TKFC

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004371 glycerone kinase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (IBA) assertion of glycerone (dihydroxyacetone) kinase activity, the defining catalytic activity of the DAK family. This is directly demonstrated for human TKFC and is a core molecular function. Reason: Human TKFC phosphorylates dihydroxyacetone (glycerone) using ATP; this activity is biochemically established and consistent with the DAK-family phylogeny. Supporting Evidence: PMID:32004446 TKFC encodes a bifunctional enzyme involved in fructose metabolism through its glyceraldehyde kinase activity and in the generation of riboflavin cyclic 4',5'-phosphate file:human/TKFC/TKFC-uniprot.txt Reaction=dihydroxyacetone + ATP = dihydroxyacetone phosphate + ADP +
GO:0019563 glycerol catabolic process	IBA GO_REF:0000033	MODIFY	Summary: IBA transfer of a glycerol catabolic role from DAK-family orthologs. In several bacteria the DAK reaction operates within glycerol degradation, but the human enzyme's physiological triose substrates are the dihydroxyacetone and D-glyceraldehyde of fructose metabolism, not glycerol. Reason: The human enzyme acts on triose (DHA/glyceraldehyde) intermediates of fructose metabolism; a glycerol catabolic process assignment is an over-generalization inherited from bacterial/yeast orthologs. A fructose catabolic process term better reflects the human biology. GO:0006001 is already held by TKFC through an existing annotation (accepted below), so in effect this IBA row is superseded by that annotation rather than adding a new term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: FUNCTIONAL DIVERGENCE Proposed replacements: fructose catabolic process Supporting Evidence: PMID:32004446 TKFC encodes a bifunctional enzyme involved in fructose metabolism through its file:human/TKFC/TKFC-uniprot.txt Reaction=D-glyceraldehyde + ATP = D-glyceraldehyde 3-phosphate + ADP +
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic assignment of cytosolic localization, consistent with the soluble cytosolic nature of DAK-family triokinases and with the cytosolic fructolysis pathway. Reason: TKFC is a soluble cytosolic enzyme; cytosol is corroborated by Reactome curation and is the compartment where fructolysis and triose phosphorylation occur. Supporting Evidence: file:human/TKFC/TKFC-uniprot.txt GO:0005829; C:cytosol; IBA:GO_Central.
GO:0004371 glycerone kinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (InterPro/RHEA/EC) assertion of glycerone kinase activity (EC 2.7.1.29). Redundant with the experimental IDA and IBA glycerone kinase annotations and correctly mapped. Reason: Consistent with the demonstrated dihydroxyacetone kinase activity (EC 2.7.1.29) and DAK-family domain content. Supporting Evidence: file:human/TKFC/TKFC-uniprot.txt EC=2.7.1.29; Evidence={ECO:0000269\|PubMed:32004446,
GO:0005524 ATP binding	IEA GO_REF:0000002	ACCEPT	Summary: ATP binding is required for the ATP-dependent triokinase/DHA kinase reactions and is supported by defined ATP-binding residues in the DhaL domain of UniProt. Reason: TKFC is an ATP-dependent kinase with mapped ATP-binding sites; ATP binding is a well-supported supporting molecular function. Supporting Evidence: file:human/TKFC/TKFC-uniprot.txt /ligand="ATP"
GO:0006071 glycerol metabolic process	IEA GO_REF:0000002	MARK AS OVER ANNOTATED	Summary: InterPro-based electronic transfer of a glycerol metabolic process. As with the IBA glycerol catabolic term, this reflects the ancestral DAK family context rather than the human enzyme's role, which centers on triose intermediates of fructose metabolism. Reason: The human enzyme's physiological substrates are dihydroxyacetone and D-glyceraldehyde in fructose metabolism; a generic glycerol metabolic process assignment over-extends the DAK family signature to a pathway not established for human TKFC. Supporting Evidence: PMID:32004446 TKFC encodes a bifunctional enzyme involved in fructose metabolism through its
GO:0034012 FAD-AMP lyase (cyclizing) activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (RHEA/EC 4.6.1.15) assertion of FAD-AMP lyase (cyclizing) / FMN cyclase activity. This is a core molecular function directly demonstrated for the human enzyme. Reason: The human protein splits FAD to riboflavin 4',5'-cyclic phosphate plus AMP (EC 4.6.1.15), an activity biochemically demonstrated and correctly captured by this IEA. Supporting Evidence: file:human/TKFC/TKFC-uniprot.txt Reaction=FAD = riboflavin cyclic-4',5'-phosphate + AMP + H(+); PMID:16289032 yielded a protein active both as FMN cyclase and ATP-dependent Dha kinase
