FTCD (formimidoyltransferase-cyclodeaminase; glutamate formimidoyltransferase-cyclodeaminase) is a bifunctional cytosolic enzyme that catalyzes the last two steps of L-histidine catabolism, channeling the histidine-derived one-carbon (formimino) unit into the folate one-carbon pool. Its N-terminal domain has glutamate formimidoyltransferase activity (EC 2.1.2.5), transferring the formimino group between N-formimidoyl-L-glutamate and tetrahydrofolate to produce L-glutamate and 5-formimino-tetrahydrofolate; its C-terminal domain has formimidoyltetrahydrofolate cyclodeaminase activity (EC 4.3.1.4), converting 5-formimino-tetrahydrofolate to 5,10-methenyl-tetrahydrofolate with release of ammonia. The protein assembles into a homooctamer arranged as a tetramer of dimers forming a planar ring, with polyglutamate (folate) binding sites, and is strongly expressed in liver. Beyond its cytosolic catalytic role it associates reversibly with the Golgi apparatus (the historical "58K Golgi protein") and, in rodent orthologs, binds microtubules and bundles vimentin filaments. Loss-of-function variants cause glutamate formiminotransferase deficiency (formiminoglutamic aciduria), an autosomal recessive inborn error of folate metabolism marked by urinary excretion of formiminoglutamate (FIGLU). The human protein is also the LC1 autoantigen recognized in type 2 autoimmune hepatitis.
Definition: The chemical reactions and pathways resulting in the breakdown of L-histidine, ultimately yielding L-glutamate, and in the process converting tetrahydrofolate to 5-formimino-tetrahydrofolate and then to 5,10-methenyl-tetrahydrofolate.
Justification: The historical GO terms 'L-histidine catabolic process to glutamate and formamide' (GO:0019556) and 'L-histidine catabolic process to glutamate and formate' (GO:0019557) are obsolete, leaving no live specific term for the folate-coupled histidine-to-glutamate route that FTCD completes. A specific descendant of GO:0006548 (L-histidine catabolic process) that captures the tetrahydrofolate-coupled glutamate-forming route would allow precise annotation.
Parent term: L-histidine catabolic process
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000139 Golgi membrane | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic (IBA) propagation of Golgi-membrane localization. FTCD (the "58K Golgi protein") genuinely associates with the Golgi apparatus, but this is a reversible, secondary localization; catalysis occurs in the cytosol. The "is_active_in" qualifier overstates the case, since the enzymatic activity is cytosolic rather than Golgi-based. Reason: Golgi association is a real, documented secondary property of FTCD but not its core cytosolic catalytic role. |
| GO:0030409 glutamate formimidoyltransferase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic support for the N-terminal formimidoyltransferase activity (EC 2.1.2.5). This is one of the two core catalytic functions of this bifunctional enzyme and is also supported experimentally (IDA, PMID:12815595). |
| GO:0030412 formimidoyltetrahydrofolate cyclodeaminase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic support for the C-terminal cyclodeaminase activity (EC 4.3.1.4), the second core catalytic function of this bifunctional enzyme, consistent with UniProt (by similarity to P53603) and the cyclodeaminase/cyclohydrolase family assignment. |
| GO:0003824 catalytic activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Root-level catalytic activity term from InterPro2GO. FTCD is an enzyme, so this is not wrong, but it is far too general given that the two specific catalytic activities (GO:0030409, GO:0030412) are already annotated. Reason: Uninformative parent term subsumed by the specific catalytic MF annotations. |
| GO:0005542 folic acid binding | IEA GO_REF:0000002 | ACCEPT | Summary: Folic acid binding is a genuine molecular function of FTCD: both catalytic activities use tetrahydrofolate/5-formimino-THF as substrate, and UniProt describes four polyglutamate (folate) binding sites in the homooctamer. Supported by the UniProt Folate-binding keyword and DrugBank folinic-acid/tetrahydrofolate ligand entries. |
| GO:0005794 Golgi apparatus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Golgi apparatus localization from UniProt Subcellular Location mapping. This is a real secondary localization of FTCD (the "58K Golgi protein"), demonstrated in human hepatocytes as reversible Golgi-membrane association, but the enzyme's catalytic role is cytosolic. |
| GO:0005814 centriole | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: Centriole/centrosome localization from UniProt Subcellular Location mapping, based on PubMed:16534631 (Golgi 58K protein localized to the centrosome, more abundant around the mother centriole). A genuine but secondary structural localization, not the catalytic compartment. |
| GO:0005829 cytosol | IEA GO_REF:0000044 | ACCEPT | Summary: Cytosol localization from UniProt Subcellular Location mapping. This is the primary, catalytically relevant compartment for FTCD (Reactome annotates "Cytosolic FTCD") and is also supported by human IDA (PMID:14697341). |
