T23O_CAEEL
ID T23O_CAEEL Reviewed; 403 AA.
AC Q09474; Q27GU8; Q8I7L6;
DT 01-NOV-1995, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1995, sequence version 1.
DT 03-AUG-2022, entry version 146.
DE RecName: Full=Tryptophan 2,3-dioxygenase {ECO:0000255|HAMAP-Rule:MF_03020};
DE Short=TDO {ECO:0000255|HAMAP-Rule:MF_03020};
DE EC=1.13.11.11 {ECO:0000255|HAMAP-Rule:MF_03020, ECO:0000269|PubMed:27995966};
DE AltName: Full=Tryptamin 2,3-dioxygenase {ECO:0000255|HAMAP-Rule:MF_03020};
DE AltName: Full=Tryptophan oxygenase {ECO:0000255|HAMAP-Rule:MF_03020};
DE Short=TO {ECO:0000255|HAMAP-Rule:MF_03020};
DE Short=TRPO {ECO:0000255|HAMAP-Rule:MF_03020};
DE AltName: Full=Tryptophan pyrrolase {ECO:0000255|HAMAP-Rule:MF_03020};
DE AltName: Full=Tryptophanase {ECO:0000255|HAMAP-Rule:MF_03020};
GN Name=tdo-2 {ECO:0000312|WormBase:C28H8.11a};
GN ORFNames=C28H8.11 {ECO:0000312|WormBase:C28H8.11a};
OS Caenorhabditis elegans.
OC Eukaryota; Metazoa; Ecdysozoa; Nematoda; Chromadorea; Rhabditida;
OC Rhabditina; Rhabditomorpha; Rhabditoidea; Rhabditidae; Peloderinae;
OC Caenorhabditis.
OX NCBI_TaxID=6239;
RN [1]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RC STRAIN=Bristol N2;
RX PubMed=9851916; DOI=10.1126/science.282.5396.2012;
RG The C. elegans sequencing consortium;
RT "Genome sequence of the nematode C. elegans: a platform for investigating
RT biology.";
RL Science 282:2012-2018(1998).
RN [2]
RP FUNCTION, PATHWAY, TISSUE SPECIFICITY, AND DISRUPTION PHENOTYPE.
RX PubMed=22927396; DOI=10.1073/pnas.1203083109;
RA van der Goot A.T., Zhu W., Vazquez-Manrique R.P., Seinstra R.I.,
RA Dettmer K., Michels H., Farina F., Krijnen J., Melki R., Buijsman R.C.,
RA Ruiz Silva M., Thijssen K.L., Kema I.P., Neri C., Oefner P.J., Nollen E.A.;
RT "Delaying aging and the aging-associated decline in protein homeostasis by
RT inhibition of tryptophan degradation.";
RL Proc. Natl. Acad. Sci. U.S.A. 109:14912-14917(2012).
RN [3]
RP FUNCTION, CATALYTIC ACTIVITY, PATHWAY, AND MUTAGENESIS OF 133-PRO--ASP-135.
RX PubMed=27995966; DOI=10.1038/srep39199;
RA Michels H., Seinstra R.I., Uitdehaag J.C., Koopman M., van Faassen M.,
RA Martineau C.N., Kema I.P., Buijsman R., Nollen E.A.;
RT "Identification of an evolutionary conserved structural loop that is
RT required for the enzymatic and biological function of tryptophan 2,3-
RT dioxygenase.";
RL Sci. Rep. 6:39199-39199(2016).
CC -!- FUNCTION: Heme-dependent dioxygenase that catalyzes the oxidative
CC cleavage of the L-tryptophan (L-Trp) pyrrole ring and converts L-
CC tryptophan to N-formyl-L-kynurenine (PubMed:27995966). Catalyzes the
CC oxidative cleavage of the indole moiety (PubMed:27995966). Involved in
CC regulation of protein homeostasis, longevity and reproducive life span
CC (PubMed:22927396, PubMed:27995966). Specifically regulates
CC proteotoxicity due to age-related aggregation of proteins like alpha-
CC synuclein, via its effects on tryptophan metabolism (PubMed:22927396).
