TDO2

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004833 L-tryptophan 2,3-dioxygenase activity	IBA GO_REF:0000033	ACCEPT	Summary: Core catalytic molecular function, propagated by phylogenetic inference and strongly corroborated by direct experimental evidence on the human enzyme. This is the defining activity of TDO2. Supporting Evidence: PMID:27762317 TDO and IDO are heme proteins that catalyze the oxidative cleavage of L-Trp (Supplementary Fig. 1), the first and rate-limiting step of the kynurenine pathway for L-Trp catabolism
GO:0006569 L-tryptophan catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Core biological process: TDO2 catalyzes the first committed step of L-tryptophan catabolism via the kynurenine pathway. Phylogenetic inference supported by direct experimental evidence. Supporting Evidence: PMID:27762317 the first and rate-limiting step of the kynurenine pathway for L-Trp catabolism
GO:0020037 heme binding	IBA GO_REF:0000033	ACCEPT	Summary: Core cofactor-binding function. TDO2 is a heme-dependent dioxygenase binding one heme per subunit, with the iron coordinated by proximal His328. Phylogenetic inference supported by direct experimental evidence. Supporting Evidence: PMID:27762317 The heme is located at one end of this four-helical bundle, with the proximal His328 ligand coming from the C-terminal region of helix αJ
GO:0004833 L-tryptophan 2,3-dioxygenase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assertion of the core catalytic activity (via UniRule/InterPro/RHEA/EC). Correct and consistent with experimental evidence.
GO:0006569 L-tryptophan catabolic process	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assertion of the core catabolic process; correct and consistent with experimental evidence.
GO:0020037 heme binding	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assertion of the core heme-binding function (via UniRule/InterPro); correct.
GO:0046872 metal ion binding	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: TDO2 binds iron only as part of its heme cofactor. The informative and experimentally supported term is heme binding (GO:0020037). This generic metal ion binding parent is an uninformative over-annotation; the specific heme-binding term should be used instead. Proposed replacements: heme binding
GO:0005515 protein binding	IPI PMID:16189514 Towards a proteome-scale map of the human protein-protein in...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput interactome screen. Uninformative and does not reflect a specific characterized function of this cytosolic metabolic enzyme. Retained per policy (experimental IPI) but flagged as over-annotation.
GO:0005515 protein binding	IPI PMID:24722188 Protein interaction network of alternatively spliced isoform...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput isoform interactome screen; uninformative.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput binary interactome map; uninformative.
GO:0005515 protein binding	IPI PMID:25910212 Widespread macromolecular interaction perturbations in human...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput interaction-perturbation screen; uninformative.
GO:0005515 protein binding	IPI PMID:28514442 Architecture of the human interactome defines protein commun...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput affinity-capture interactome (BioPlex); uninformative.
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput interactome-variant screen; uninformative.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput binary interactome (HuRI); uninformative.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput interactome screen; uninformative.
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	MARK AS OVER ANNOTATED	Summary: Generic protein binding from a high-throughput affinity-capture interactome (BioPlex 3.0); uninformative.
GO:0042802 identical protein binding	IPI PMID:24722188 Protein interaction network of alternatively spliced isoform...	KEEP AS NON CORE	Summary: Self-interaction detected by interactome screening. This reflects the well-established TDO homotetramer (dimer of dimers). Kept as non-core supporting evidence for oligomerization; the informative term for the assembly process is protein homotetramerization (GO:0051289).
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Self-interaction from interactome screening, consistent with the TDO homotetramer. Kept as non-core.
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Self-interaction from interactome screening, consistent with the TDO homotetramer. Kept as non-core.
GO:0005829 cytosol	IEA GO_REF:0000120	ACCEPT	Summary: Electronic assertion of cytosolic localization, consistent with experimental evidence (active enzyme assayed from liver cytosol) and Reactome. Correct.
GO:0016597 amino acid binding	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: The substrate L-tryptophan is an amino acid, so this generic parent captures substrate binding. It is already entailed by the specific catalytic activity (GO:0004833) and is uninformative on its own. Kept as non-core.
GO:0045471 response to ethanol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Stimulus-response term electronically transferred from the rat ortholog via Ensembl Compara. A narrow physiological/transcriptional-response observation, not a core function of the enzyme. Kept as non-core.
GO:0051414 response to cortisol	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Glucocorticoid inducibility is a well-established property of hepatic TDO; this term (transferred from the rat ortholog) is biologically plausible and consistent with the glucocorticoid-response element in the TDO2 gene and Reactome. Regulatory response, not a core molecular function; kept as non-core.
