group to afford the core skeleton of
CC terretonin (PubMed:25671343, PubMed:28759016). Trt14 catalyzes the D-
CC ring expansion of terretonin involving intramolecular methoxy
CC rearrangement as well as the hydrolysis of the expanded D-ring and the
CC methyl ester moiety (PubMed:25671343, PubMed:28759016). Finally, the
CC nonheme iron-dependent dioxygenase trt7 accomplishes the last two
CC oxidation reactions steps to complete the biosynthesis of terretonin
CC (PubMed:25671343). Terretonin C is produced via spontaneous
CC decarboxylation of the terretonin precursor (PubMed:23116177). Another
CC shunt product of the terretonin biosynthesis is dihydrofarnesyl-DMOA,
CC derived from epoxyfarnesyl-DMOA through hydrolysis of the epoxide
CC (PubMed:22549923, PubMed:22782788, PubMed:23116177).
CC {ECO:0000269|PubMed:22549923, ECO:0000269|PubMed:22782788,
CC ECO:0000269|PubMed:23116177, ECO:0000269|PubMed:25671343,
CC ECO:0000269|PubMed:28759016}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=acetyl-CoA + 3 malonyl-CoA + 2 S-adenosyl-L-methionine = 3,5-
CC dimethylorsellinate + 3 CO2 + 4 CoA + 2 S-adenosyl-L-homocysteine;
CC Xref=Rhea:RHEA:49628, ChEBI:CHEBI:16526, ChEBI:CHEBI:57287,
CC ChEBI:CHEBI:57288, ChEBI:CHEBI:57384, ChEBI:CHEBI:57856,
CC ChEBI:CHEBI:59789, ChEBI:CHEBI:131856;
CC Evidence={ECO:0000269|PubMed:22549923, ECO:0000269|PubMed:22782788};
CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:49629;
CC Evidence={ECO:0000269|PubMed:22549923, ECO:0000269|PubMed:22782788};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:23116177}.
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 (PubMed:23116177).
CC {ECO:0000250|UniProtKB:Q5B0D0, ECO:0000305|PubMed:23116177}.
CC -!- DOMAIN: The release of the polyketide chain from the non-reducing
CC polyketide synthase is mediated by the thioesterase (TE) domain
CC localized at the C-ter of the protein (By similarity).
CC {ECO:0000250|UniProtKB:Q5ATJ7}.
CC -!- DISRUPTION PHENOTYPE: Impairs the synthesis of terretonin
CC (PubMed:23116177). {ECO:0000269|PubMed:23116177}.
CC -!- SEQUENCE CAUTION:
CC Sequence=EAU29529.1; Type=Erroneous gene model prediction; Evidence={ECO:0000305};
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DR EMBL; CH476609; EAU29529.1; ALT_SEQ; Genomic_DNA.
DR RefSeq; XP_001209382.1; XM_001209382.1.
DR AlphaFoldDB; Q0C8A4; -.
DR SMR; Q0C8A4; -.
DR STRING; 33178.CADATEAP00002189; -.
DR GeneID; 4319423; -.
DR eggNOG; KOG1202; Eukaryota.
DR HOGENOM; CLU_000022_6_3_1; -.
DR OrthoDB; 93381at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0004315; F:3-oxoacyl-[acyl-carrier-protein] synthase activity; IEA:InterPro.
DR GO; GO:0016787; F:hydrolase 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 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; -; 1.
DR Gene3D; 3.40.47.10; -; 1.
DR Gene3D; 3.40.50.150; -; 1.
DR Gene3D; 3.40.50.1820; -; 1.
DR InterPro; IPR029058; AB_hydrolase.
DR InterPro; IPR013094; AB_hydrolase_3.
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; 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; 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; IPR016039; Thiolase-like.
DR Pfam; PF07859; Abhydrolase_3; 1.
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; PF00550; PP-binding; 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; SSF52151; SSF52151; 1.
DR SUPFAM; SSF53335; SSF53335; 1.
DR SUPFAM; SSF53474; SSF53474; 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 Methyltransferase; Multifunctional enzyme; Phosphopantetheine;
KW Phosphoprotein; Reference proteome; Transferase.