CC {ECO:0000255|HAMAP-Rule:MF_03020, ECO:0000269|PubMed:22927396,
CC ECO:0000269|PubMed:27995966}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=L-tryptophan + O2 = N-formyl-L-kynurenine;
CC Xref=Rhea:RHEA:24536, ChEBI:CHEBI:15379, ChEBI:CHEBI:57912,
CC ChEBI:CHEBI:58629; EC=1.13.11.11; Evidence={ECO:0000255|HAMAP-
CC Rule:MF_03020, ECO:0000269|PubMed:27995966};
CC -!- COFACTOR:
CC Name=heme; Xref=ChEBI:CHEBI:30413;
CC Evidence={ECO:0000255|HAMAP-Rule:MF_03020};
CC Note=Binds 1 heme group per subunit. {ECO:0000255|HAMAP-Rule:MF_03020};
CC -!- PATHWAY: Amino-acid degradation; L-tryptophan degradation via
CC kynurenine pathway; L-kynurenine from L-tryptophan: step 1/2.
CC {ECO:0000255|HAMAP-Rule:MF_03020, ECO:0000269|PubMed:22927396,
CC ECO:0000305|PubMed:27995966}.
CC -!- SUBUNIT: Homotetramer. Dimer of dimers. {ECO:0000255|HAMAP-
CC Rule:MF_03020}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=2;
CC Name=a {ECO:0000312|WormBase:C28H8.11a};
CC IsoId=Q09474-1; Sequence=Displayed;
CC Name=c {ECO:0000312|WormBase:C28H8.11c};
CC IsoId=Q09474-3; Sequence=VSP_057311;
CC -!- TISSUE SPECIFICITY: Expressed in body wall muscle cells, hypodermis,
CC PLM neurons and touch-receptor neurons. {ECO:0000269|PubMed:22927396}.
CC -!- DISRUPTION PHENOTYPE: RNAi-mediated knockdown of the protein increases
CC longevity and causes a delayed and extended reproductive life span
CC without increasing total progeny. Animals show increased levels of
CC tryptophan, reduced sensitivity to proteotoxic aggregates of alpha-
CC synuclein and reduced age-related decline of motility. A double
CC knockdown of tdo-2 together with an enzyme downstream in the kynurenine
CC pathway, kmo-1, flu-2, afmd-1 or haao-1, causes an increase in motility
CC and tryptophan levels and suppresses the proteotoxicity similarly to
CC knock-down of tdo-2 alone. RNAi-mediated knockdown in a tph-1 deletion
CC background, which is necessary for synthesis of serotonin from
CC trypotophan, shows increased motility, but variable suppression of
CC proteotoxicity. RNAi-mediated knockdown in a mutant background for daf-
CC 16, which functions in the IIS pathway, shows suppression of
CC proteotoxicity and only a small increase in median, but not mean life
CC span. RNAi-mediated knockdown in a mutant background for hsf-1, which
CC also functions in the IIS pathway, shows suppression of proteotoxicity
CC and a small increase in life span. RNAi-mediated knockdown in a mutant
CC background for hif-1, which functions in the hypoxia stress response
CC pathway, shows an increase in median, but not mean life span that is
CC lower than for the tdo-2 knockdown alone. RNAi-mediated knockdown in a
CC mutant background for eat-2, which is used as a model for dietary
CC restriction, shows suppression of proteotoxicity and an increase in
CC life span. {ECO:0000269|PubMed:22927396}.
CC -!- SIMILARITY: Belongs to the tryptophan 2,3-dioxygenase family.
CC {ECO:0000255|HAMAP-Rule:MF_03020}.
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DR EMBL; BX284603; CCD65972.1; -; Genomic_DNA.
DR EMBL; BX284603; CCD65974.1; -; Genomic_DNA.
DR PIR; B88470; B88470.
DR RefSeq; NP_001040847.1; NM_001047382.4. [Q09474-3]
DR RefSeq; NP_498284.1; NM_065883.4. [Q09474-1]
DR AlphaFoldDB; Q09474; -.
DR SMR; Q09474; -.
DR BioGRID; 41057; 7.
DR DIP; DIP-26438N; -.
DR IntAct; Q09474; 3.
DR STRING; 6239.C28H8.11a.1; -.
DR EPD; Q09474; -.
DR PaxDb; Q09474; -.
DR PeptideAtlas; Q09474; -.
DR EnsemblMetazoa; C28H8.11a.1; C28H8.11a.1; WBGene00016201. [Q09474-1]
DR EnsemblMetazoa; C28H8.11c.1; C28H8.11c.1; WBGene00016201. [Q09474-3]
DR GeneID; 175836; -.