| GO:0016740 transferase activity | IEA GO_REF:0000002 | MARK AS OVER ANNOTATED | Summary: Generic transferase activity from InterPro2GO. Correct in kind (the formimidoyltransferase is an EC 2 transferase) but far too general; subsumed by GO:0030409. Reason: Uninformative parent term subsumed by the specific formimidoyltransferase MF. |
| GO:0030409 glutamate formimidoyltransferase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (RHEA/EC 2.1.2.5) support for the formimidoyltransferase activity. Redundant with the experimental IDA and phylogenetic IBA for the same core function. |
| GO:0030412 formimidoyltetrahydrofolate cyclodeaminase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (RHEA/EC 4.3.1.4) support for the cyclodeaminase activity, the second core catalytic function. Redundant with the IBA/ISS annotations for the same activity. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a systematic high-throughput binary interactome screen (Rolland et al., Cell 2014). Uninformative about FTCD's function; the reported partners do not indicate a coherent additional role. Reason: Non-informative GO:0005515 from a large-scale interactome map with no FTCD-specific functional follow-up. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from the HuRI systematic binary interactome map (Luck et al., Nature 2020). Uninformative about FTCD's molecular function. Reason: Non-informative GO:0005515 from a large-scale interactome map with no FTCD-specific functional follow-up. |
| GO:0000139 Golgi membrane | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Golgi-membrane localization transferred from the rat ortholog (O88618) via Ensembl Compara. Consistent with the documented reversible Golgi-membrane association of human FTCD (PMID:14697341); a genuine secondary localization. |
| GO:0005783 endoplasmic reticulum | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ER localization transferred from the rat ortholog (O88618) via Ensembl Compara, mirroring the UniProt ISS annotation. A secondary membrane-associated pool, not the catalytic compartment. |
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: ERGIC localization transferred from the rat ortholog (O88618) via Ensembl Compara, mirroring the UniProt ISS annotation. Secondary localization consistent with the endomembrane-associated pool of FTCD. |
| GO:0007010 cytoskeleton organization | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Cytoskeleton organization transferred from the rat ortholog (O88618), reflecting the rodent vimentin-bundling / microtubule-binding property. The dedicated human study found that human FTCD does not interact with cytoskeleton proteins (PMID:14697341), so this process annotation is at best a rodent-specific, non-core property for the human gene. Reason: Transferred from rodent; the human ortholog paper (PMID:14697341) reports no interaction with cytoskeleton proteins. |
| GO:0008017 microtubule binding | IEA GO_REF:0000107 | MARK AS OVER ANNOTATED | Summary: Microtubule binding transferred from the rat ortholog (O88618). In rats FTCD binds brain microtubules and vimentin, but the human protein was reported not to interact with cytoskeleton proteins (PMID:14697341); non-core / rodent-specific for human. Reason: Rodent-specific property; not reproduced for human FTCD. |
| GO:0005794 Golgi apparatus | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Golgi apparatus localization by sequence similarity to the fish/rodent ortholog. Real secondary localization of FTCD, not the primary catalytic compartment. |
| GO:0030412 formimidoyltetrahydrofolate cyclodeaminase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Cyclodeaminase activity (EC 4.3.1.4) by sequence similarity, consistent with UniProt's by-similarity assignment (from P53603) and the C-terminal cyclodeaminase/cyclohydrolase family. Second core catalytic function. |
| GO:0030409 glutamate formimidoyltransferase activity | IDA PMID:12815595 The molecular basis of glutamate formiminotransferase defici... | ACCEPT | Summary: Direct experimental support for the formimidoyltransferase activity: mutagenesis of FTCD and measurement of formimidoyltransferase activity (disease variants R135C and R299P reduce activity to 61% and 57% of wild-type). This is the core, experimentally established molecular function of FTCD. |
| GO:0030409 glutamate formimidoyltransferase activity | ISS GO_REF:0000024 | ACCEPT | Summary: Formimidoyltransferase activity by sequence similarity; redundant with the experimental IDA and IBA annotations for the same core catalytic function. |
| GO:0000139 Golgi membrane | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Golgi-membrane localization by sequence similarity to the rodent ortholog, consistent with the human IDA (PMID:14697341). Genuine secondary localization. |
| GO:0000139 Golgi membrane | IDA PMID:14697341 Characterization of the antigenicity of the formiminotransfe... | KEEP AS NON CORE | Summary: Direct human evidence of Golgi-membrane association: FTCD antigen is found associated with the Golgi membranes and binds reversibly to them. A real secondary localization, but the catalytic function is cytosolic, so this is non-core. |
