IDO1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004833 L-tryptophan 2,3-dioxygenase activity	IBA GO_REF:0000033	MODIFY	Summary: Phylogenetic (IBA) annotation to the tryptophan 2,3-dioxygenase reaction. IDO1 does catalyze this L-Trp -> N-formyl-L-kynurenine chemistry, but GO:0004833 is properly the term for tryptophan 2,3-dioxygenase (TDO)-type enzymes; the IDO-specific, more informative term for this gene is GO:0033754 (indoleamine 2,3-dioxygenase activity, EC 1.13.11.52), which is also annotated experimentally. Modify to the IDO-specific term. Reason: The reaction chemistry is correct, but the IDO-specific term GO:0033754 better captures IDO1's molecular function (broad indoleamine substrate specificity; distinct from hepatic TDO2). See UniProt EC 1.13.11.52 and PMID:18026683. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Proposed replacements: indoleamine 2,3-dioxygenase activity
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IDO1 is a cytosolic enzyme; UniProt records subcellular location as Cytoplasm, cytosol, and Reactome describes cytosolic IDO. Correct but general; the more specific cytosol annotation is also present. Reason: Consistent with UniProt SUBCELLULAR LOCATION (Cytoplasm, cytosol). Location is supportive context, not a core function.
GO:0006569 L-tryptophan catabolic process	IBA GO_REF:0000033	ACCEPT	Summary: Core biological process: IDO1 catalyzes the first, rate-limiting step of L-tryptophan catabolism via the kynurenine pathway. Well supported by UniProt (PATHWAY: L-tryptophan degradation via kynurenine pathway) and by experimental characterization. Reason: Directly reflects IDO1's core catabolic role; supported by UniProt and by PMID:18026683 / PMID:2109605.
GO:0033754 indoleamine 2,3-dioxygenase activity	IBA GO_REF:0000033	ACCEPT	Summary: Correct, IDO-specific core molecular function (EC 1.13.11.52). Phylogenetic inference consistent with the experimental EXP/IMP annotations to the same term. Reason: This is the primary molecular function of IDO1; also supported experimentally (PMID:18026683 EXP, PMID:25310899 IMP).
GO:0034354 'de novo' NAD+ biosynthetic process from L-tryptophan	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: IDO1 performs only the first committed step (L-Trp -> N-formyl-L-kynurenine) of the pathway that can ultimately feed de novo NAD+ biosynthesis via quinolinate. Annotating IDO1 to the whole multi-step de novo NAD+ biosynthetic process is an over-propagation; the immediate/physiological role of IDO1 is the kynurenine-pathway entry step, and in immune contexts the products are used for signaling/tolerance rather than committed NAD+ synthesis. Reason: Propagated across PANTHER:PTN002009580 from fungal Bna2, which serves as the sole constitutive tryptophan-catabolizing enzyme for de novo NAD+ biosynthesis in S. cerevisiae (which lacks TDO). In mammals, constitutive hepatic de novo NAD+ synthesis from L-tryptophan is driven primarily by TDO2, whereas IDO1 catalyzes only the entry step of L-tryptophan catabolism to N-formyl-L-kynurenine (captured by GO:0006569) in extrahepatic and immunoregulatory contexts where kynurenine metabolites and tryptophan depletion mediate immune signaling rather than committed de novo NAD+ synthesis. Moreover, GO:0034354 is obsolete in current GO. Marked as over-annotated due to pathway-level role conflation across divergent subfamilies. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: ROLE CONFLATION FUNCTIONAL DIVERGENCE Sources checked: PANTHER:PTN002009580 · Indoleamine 2,3-dioxygenase family ancestor SUPPORTS SOURCE BUT NOT TARGET SGD:S000003839 · BNA2 SUPPORTS SOURCE BUT NOT TARGET Yeast Bna2 is the sole tryptophan-degrading enzyme supplying de novo NAD+ synthesis in S. cerevisiae (which lacks TDO), whereas mammalian IDO1 catalyzes the entry step of L-tryptophan catabolism in extrahepatic/immunoregulatory contexts while hepatic TDO2 drives constitutive de novo NAD+ synthesis; furthermore, GO:0034354 is obsolete in current GO. Supporting Evidence: PMID:18026683 Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are tryptophan-degrading enzymes that catalyze the same reaction, the first step in tryptophan catabolism via the kynurenine pathway.
