TRT14_ASPTN
ID TRT14_ASPTN Reviewed; 142 AA.
AC Q0C8A2;
DT 06-JUL-2016, integrated into UniProtKB/Swiss-Prot.
DT 17-OCT-2006, sequence version 1.
DT 03-AUG-2022, entry version 46.
DE RecName: Full=Isomerase trt14 {ECO:0000303|PubMed:25671343};
DE EC=5.-.-.- {ECO:0000269|PubMed:25671343, ECO:0000269|PubMed:28759016};
DE AltName: Full=Terretonin synthesis protein 14 {ECO:0000303|PubMed:23116177};
GN Name=trt14 {ECO:0000303|PubMed:23116177}; ORFNames=ATEG_10082;
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] {ECO:0007744|PDB:5WQF, ECO:0007744|PDB:5WQG, ECO:0007744|PDB:5WQH, ECO:0007744|PDB:5WQI}
RP X-RAY CRYSTALLOGRAPHY (1.90 ANGSTROMS) IN COMPLEX WITH SUBSTRATE, SUBUNIT,
RP FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, PATHWAY, AND
RP MUTAGENESIS OF TYR-19; ARG-31; SER-37; ARG-39 AND ARG-48.
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: Isomerase; part of the gene cluster that mediates the
CC biosynthesis of terretonin, a fungal meroterpenoid that acts as a
CC mycotoxin (PubMed:22549923, PubMed:23116177, PubMed:25671343). The
CC first step of the pathway is the synthesis of 3,5-dimethylorsellinic
CC acid (DMOA) by the polyketide synthase trt4 (PubMed:22549923,
CC PubMed:23116177). DMOA is then prenylated into farnesyl-DMOA by the
CC polyprenyl transferase trt2 (PubMed:22549923, PubMed:22782788,
CC PubMed:23116177). Methylation by the methyltransferase trt5 then leads
CC to farnesyl-DMOA methyl ester which is further subject to epoxidation
CC by the FAD-dependent monooxygenase trt8 to yield epoxyfarnesyl-DMOA
CC methyl ester (PubMed:22549923, PubMed:22782788, PubMed:23116177).
CC Cyclization of epoxyfarnesyl-DMOA methyl ester by the terpene cyclase
CC trt1 leads to a tetracycle intermediate which is in turn converted to
CC preterretonin (PubMed:22549923, PubMed:22782788, PubMed:23116177).
CC Dehydrogenase trt9 comes next to transform preterretonin to
CC preterrenoid (PubMed:22549923, PubMed:23116177). The FAD-dependent
CC monooxygenase trt3 is then required for the C-hydroxylation at C16 of
CC preterrenoid to yield terrenoid (PubMed:22549923, PubMed:23116177). The
CC cytochrome P450 trt6 catalyzes three successive oxidations to transform
CC terrenoid into an unstable intermediate, which then undergoes the D-
CC ring expansion and unusual rearrangement of the methoxy group to afford
CC the core skeleton of terretonin (PubMed:25671343, PubMed:28759016).
CC Trt14 catalyzes the D-ring expansion of terretonin involving
CC intramolecular methoxy rearrangement as well as the hydrolysis of the
CC expanded D-ring and the methyl ester moiety (PubMed:25671343,
CC PubMed:28759016). Finally, the nonheme iron-dependent dioxygenase trt7
CC accomplishes the last two oxidation reactions steps to complete the
CC biosynthesis of terretonin (PubMed:25671343). Terretonin C is produced
CC via spontaneous decarboxylation of the terretonin precursor
CC (PubMed:23116177). Another shunt product of the terretonin biosynthesis
CC is dihydrofarnesyl-DMOA, derived from epoxyfarnesyl-DMOA through
CC hydrolysis of the epoxide (PubMed:22549923, PubMed:22782788,
CC PubMed:23116177). {ECO:0000269|PubMed:22549923,
CC ECO:0000269|PubMed:22782788, ECO:0000269|PubMed:23116177,
CC ECO:0000269|PubMed:25671343, ECO:0000269|PubMed:28759016}.
CC -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC Kinetic parameters:
CC KM=169.2 uM for the stable regioisomer of the product of trt6
CC {ECO:0000269|PubMed:28759016};
CC -!- PATHWAY: Secondary metabolite biosynthesis; terpenoid biosynthesis.
CC {ECO:0000269|PubMed:23116177, ECO:0000269|PubMed:28759016}.
CC -!- SUBUNIT: Homodimer. {ECO:0000269|PubMed:28759016}.
CC -!- DISRUPTION PHENOTYPE: Impairs the synthesis of terretonin but
CC accumulates terretonin C (PubMed:23116177).
CC {ECO:0000269|PubMed:23116177}.
CC -!- SIMILARITY: Belongs to the trt14 isomerase family. {ECO:0000305}.
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DR EMBL; CH476609; EAU29531.1; -; Genomic_DNA.
