TRT8_ASPTN
ID TRT8_ASPTN Reviewed; 397 AA.
AC Q0C899;
DT 06-JUL-2016, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 59.
DE RecName: Full=FAD-dependent monooxygenase trt8 {ECO:0000303|PubMed:22549923};
DE EC=1.-.-.- {ECO:0000269|PubMed:22549923, ECO:0000269|PubMed:22782788};
DE AltName: Full=Terretonin synthesis protein 8 {ECO:0000303|PubMed:22549923};
GN Name=trt8 {ECO:0000303|PubMed:22549923}; ORFNames=ATEG_10085;
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: FAD-dependent monooxygenase; part of the gene cluster that
CC mediates the biosynthesis of terretonin, a fungal meroterpenoid that
CC 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 -!- COFACTOR:
CC Name=FAD; Xref=ChEBI:CHEBI:57692; Evidence={ECO:0000305};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:23116177}.
CC -!- DISRUPTION PHENOTYPE: Impairs the synthesis of terretonin but
CC accumulates dimethylorsellinate through the decomposition of an
CC unstable intermediate (PubMed:23116177). {ECO:0000269|PubMed:23116177}.
CC -!- SIMILARITY: Belongs to the paxM FAD-dependent monooxygenase family.
CC {ECO:0000305}.
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DR EMBL; CH476609; EAU29534.1; -; Genomic_DNA.
DR RefSeq; XP_001209387.1; XM_001209387.1.
DR AlphaFoldDB; Q0C899; -.
DR SMR; Q0C899; -.
DR STRING; 33178.CADATEAP00002387; -.
DR EnsemblFungi; EAU29534; EAU29534; ATEG_10085.
DR GeneID; 4319492; -.
DR VEuPathDB; FungiDB:ATEG_10085; -.
DR eggNOG; KOG2614; Eukaryota.
DR HOGENOM; CLU_694402_0_0_1; -.
DR OrthoDB; 817726at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0071949; F:FAD binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; 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; 3.50.50.60; -; 1.
DR InterPro; IPR002938; FAD-bd.
DR InterPro; IPR036188; FAD/NAD-bd_sf.
DR Pfam; PF01494; FAD_binding_3; 1.
DR SUPFAM; SSF51905; SSF51905; 1.
PE 1: Evidence at protein level;
KW FAD; Flavoprotein; Monooxygenase; NADP; Oxidoreductase; Reference proteome.
FT CHAIN 1..397
FT /note="FAD-dependent monooxygenase trt8"
FT /id="PRO_0000436597"
FT BINDING 28..29
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 37..38
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 296
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 306..313
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
FT BINDING 316..320
FT /ligand="FAD"
FT /ligand_id="ChEBI:CHEBI:57692"
FT /evidence="ECO:0000250|UniProtKB:A6T923"
SQ SEQUENCE 397 AA; 44567 MW; 89A4074022E6E931 CRC64;
MSVYRLFTVS IMDMCVLKAN CKDPLGFTVE YTCVFGISSP IPGLHGGEHV NSYGEGVCVI
TFHNKDGRVF WFIIEKLPKK YTYPISPRFT PQDASEFCGR LADVHVFNDV TVGHLWRNRT
VVSMNALEEG LLSTWSFERM VLLGDSVHKM TPNIGQGANT AIEDAAALAS LIHQMINPMT
PQNASKAAIG HLFQKFQDLR MSRVQSTVQR AHFGARFHTR DDHLKALVGR YIFPYVGNLV
MARTVKVIGG GHKIEFLPPP KRSMPWTAQT DHSQHKMHGS KVLWAYLSHP DQHWSDDPRG
TAQLRSQSLG THRTSTVGRT LFIELVIVMI DVVYARQDIG EDVNAGVKDM AVQSRNSMRF
LPYVLSYGST ESLLAAGWRQ VWVFRLLSYL FGALLGL