GO:0050354 triokinase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (RHEA/EC 2.7.1.28, plus mouse ortholog) assertion of triokinase activity, phosphorylation of D-glyceraldehyde to D-glyceraldehyde 3-phosphate. Core molecular function, redundant with the experimental IDA annotations. Reason: Human TKFC phosphorylates D-glyceraldehyde (EC 2.7.1.28); this IEA is correctly mapped. Supporting Evidence: file:human/TKFC/TKFC-uniprot.txt EC=2.7.1.28; Evidence={ECO:0000269\|PubMed:32004446,
GO:0005515 protein binding	IPI PMID:17600090 Negative regulation of MDA5- but not RIG-I-mediated innate a...	MARK AS OVER ANNOTATED	Summary: IntAct-derived protein binding capturing the physical interaction with MDA5 (IFIH1, Q9BYX4). The bare protein binding term is uninformative; the biologically meaningful consequence is already captured by the negative regulation of MDA-5 signaling annotation from the same paper. Reason: Bare protein binding is not an informative molecular function. The specific IFIH1 interaction and its functional consequence are better represented by GO:0039534. Supporting Evidence: PMID:17600090 we identified DAK, a functionally unknown dihydroacetone kinase, as a specific MDA5-interacting protein
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: IntAct/interactome-map protein binding annotation (interaction with SDCBP/syntenin-1, O00560) from a proteome-scale binary interaction screen. Bare protein binding is uninformative and the SDCBP interaction has no established functional interpretation for TKFC. Reason: High-throughput binary interaction; the uninformative protein binding term does not describe a molecular function and lacks functional context for this gene. Supporting Evidence: PMID:25416956 A proteome-scale map of the human interactome network.
GO:0006001 fructose catabolic process	IEA GO_REF:0000107	ACCEPT	Summary: Ensembl-Compara transfer (from mouse ortholog) of a fructose catabolic role. This is the physiologically correct process for human TKFC. Reason: TKFC's triokinase activity operates in the terminal step of fructolysis producing glyceraldehyde 3-phosphate (and DHAP). The more specific child term previously proposed here (GO:0061624, fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate) is obsolete in the GO release 2026-07-26 as a pathway variant, with replaced_by GO:0006001, so this term is the core process annotation. Supporting Evidence: PMID:32004446 TKFC encodes a bifunctional enzyme involved in fructose metabolism through its file:human/TKFC/TKFC-uniprot.txt fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate
GO:0004371 glycerone kinase activity	IDA PMID:32004446 Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase ...	ACCEPT	Summary: Direct assay (IDA) of glycerone/dihydroxyacetone kinase activity for human TKFC; patient variants in the FMN lyase domain severely decrease glycerone kinase activity. Core function. Reason: Experimentally demonstrated dihydroxyacetone (glycerone) kinase activity of the human enzyme. Supporting Evidence: PMID:32004446 TKFC encodes a bifunctional enzyme involved in fructose metabolism through its glyceraldehyde kinase activity file:human/TKFC/TKFC-uniprot.txt very severe decrease of triokinase and glycerone kinase activities
GO:0050354 triokinase activity	IDA PMID:32004446 Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase ...	ACCEPT	Summary: Direct assay (IDA) of triokinase activity (D-glyceraldehyde phosphorylation) for human TKFC; TKFCD patient variants very severely decrease triokinase activity. Core function. Reason: Experimentally demonstrated triokinase activity; loss of this activity underlies the human TKFC deficiency phenotype. Supporting Evidence: PMID:32004446 We report an inborn error of metabolism caused by TKFC deficiency file:human/TKFC/TKFC-uniprot.txt very severe decrease of triokinase and glycerone kinase activities
GO:0005829 cytosol	TAS Reactome:R-HSA-70349	ACCEPT	Summary: Reactome-curated cytosolic localization associated with the fructose-catabolism reaction in which the DAK dimer phosphorylates D-glyceraldehyde to glyceraldehyde 3-phosphate. Reason: Consistent with the cytosolic localization of TKFC and its role in cytosolic fructolysis. Supporting Evidence: file:human/TKFC/TKFC-uniprot.txt GO:0005829; C:cytosol; IBA:GO_Central.