DR RefSeq; XP_001209384.1; XM_001209384.1.
DR PDB; 5WQF; X-ray; 2.00 A; A/B/C/D/E/F=1-142.
DR PDB; 5WQG; X-ray; 2.30 A; A/B/C/D/E/F=1-142.
DR PDB; 5WQH; X-ray; 2.10 A; A/B/C/D/E/F=1-142.
DR PDB; 5WQI; X-ray; 1.90 A; A/B/C/D/E/F=1-142.
DR PDBsum; 5WQF; -.
DR PDBsum; 5WQG; -.
DR PDBsum; 5WQH; -.
DR PDBsum; 5WQI; -.
DR AlphaFoldDB; Q0C8A2; -.
DR SMR; Q0C8A2; -.
DR EnsemblFungi; EAU29531; EAU29531; ATEG_10082.
DR GeneID; 4319489; -.
DR VEuPathDB; FungiDB:ATEG_10082; -.
DR eggNOG; ENOG502S4TQ; Eukaryota.
DR HOGENOM; CLU_108113_3_0_1; -.
DR OMA; NEYMIVL; -.
DR OrthoDB; 1409451at2759; -.
DR UniPathway; UPA00213; -.
DR Proteomes; UP000007963; Unassembled WGS sequence.
DR GO; GO:0016853; F:isomerase activity; IEA:UniProtKB-KW.
DR GO; GO:0016114; P:terpenoid biosynthetic process; IEA:UniProtKB-UniPathway.
PE 1: Evidence at protein level;
KW 3D-structure; Isomerase; Reference proteome.
FT CHAIN 1..142
FT /note="Isomerase trt14"
FT /id="PRO_0000436599"
FT REGION 37..39
FT /note="Substrate"
FT /evidence="ECO:0007744|PDB:5WQG, ECO:0007744|PDB:5WQH,
FT ECO:0007744|PDB:5WQI"
FT BINDING 19
FT /ligand="substrate"
FT /evidence="ECO:0007744|PDB:5WQH, ECO:0007744|PDB:5WQI"
FT BINDING 39
FT /ligand="substrate"
FT /evidence="ECO:0007744|PDB:5WQI"
FT BINDING 48
FT /ligand="substrate"
FT /evidence="ECO:0007744|PDB:5WQG, ECO:0007744|PDB:5WQH,
FT ECO:0007744|PDB:5WQI"
FT MUTAGEN 19
FT /note="Y->A: Leads to a dramatic decrease of the catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:28759016"
FT MUTAGEN 19
FT /note="Y->F: Alters the stereochemistry and the specificity
FT of the enzyme reaction."
FT /evidence="ECO:0000269|PubMed:28759016"
FT MUTAGEN 31
FT /note="R->A: Does not significantly affect the catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:28759016"
FT MUTAGEN 37
FT /note="S->V: Does not significantly affect the catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:28759016"
FT MUTAGEN 39
FT /note="R->A: Leads to a dramatic decrease of the catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:28759016"
FT MUTAGEN 48
FT /note="R->A: Leads to a dramatic decrease of the catalytic
FT activity."
FT /evidence="ECO:0000269|PubMed:28759016"
FT HELIX 5..21
FT /evidence="ECO:0007829|PDB:5WQI"
FT HELIX 24..27
FT /evidence="ECO:0007829|PDB:5WQI"
FT TURN 28..30
FT /evidence="ECO:0007829|PDB:5WQI"
FT STRAND 31..39
FT /evidence="ECO:0007829|PDB:5WQI"
FT HELIX 42..44
FT /evidence="ECO:0007829|PDB:5WQI"
FT STRAND 46..48
FT /evidence="ECO:0007829|PDB:5WQI"
FT HELIX 50..61
FT /evidence="ECO:0007829|PDB:5WQI"
FT STRAND 64..72
FT /evidence="ECO:0007829|PDB:5WQI"
FT HELIX 74..76
FT /evidence="ECO:0007829|PDB:5WQI"
FT STRAND 78..80
FT /evidence="ECO:0007829|PDB:5WQI"
FT TURN 81..84
FT /evidence="ECO:0007829|PDB:5WQI"
FT STRAND 85..96
FT /evidence="ECO:0007829|PDB:5WQI"
FT STRAND 99..111
FT /evidence="ECO:0007829|PDB:5WQI"
FT STRAND 115..125
FT /evidence="ECO:0007829|PDB:5WQI"
FT HELIX 127..138
FT /evidence="ECO:0007829|PDB:5WQI"
SQ SEQUENCE 142 AA; 16134 MW; 7598D4A2D31C9D1A CRC64;
MSPTREDLVA TAKLFIAKYN EFTPESIISV RTPNSVSHRL FPTRNATRNI GESMEACANA
KEVFKSLTVS VIDDNDTIVD ERTRKVVFYL ASRGDTIVGE WKSECIFIFQ MSEDGKLVDR
IWAGFDTAYM DEFESRLDGI TF