| GO:0005783 endoplasmic reticulum | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ER localization by sequence similarity to the rodent ortholog. Secondary endomembrane- associated pool, not the catalytic compartment. |
| GO:0005793 endoplasmic reticulum-Golgi intermediate compartment | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ERGIC localization by sequence similarity to the rodent ortholog. Secondary localization consistent with the endomembrane-associated pool of FTCD. |
| GO:0005829 cytosol | IDA PMID:14697341 Characterization of the antigenicity of the formiminotransfe... | ACCEPT | Summary: Direct human evidence that FTCD is present free in the cytosol (in addition to Golgi-membrane association). The cytosol is the primary, catalytically relevant localization of FTCD. |
| GO:0008017 microtubule binding | ISS GO_REF:0000024 | MARK AS OVER ANNOTATED | Summary: Microtubule binding by sequence similarity to the rodent ortholog. In rats FTCD binds brain microtubules; however the human protein was reported not to interact with cytoskeleton proteins (PMID:14697341), so this is a rodent-specific / non-core property for human FTCD. Reason: Rodent-specific property; not reproduced for human FTCD. |
| GO:0008017 microtubule binding | IDA PMID:14697341 Characterization of the antigenicity of the formiminotransfe... | MARK AS OVER ANNOTATED | Summary: Microtubule-binding IDA attributed to PMID:14697341. That paper characterizes rat FTCD as binding brain microtubules and vimentin, but explicitly reports that the human protein does not interact with liver-specific cytoskeleton proteins. The human microtubule-binding is therefore weakly supported / arguably contradicted by the same study; retained (experimental) but flagged as an over-annotation rather than a core human function. Reason: The cited human study reports no cytoskeleton interaction for human FTCD; microtubule binding is a rodent property. |
| GO:0030868 smooth endoplasmic reticulum membrane | IDA PMID:14697341 Characterization of the antigenicity of the formiminotransfe... | KEEP AS NON CORE | Summary: Localization to smooth ER membrane from subcellular fractionation of human hepatocytes. A secondary membrane-associated pool consistent with the ER/Golgi endomembrane associations; not the primary cytosolic catalytic compartment. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Detected in an extracellular-vesicle proteome. The protein is plausible EV content, but this is not where it functions. Reason: Cytosolic enzyme. Cytosolic protein (UniProt); cytosolic proteins, including abundant enzymes and cytoskeletal proteins, are expected and often promiscuous EV contents (MISEV2018 (PMID:30637094) category 2b). True, but not its core location. (Manual re-review for OMICS_EVIDENCE, 2026-10-10; previous action: MARK_AS_OVER_ANNOTATED.) |
| GO:0005829 cytosol | TAS Reactome:R-HSA-70920 | ACCEPT | Summary: Reactome (traceable author statement) places the FTCD reaction in the cytosol ("Cytosolic formimidoyltransferase-cyclodeaminase"). Consistent with the primary catalytic localization. |
| GO:0005737 cytoplasm | TAS PMID:10029623 Formiminotransferase cyclodeaminase is an organ-specific aut... | KEEP AS NON CORE | Summary: Cytoplasm localization (TAS). FTCD was identified as a liver cytosolic autoantigen; the cytoplasm term is correct but general relative to the more precise cytosol annotation. Reason: Correct but a general parent of the more informative cytosol annotation. |
| GO:0006760 folic acid-containing compound metabolic process | TAS PMID:10029623 Formiminotransferase cyclodeaminase is an organ-specific aut... | ACCEPT | Summary: Folate metabolism process annotation. Captures FTCD's core biological role: it channels the histidine-derived one-carbon (formimino) unit into the folate one-carbon pool, generating 5-formimino-THF and then 5,10-methenyl-THF. The more specific L-histidine catabolic process (GO:0006548) is also applicable and is proposed as an additional term. |
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Download this section (compressed HTML)Q: Does human FTCD bind or bundle vimentin/microtubules under any physiological condition, or is this activity restricted to rodent orthologs? The human ortholog study (PMID:14697341) reported no cytoskeleton interaction, in contrast to rat FTCD.
Q: What is the functional significance, if any, of FTCD's reversible Golgi-membrane and centrosome association given that its catalytic activity is cytosolic?
Experiment: Reconstitute recombinant human FTCD and measure both formimidoyltransferase (EC 2.1.2.5) and cyclodeaminase (EC 4.3.1.4) activities directly on the human enzyme, since the current cyclodeaminase annotation for human FTCD rests on homology rather than direct human assay.
Experiment: Test purified human FTCD for direct microtubule and vimentin binding in vitro and by co-localization in human cells, to resolve the human-versus-rodent discrepancy in cytoskeleton association.
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