FT CHAIN 1..2422
FT /note="Non-reducing polyketide synthase trt4"
FT /id="PRO_0000436593"
FT DOMAIN 1535..1612
FT /note="Carrier"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
FT REGION 14..196
FT /note="N-terminal acylcarrier protein transacylase domain
FT (SAT)"
FT /evidence="ECO:0000255"
FT REGION 289..314
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 329..692
FT /note="Ketosynthase (KS) domain"
FT /evidence="ECO:0000255"
FT REGION 856..1121
FT /note="Malonyl-CoA:ACP transacylase (MAT) domain"
FT /evidence="ECO:0000255"
FT REGION 1191..1494
FT /note="Product template (PT) domain"
FT /evidence="ECO:0000255"
FT REGION 1615..1636
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 1774..2007
FT /note="Methyltransferase (CMeT) domain"
FT /evidence="ECO:0000255"
FT REGION 2036..2383
FT /note="Thioesterase (TE) domain"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT COMPBIAS 292..314
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT ACT_SITE 494
FT /note="For beta-ketoacyl synthase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 904
FT /note="For acyl/malonyl transferase activity"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU10022"
FT ACT_SITE 2159
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 2320
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT ACT_SITE 2352
FT /note="For thioesterase activity"
FT /evidence="ECO:0000250|UniProtKB:Q5ATJ7"
FT MOD_RES 1572
FT /note="O-(pantetheine 4'-phosphoryl)serine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00258"
SQ SEQUENCE 2422 AA; 264859 MW; AC00A41821C0073E CRC64;
MGSLQDAHPH RVSVLFGPKC PKTDRSVLHI RRYLSSHRNT GWLEDAVQAL PSVWHDVTKV
WPAAEKIPGF CVGYLAAVAA CWETDQTEFP KAVATMLRIA VCIGAVVDLD ELEKQRATSM
AVRWKTSADY KLLTALLSRY PGAYIACVTD ESAATVTIWE SQAAALVKEL ESNGLVVKST
QLRGRFHHSD HTSVVQEFLK LCQEDNRFHL PNGNPAVGLP RSNIDGEVPT LQSLLSVANE
SILISQANWN LTVSATISSL QLTDAKSIVS IGAGQCIPRK ARGRILHTVE PPDSHHNTNT
TQDSDVTTNA SPLTAGYVNG TGPAATATTV PIAVTGMACR YPQADSMEEL WKILEQGHCT
VSPMPKNRFK LDELQREPKG PFWGNFLSRP DTFDHRFFKI SAREAESMDP QQRLLLQVAY
EAIESAGYCG LRASQLPQDV GCYVGVGTED YSENVASRNA TAFSATGTLQ AFNSGRVSHY
FGWTGPSVTI DTACSSAAVA IHLACQALQT NDCSMAVAGG VNVMTDPRWS QNLAAASFLS
PTGASKAFDA DANGYCRGEG AGLVVLRPLE AALRDGDPIH AVITGTSVNQ GANCSPITVP
DSNSQTTLYL KALSISGIKP DVVTYVEAHG TGTQVGDPIE FQSIRKTFAV PHRTERLYVG
SIKDNIGHTE TSSGVAGMLK TILMLQKRRI PKQANFTRLN PMITLQKEDQ IFIPVESTDW
KAEKRVAMVT NYGAAGSNAA IVLQEPTCTS RTPISGYREY LPSVIPVFVA ARTEESIREY
CKALQTAFLE APQVNNVEVQ DIAFNLARKQ NRDMEYSVAF TTASGNDAEL RERLEDIVSG
RTRIEKKCQA AHPVVLCFGG QTGNTASISQ NLVQSSELLR FHLYATAKAW LDSGLRVDRM
IGHSFGQLTA VCVAGGLSLL DAMRLISSRA QLIRSEWKSD TGLMLSVRGE KETVQALLDA
VSNAADIACV NGPESFVVAG DEATIHKMEN IAVERGMKLR MQRLKNTHAF HSKLVDSILP
GLTKIASTLN YRPLRIPVEP CSELADDWSL PTGDKIVQHS RKAVYFHNAI RRTISHMDSP
CIWLEAGSAS PIIRMVRRAV DASPSPRDHV YCPIDLSGPQ AEENFAKVFS SLWSKGVQVQ
FWPFHGSQTG YRWINLPPYQ FAKTSHWIDY DPNAFYSDPP KREAGRTDEP SLVKLLNNDG
NVYLFGVNVN DPLFRMCTAG HAVVDQNLCP ASLYFELVVR GAVAVLPLEN DPTMYHIAGL
DISAPLVLDM PGSVFLELTQ RGSGPGQFTF VLFTRDGNQD SVAHATGKIS ISSEANDSGI
SSRFGSLRRL VNPSRWGFIA TSPSSSGLKR STVYQAFRRV VNYADYYRGV EEVYAVGHEA
TGRVLLPSSP TNKASCDPIL IDNFIQVAGI HVNCLSETLD EEVFVCSSVG DVIIGELFVR
RDPGVSVPWI VYSSSERESM KKSLCDIFVV DEATGSLALC ILSATFTCVS IQSLKRTLTR
LNNKALASTG VDVVVPAVAV APAAPAASAA MPDSSRSEDG LRVVQAMLSE LLGISAGEIP
ASAALGDVGV DSLMSTEVLS EINKRFKVVI TNSELTAIAD VSGLVQRIFP GGSVAHVETH
SQPPDKIGIT TGDRMPPPRV PPPTVIQEQS LPGFVDKARE LFAASRTSNE YRQKTRFLGF
CDSVFPQQME LVTVYVVAAL KALNVDLQSL RFGQAVPSVE VLPQHGKVMN QLFAVLEYSG
LVERRGTGMI RGHRAVNKST ATILHKKILS EHPQHASEHK LLHTTGSRLA DCLIGAADPL
SLLFQDAQAR ALMQDVYSNA PMFKSATMHL AQFLKDLLGQ RCFQRRISIL EIGAGTGGTT
DYILKQLSSV AGLTFEYTFT DISSSLVTLA RKRFKTYHFM HYATLDIEQD PAPELQGQYD
IIISSNCIHA TRSLATSCSN IQKLLRPQGI LCLIELTRNL FWFDLVFGLL EGWWLFNDGR
SHALAHERLW DQTLRQAGFN WVDWTDNDSE ESKILRMIVA SPSQPVLCSP GEAKSNAVAE
ETLVYSRKDG LELCADIYYP HGLDGEDRKR PVAILIHGGG HIMLSRKDVR PMQVKMLLDM
GFLPVSIDYR LCPEVPLLEG PMVDACDALA WARHELPQLQ LKRPDIRPDG GNVVAVGWSS
GGHLAMTLAW TAPARSVRAP EAILSFYSPT DYTDPFWTKP NFPYQESVCM SDVPTSDPLL
ALHDTAITSY NPAPGKGVLG GWMSPSDPRS RIALHMNWTG QTLPVLFYGC KYKSLAAAAK
GDEVLLPAPH MSEVEKACPL SQVRAGRYKT PTFLIHGTLD DLIPVQQAQR IHQQMLVCGV
ESVLRIVSDG LHLFDIIPHL KENKDASQAV LDGLAPHIPT DEYPNPPPKL PKMDTSYPKC
LYLISGVPVK ALEIMSCYVF HR