GO:0005829 cytosol	TAS Reactome:R-HSA-913725	ACCEPT	Summary: Reactome-curated cytosolic localization associated with the IFIH1:TKFC / viral dsRNA sensing context; consistent with cytosolic TKFC. Reason: TKFC is cytosolic; the MDA5 (IFIH1) interaction occurs in the cytoplasm. Supporting Evidence: file:human/TKFC/TKFC-uniprot.txt GO:0005829; C:cytosol; IBA:GO_Central.
GO:0005829 cytosol	TAS Reactome:R-HSA-9754745	ACCEPT	Summary: Reactome-curated cytosolic localization in the SARS-CoV-2 innate-immune module (IFIH1:TKFC binding dsRNA intermediates); consistent with cytosolic TKFC. Reason: Cytosolic localization corroborated across multiple Reactome curations. Supporting Evidence: file:human/TKFC/TKFC-uniprot.txt GO:0005829; C:cytosol; IBA:GO_Central.
GO:0005829 cytosol	TAS Reactome:R-HSA-9755244	ACCEPT	Summary: Reactome-curated cytosolic localization in a SARS-CoV-2 innate-immune deISGylation module; consistent with cytosolic TKFC. Reason: Cytosolic localization corroborated across multiple Reactome curations. Supporting Evidence: file:human/TKFC/TKFC-uniprot.txt GO:0005829; C:cytosol; IBA:GO_Central.
GO:0039534 negative regulation of MDA-5 signaling pathway	IDA PMID:17600090 Negative regulation of MDA5- but not RIG-I-mediated innate a...	ACCEPT	Summary: Direct experimental demonstration that DAK/TKFC specifically suppresses MDA5- (IFIH1) but not RIG-I-mediated innate antiviral signaling: overexpression inhibits, and knockdown activates, MDA5-dependent IFN-beta induction. This moonlighting regulatory role is well supported. Reason: Precisely matches the experimental findings of PMID:17600090; TKFC binds MDA5 and negatively regulates its signaling. Supporting Evidence: PMID:17600090 These findings suggest that DAK is a physiological suppressor of MDA5 and specifically inhibits MDA5- but not RIG-I-mediated innate antiviral signaling.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	Summary: High-throughput mass-spectrometry detection in urinary/prostatic exosome preparations. For a cytosolic metabolic enzyme this represents incidental detection in bulk exosome proteomics rather than a functional localization. Reason: Abundant cytosolic enzymes are common background in exosome proteomics; there is no functional evidence for an extracellular-exosome role for TKFC. Supporting Evidence: PMID:23533145 In pooled EPS-urine exosome samples, ~900 proteins were detected.
GO:0005634 nucleus	HDA PMID:21630459 Proteomic characterization of the human sperm nucleus.	MARK AS OVER ANNOTATED	Summary: High-throughput detection in a human sperm nucleus proteome. TKFC is an established cytosolic enzyme; detection in a purified sperm-nucleus preparation likely reflects contamination or non-functional presence rather than a curated nuclear function. Reason: No functional evidence supports a nuclear role; the sole support is bulk proteomic detection in one specialized cell type, inconsistent with the cytosolic biology. Supporting Evidence: PMID:21630459 403 different proteins have been identified from the isolated sperm nuclei.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: High-throughput mass-spectrometry detection in urinary exosomes (1132 proteins identified). As with the other exosome dataset, this is incidental detection of a cytosolic enzyme. Reason: Bulk urinary-exosome proteomics; no functional evidence for an extracellular-exosome role. Supporting Evidence: PMID:19056867 the analysis identified 1132 proteins unambiguously
GO:0005975 carbohydrate metabolic process	IDA PMID:16289032 Identification of human and rat FAD-AMP lyase (cyclic FMN fo...	KEEP AS NON CORE	Summary: General carbohydrate metabolic process annotation supported by the demonstration of ATP- dependent dihydroxyacetone kinase activity. Correct but a high-level parent of the specific fructose/triose metabolic role. Reason: The essence is correct but the term is a broad parent; the specific triokinase/fructose catabolic role is the informative core function. Supporting Evidence: PMID:16289032 yielded a protein active both as FMN cyclase and ATP-dependent Dha kinase
GO:0005975 carbohydrate metabolic process	IDA PMID:4688871 Dihydroxyacetone metabolism by human erythrocytes: demonstra...	KEEP AS NON CORE	Summary: General carbohydrate metabolic process annotation from the erythrocyte triokinase characterization. Correct but high-level relative to the specific triokinase function. Reason: Broad parent term; retained as non-core with the specific triokinase MF representing the core function. Supporting Evidence: PMID:4688871 demonstration of triokinase activity and its characterization.