GO:0071548 response to dexamethasone	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Response to the synthetic glucocorticoid dexamethasone, consistent with glucocorticoid induction of hepatic TDO. Transferred from the rat ortholog; regulatory, non-core.
GO:1904842 response to nitroglycerin	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Narrow stimulus-response term electronically transferred from the rat ortholog. Not a core function of the enzyme; kept as non-core.
GO:0005829 cytosol	IDA PMID:29959909 Development of a mass spectrometry-based tryptophan 2, 3-dio...	ACCEPT	Summary: Direct evidence: active TDO2 enzyme assayed from hepatic cytosol across species. Core cellular component. Supporting Evidence: PMID:29959909 liver cytosol contained sufficient active TDO2 for evaluating the potency of TDO2 inhibitors across multiple species
GO:0004833 L-tryptophan 2,3-dioxygenase activity	EXP PMID:25066423 Structural and functional analyses of human tryptophan 2,3-d...	ACCEPT	Summary: Experimental confirmation of the core catalytic activity via structural and kinetic/mutational analysis of human TDO. Core molecular function. Supporting Evidence: PMID:25066423 Here, we report the crystal structure of human TDO (hTDO) without the heme cofactor to 2.90 Å resolution.
GO:0004833 L-tryptophan 2,3-dioxygenase activity	IDA PMID:28285122 Hypertryptophanemia due to tryptophan 2,3-dioxygenase defici...	ACCEPT	Summary: Direct assay of recombinant human TDO catalytic activity (Michaelis-Menten kinetics, kcat/Km for L-tryptophan). Core molecular function. Supporting Evidence: PMID:28285122 similar to 0.54 ± 0.02 s−1 for the wild-type, but the Km value was noticeably increased at 236 ± 39 μM, compared to 132 ± 25 μM for the wild-type
GO:0020037 heme binding	IDA PMID:28285122 Hypertryptophanemia due to tryptophan 2,3-dioxygenase defici...	ACCEPT	Summary: Direct evidence of heme binding from UV-Vis (Soret/ferric-ferrous) spectroscopy of the purified human enzyme. Core cofactor-binding function. Supporting Evidence: PMID:28285122 The Soret peak of the heme center at the ferric, ferrous, and ferric-CN complex states were 407, 430, and 418 nm, respectively.
GO:0051289 protein homotetramerization	IDA PMID:28285122 Hypertryptophanemia due to tryptophan 2,3-dioxygenase defici...	ACCEPT	Summary: Direct evidence (gel filtration) that human TDO assembles as a homotetramer, as for the native enzyme. This is the informative oligomerization term. Accepted as a supporting structural feature rather than the primary metabolic core function. Supporting Evidence: PMID:28285122 Met108Ile is predominately a homotetramer as reported for the native human enzyme
GO:0004833 L-tryptophan 2,3-dioxygenase activity	IDA PMID:27762317 Molecular basis for catalysis and substrate-mediated cellula...	ACCEPT	Summary: Direct structural/biochemical characterization of human TDO catalysis (ternary complex with L-Trp and O2; product NFK complex; steady-state kinetics). Core molecular function. Supporting Evidence: PMID:27762317 the first and rate-limiting step of the kynurenine pathway for L-Trp catabolism
GO:0006569 L-tryptophan catabolic process	IDA PMID:27762317 Molecular basis for catalysis and substrate-mediated cellula...	ACCEPT	Summary: Direct evidence that TDO catalyzes the first, rate-limiting step of L-tryptophan catabolism via the kynurenine pathway. Core biological process. Supporting Evidence: PMID:27762317 the first and rate-limiting step of the kynurenine pathway for L-Trp catabolism
GO:0020037 heme binding	IDA PMID:27762317 Molecular basis for catalysis and substrate-mediated cellula...	ACCEPT	Summary: Direct structural evidence of heme binding with the iron coordinated by proximal His328. Core cofactor-binding function. Supporting Evidence: PMID:27762317 The heme is located at one end of this four-helical bundle, with the proximal His328 ligand coming from the C-terminal region of helix αJ
GO:0051289 protein homotetramerization	IDA PMID:27762317 Molecular basis for catalysis and substrate-mediated cellula...	ACCEPT	Summary: Direct structural evidence that human TDO is a homotetramer (dimer of dimers). Informative oligomerization term; accepted as a supporting structural feature. Supporting Evidence: PMID:27762317 Three long helices (αB, αC, and αJ), with 6–10 turns each, are at the center of the hTDO tetramer interface
GO:0005829 cytosol	TAS Reactome:R-HSA-71188	ACCEPT	Summary: Author-asserted cytosolic localization (Reactome). Consistent with IDA evidence and accepted as core cellular component. Supporting Evidence: Reactome:R-HSA-71188 Cytosolic tryptophan 2,3-dioxygenase (TDO) tetramer catalyzes the conversion of L-tryptophan and oxygen to formylkynurenine.
GO:0004833 L-tryptophan 2,3-dioxygenase activity	TAS PMID:8666386 Sequence of human tryptophan 2,3-dioxygenase (TDO2): presenc...	ACCEPT	Summary: Author-asserted (traceable) catalytic activity from the original human TDO2 cDNA/sequence report. Consistent with all experimental evidence; core molecular function.

Gene Description

Existing Annotations Review

Core Functions

Heme-dependent tryptophan 2,3-dioxygenase catalyzing the committed, rate-limiting conversion of L-tryptophan and O2 to N-formyl-L-kynurenine, the first step of the kynurenine pathway.

Binds one heme cofactor per subunit (iron coordinated by proximal His328), required for the dioxygenase chemistry.

Catalyzes the first committed step of L-tryptophan catabolism via the kynurenine pathway, degrading the bulk of dietary tryptophan and ultimately supplying de novo NAD+ biosynthesis; acts as a cytosolic homotetramer.

References

📚 Additional Documentation

Notes

📄 View Raw YAML