GO:0004833 L-tryptophan 2,3-dioxygenase activity	IEA GO_REF:0000116	MODIFY	Summary: Rhea-based electronic mapping (RHEA:24536, L-tryptophan + O2 = N-formyl-L-kynurenine) to the L-tryptophan 2,3-dioxygenase term. The reaction is correct for IDO1, but the IDO-specific term GO:0033754 is more appropriate for this gene. Modify to the IDO-specific term. Reason: Reaction chemistry correct (matches UniProt Rhea:24536), but GO:0033754 is the informative IDO-specific molecular function. Proposed replacements: indoleamine 2,3-dioxygenase activity
GO:0005829 cytosol	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Correct subcellular location. UniProt SUBCELLULAR LOCATION is Cytoplasm, cytosol; Reactome also describes cytosolic IDO. Reason: Accurate localization (cytosol) but supportive context rather than a core function.
GO:0006569 L-tryptophan catabolic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic annotation to the core catabolic process, consistent with the IBA/TAS annotations to the same term and with UniProt PATHWAY. Correct. Reason: Reflects IDO1's core role in L-tryptophan catabolism via the kynurenine pathway.
GO:0020037 heme binding	IEA GO_REF:0000002	ACCEPT	Summary: Core molecular function: IDO1 is a heme (heme b)-dependent dioxygenase that binds one heme group per subunit, with the catalytic ferrous iron ligated by proximal His346. Directly supported by UniProt COFACTOR/BINDING and multiple crystal structures. Reason: Heme binding is essential for catalysis; strongly supported by UniProt COFACTOR (heme b) and structural evidence (PubMed:16477023, 25313323).
GO:0033754 indoleamine 2,3-dioxygenase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation (ARBA + Rhea RHEA:14189) to the IDO-specific core molecular function. Consistent with the experimental annotations to the same term. Reason: Correct core molecular function (EC 1.13.11.52), corroborated experimentally.
GO:0046872 metal ion binding	IEA GO_REF:0000002	KEEP AS NON CORE	Summary: IDO1 binds the iron of its catalytic heme b cofactor; UniProt keyword Iron and the proximal Fe-binding residue His346 support metal (iron) ion binding. This is a general parent of the more specific heme binding annotation. Reason: Accurate (heme iron), but the more specific and informative MF for the cofactor is GO:0020037 (heme binding); retain metal ion binding as a general non-core annotation.
GO:0004833 L-tryptophan 2,3-dioxygenase activity	EXP PMID:18026683 Evolution of vertebrate indoleamine 2,3-dioxygenases.	MODIFY	Summary: Experimental characterization of recombinant IDO catalyzing the L-tryptophan -> N-formyl-L-kynurenine reaction. The activity is genuine, but the IDO-specific term GO:0033754 (also annotated EXP from the same paper) better represents IDO1's molecular function than the TDO-type term GO:0004833. Reason: Experimental activity is correct; MODIFY (not REMOVE) to the informative IDO-specific term GO:0033754, which is already present as an EXP annotation from this paper. Proposed replacements: indoleamine 2,3-dioxygenase activity
GO:0033754 indoleamine 2,3-dioxygenase activity	EXP PMID:18026683 Evolution of vertebrate indoleamine 2,3-dioxygenases.	ACCEPT	Summary: Experimental (EXP) support for the core molecular function: recombinant IDO characterized enzymatically, with kinetic parameters for L- and D-tryptophan. This is the primary, best-supported molecular function of IDO1. Reason: Directly demonstrates indoleamine 2,3-dioxygenase activity (EC 1.13.11.52); basis for the UniProt catalytic-activity and kinetic annotations.
GO:0033754 indoleamine 2,3-dioxygenase activity	IMP PMID:25310899 Human renal tubular epithelial cells suppress alloreactive T...	ACCEPT	Summary: IMP annotation from a study where IDO activity in renal tubular epithelial cells was manipulated with the IDO inhibitor 1-methyl-L-tryptophan, supporting a functional (immunosuppressive) IDO enzymatic activity. Curator read the full text; consistent with the enzyme's core function. Reason: Supports indoleamine 2,3-dioxygenase activity in a cellular immune context; an experimental annotation - retain.