DR KEGG; cel:CELE_C28H8.11; -.
DR UCSC; C28H8.11c.3; c. elegans.
DR CTD; 175836; -.
DR WormBase; C28H8.11a; CE01822; WBGene00016201; tdo-2. [Q09474-1]
DR WormBase; C28H8.11c; CE39680; WBGene00016201; tdo-2. [Q09474-3]
DR eggNOG; KOG3906; Eukaryota.
DR GeneTree; ENSGT00390000008593; -.
DR HOGENOM; CLU_045599_1_1_1; -.
DR InParanoid; Q09474; -.
DR OMA; WRWRNDH; -.
DR OrthoDB; 896211at2759; -.
DR PhylomeDB; Q09474; -.
DR BRENDA; 1.13.11.11; 1045.
DR Reactome; R-CEL-71240; Tryptophan catabolism.
DR UniPathway; UPA00333; UER00453.
DR PRO; PR:Q09474; -.
DR Proteomes; UP000001940; Chromosome III.
DR Bgee; WBGene00016201; Expressed in larva and 4 other tissues.
DR GO; GO:0020037; F:heme binding; IBA:GO_Central.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0004833; F:tryptophan 2,3-dioxygenase activity; IBA:GO_Central.
DR GO; GO:0019442; P:tryptophan catabolic process to acetyl-CoA; IBA:GO_Central.
DR GO; GO:0019441; P:tryptophan catabolic process to kynurenine; IEA:UniProtKB-UniPathway.
DR HAMAP; MF_01972; T23O; 1.
DR InterPro; IPR037217; Trp/Indoleamine_2_3_dOase-like.
DR InterPro; IPR004981; Trp_2_3_dOase.
DR PANTHER; PTHR10138; PTHR10138; 1.
DR Pfam; PF03301; Trp_dioxygenase; 1.
DR SUPFAM; SSF140959; SSF140959; 1.
PE 1: Evidence at protein level;
KW Alternative splicing; Dioxygenase; Heme; Iron; Metal-binding;
KW Oxidoreductase; Reference proteome; Tryptophan catabolism.
FT CHAIN 1..403
FT /note="Tryptophan 2,3-dioxygenase"
FT /id="PRO_0000072398"
FT MOTIF 133..135
FT /note="PLD motif; required for enzymatic activity"
FT /evidence="ECO:0000269|PubMed:27995966"
FT BINDING 69..73
FT /ligand="substrate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03020"
FT BINDING 140
FT /ligand="substrate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03020"
FT BINDING 327
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:0000255|HAMAP-Rule:MF_03020"
FT BINDING 341
FT /ligand="substrate"
FT /evidence="ECO:0000255|HAMAP-Rule:MF_03020"
FT VAR_SEQ 1..291
FT /note="Missing (in isoform c)"
FT /evidence="ECO:0000305"
FT /id="VSP_057311"
FT MUTAGEN 133..135
FT /note="Missing: Abolishes catalytic activity. Animals have
FT an extended lifespan, an extended reproductive lifespan,
FT have fewer hatched progeny and display increased motility."
FT /evidence="ECO:0000269|PubMed:27995966"
SQ SEQUENCE 403 AA; 46716 MW; 8F1E98075CA86A65 CRC64;
MACPYLGSGE LTHRVTFMEG GEECQQGVNK VEMGFGQTYS EYLQLDKILT AQRLKSEADG
QRVDDEHLFI VIHQAHELWF KQIIFDLDNV RKLLNNTIVD ETKTLKIVSG LDRMTKILSL
LTEQITLLDT MSPLDFVDFR KYLTPASGFQ SLQFRVLENK LGVRQERRIK YNAQHYKNVF
NDTDLKTLNV TEEEKSLLTL IESWLERTPG LKSTSEDEGF WIKYEKSVNK YLADLAKQAA
DPSNTEEIAK QLTAEYHKTA DAFQSILDPR QHEQHIRNGN RLLSHDATKG AMMIYFYRDM
PRFSQPYQIL TFLMDIDSLF TKWRYNHVLL VQRMLGAKQG TGGSSGYMYL RSTVSDRYKV
FLDLFNLSTW LIPREYIPML SPRMVKTLSE HSNLSHSQSS ESD
