TRT6_ASPTN
ID TRT6_ASPTN Reviewed; 489 AA.
AC Q0C8A1;
DT 06-JUL-2016, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 78.
DE RecName: Full=Cytochrome P450 monooxygenase trt6 {ECO:0000303|PubMed:22549923};
DE EC=1.-.-.- {ECO:0000269|PubMed:25671343};
DE AltName: Full=Terretonin synthesis protein 6 {ECO:0000303|PubMed:22549923};
GN Name=trt6 {ECO:0000303|PubMed:22549923}; ORFNames=ATEG_10083;
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.
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.
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, AND CATALYTIC ACTIVITY.
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: Cytochrome P450 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=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000250|UniProtKB:P04798};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:23116177}.
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000255}; Single-pass membrane
CC protein {ECO:0000255}.
CC -!- DISRUPTION PHENOTYPE: Impairs the synthesis of terretonin but
CC accumulates terrenoid (PubMed:23116177). {ECO:0000269|PubMed:23116177}.
CC -!- SIMILARITY: Belongs to the cytochrome P450 family. {ECO:0000305}.
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DR EMBL; CH476609; EAU29532.1; -; Genomic_DNA.
DR RefSeq; XP_001209385.1; XM_001209385.1.
DR AlphaFoldDB; Q0C8A1; -.
DR SMR; Q0C8A1; -.
DR EnsemblFungi; EAU29532; EAU29532; ATEG_10083.
DR GeneID; 4319490; -.
DR VEuPathDB; FungiDB:ATEG_10083; -.
DR eggNOG; KOG0158; Eukaryota.
DR HOGENOM; CLU_022195_0_3_1; -.
DR OMA; IVAYHTT; -.
DR OrthoDB; 572303at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0020037; F:heme binding; IEA:InterPro.
DR GO; GO:0005506; F:iron ion binding; IEA:InterPro.
DR GO; GO:0004497; F:monooxygenase activity; IEA:UniProtKB-KW.
DR GO; GO:0016705; F:oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen; IEA:InterPro.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
DR Gene3D; 1.10.630.10; -; 1.
DR InterPro; IPR001128; Cyt_P450.
DR InterPro; IPR017972; Cyt_P450_CS.
DR InterPro; IPR002403; Cyt_P450_E_grp-IV.
DR InterPro; IPR036396; Cyt_P450_sf.
DR Pfam; PF00067; p450; 1.
DR PRINTS; PR00465; EP450IV.
DR SUPFAM; SSF48264; SSF48264; 1.
DR PROSITE; PS00086; CYTOCHROME_P450; 1.
PE 1: Evidence at protein level;
KW Glycoprotein; Heme; Iron; Membrane; Metal-binding; Monooxygenase;
KW Oxidoreductase; Reference proteome; Transmembrane; Transmembrane helix.
FT CHAIN 1..489
FT /note="Cytochrome P450 monooxygenase trt6"
FT /id="PRO_0000436595"
FT TRANSMEM 10..30
FT /note="Helical"
FT /evidence="ECO:0000255"
FT BINDING 430
FT /ligand="heme"
FT /ligand_id="ChEBI:CHEBI:30413"
FT /ligand_part="Fe"
FT /ligand_part_id="ChEBI:CHEBI:18248"
FT /note="axial binding residue"
FT /evidence="ECO:0000250|UniProtKB:P04798"
FT CARBOHYD 364
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
FT CARBOHYD 407
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00498"
SQ SEQUENCE 489 AA; 55201 MW; CB2AC27B215B003E CRC64;
MLEPVSTAQS LWSFGLWILV ILSPVLFFAS RELGILNAKK RFAKNGFEEV LAGLRKSDVF
GLMTINGPKI VLAPKFAQEI RSNPALSVSA FSSSELHAHI RGFDVFRQGE ADDILQDTVR
SKITQSIGDL IQPLSEECSL TLKPKWTDSP EWHEVCPHTT ILDIIARLSS RAFIGDELCR
NPKWLRLTVD FTVDSFRAAE ALNWWPYALR PLVARFLPSC LKLHKYIQDA DNMMKPVLES
RRQAQAKDPQ KSYPDTIQWF EETAQGRPYD PVRLQLTLAF ASIHTTADLV IQTILDLCSA
KNWDELCRSL REEIISSFRE EGWRKPLLAK LKIMDSALKE SQRLKPVSIV GMGRIAKEAV
KLSNNTIIPK GTRLLVSNTA MWDPEIYPDP RTYDPYRFLR LREASENESA GQLVSLSPTH
LSFGLGKHAC PGRFFAAAEV KIILCHILLK YDIKLADGCK PKPLRAGTNL VADPTAKLLV
RRRQEEVAL