GO:0046006 regulation of activated T cell proliferation	IMP NOT PMID:25310899 Human renal tubular epithelial cells suppress alloreactive T...	ACCEPT	Summary: NOT annotation. In renal tubular epithelial cells, the IDO inhibitor 1-methyl-L-tryptophan only partially restored or failed to restore suppressed CD4+/CD8+ T-cell proliferation, indicating that IDO does not account for the regulation of activated T-cell proliferation in this system (other factors, e.g. ICAM-1, were implicated). The negation correctly captures this. Reason: Experimental (IMP) NOT annotation supported by the finding that the IDO inhibitor failed to restore T-cell proliferation. Retain the negation.
GO:0070234 positive regulation of T cell apoptotic process	IMP PMID:25310899 Human renal tubular epithelial cells suppress alloreactive T...	KEEP AS NON CORE	Summary: IDO activity (blockable by 1-methyl-L-tryptophan) enhanced apoptosis of proliferating T cells in the renal tubular epithelial cell system. This is a genuine downstream immunoregulatory consequence of tryptophan depletion / kynurenine accumulation, not the primary molecular function. Reason: Experimental (IMP) immunoregulatory role; genuine but downstream of the enzymatic activity. Keep as non-core.
GO:0005829 cytosol	TAS Reactome:R-HSA-198563	KEEP AS NON CORE	Summary: Reactome TAS for cytosolic localization of the active enzyme, consistent with UniProt SUBCELLULAR LOCATION (Cytoplasm, cytosol). Reason: Accurate localization; supportive context rather than a core function.
GO:0009055 electron transfer activity	TAS PMID:2109605 Molecular cloning, sequencing and expression of human interf...	MARK AS OVER ANNOTATED	Summary: IDO1 is a heme-containing dioxygenase that incorporates both atoms of O2 into tryptophan; it is not an electron carrier/electron transfer protein. The cited paper (PMID:2109605) is a cDNA cloning and IFN-gamma-inducibility study that reports IDO/tryptophan-degrading activity but provides no evidence for electron transfer activity. This MF is an over-annotation (likely conflating cytochrome b5-mediated reduction of the heme, which is an activity of the partner reductant, not of IDO1 itself). Reason: No support for electron transfer activity as a molecular function of IDO1; the enzyme's function is heme-dependent dioxygenation. Source paper does not establish this activity. Not REMOVE per policy for non-IEA evidence.
GO:0006569 L-tryptophan catabolic process	TAS PMID:2109605 Molecular cloning, sequencing and expression of human interf...	ACCEPT	Summary: TAS for the core catabolic process. The cloning paper established that the gene encodes the tryptophan-degrading enzyme induced by IFN-gamma, supporting involvement in L-tryptophan catabolism. Reason: Reflects IDO1's core role in tryptophan catabolism (kynurenine pathway); supported by the source publication.
GO:0007565 female pregnancy	TAS PMID:9712583 Prevention of allogeneic fetal rejection by tryptophan catab...	KEEP AS NON CORE	Summary: Maternal-fetal immune tolerance role: pharmacologic IDO inhibition caused T cell-mediated rejection of allogeneic concepti, showing IDO-mediated tryptophan catabolism protects the fetus from maternal immune rejection. A genuine, important physiological role, but downstream of the enzymatic activity and specific to reproductive immunology. Reason: Well-supported immunoregulatory role in pregnancy (maternal-fetal tolerance), but not the primary molecular function; keep as non-core.

Gene Description

Existing Annotations Review

Core Functions

Heme-dependent indoleamine 2,3-dioxygenase catalyzing the first and rate-limiting step of the kynurenine pathway, oxidizing L-tryptophan with O2 to N-formyl-L-kynurenine (EC 1.13.11.52).

Binds one heme b group (and its iron) per subunit, required as the catalytic cofactor for dioxygenation of tryptophan; the ferrous heme iron is ligated by proximal His346.

References

📚 Additional Documentation

Notes

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