GO:0045088 regulation of innate immune response	IDA PMID:16289032 Identification of human and rat FAD-AMP lyase (cyclic FMN fo...	KEEP AS NON CORE	Summary: General innate-immune regulation term. The specific, well-supported innate-immune role of TKFC is negative regulation of MDA5 signaling (GO:0039534, PMID:17600090); this broad parent is here attributed to the FAD-AMP lyase biochemistry paper (PMID:16289032). Reason: The direction is correct but the term is a high-level parent of the specific MDA5 role; retained as non-core. The specific function is captured by GO:0039534. Supporting Evidence: PMID:17600090 DAK is a physiological suppressor of MDA5 and specifically inhibits MDA5- but not RIG-I-mediated innate antiviral signaling.
GO:0046835 carbohydrate phosphorylation	IDA PMID:4688871 Dihydroxyacetone metabolism by human erythrocytes: demonstra...	KEEP AS NON CORE	Summary: Carbohydrate phosphorylation process supported by the erythrocyte triokinase characterization (ATP-dependent phosphorylation of trioses). Accurately describes the biological process of the kinase activity, at an appropriate level of generality. Reason: Correct process directly reflecting TKFC's ATP-dependent triose phosphorylation; kept as non-core alongside the specific triokinase MF and fructose catabolic process. Supporting Evidence: PMID:4688871 demonstration of triokinase activity and its characterization.
GO:0004371 glycerone kinase activity	IDA PMID:16289032 Identification of human and rat FAD-AMP lyase (cyclic FMN fo...	ACCEPT	Summary: Direct demonstration that the heterologously expressed human protein is active as an ATP- dependent dihydroxyacetone (glycerone) kinase. Core molecular function. Reason: Experimentally established dihydroxyacetone kinase activity of human TKFC. Supporting Evidence: PMID:16289032 yielded a protein active both as FMN cyclase and ATP-dependent Dha kinase
GO:0004371 glycerone kinase activity	IDA PMID:4688871 Dihydroxyacetone metabolism by human erythrocytes: demonstra...	ACCEPT	Summary: Direct demonstration of triokinase (dihydroxyacetone/glycerone kinase) activity in human erythrocytes with kinetic characterization. Core molecular function. Reason: Classic biochemical demonstration of the human triokinase/DHA kinase activity. Supporting Evidence: PMID:4688871 demonstration of triokinase activity and its characterization.
GO:0034012 FAD-AMP lyase (cyclizing) activity	IDA PMID:16289032 Identification of human and rat FAD-AMP lyase (cyclic FMN fo...	ACCEPT	Summary: Direct demonstration that the human protein possesses FMN cyclase / FAD-AMP lyase (cyclizing) activity, copurifying with the DHA kinase activity and sustained by a single protein. Core molecular function. Reason: Experimentally established FAD-AMP lyase (cyclizing)/FMN cyclase activity of human TKFC. Supporting Evidence: PMID:16289032 yielded a protein active both as FMN cyclase and ATP-dependent Dha kinase, each activity being inhibited by the substrate(s) of the other.
GO:0050354 triokinase activity	IDA PMID:4688871 Dihydroxyacetone metabolism by human erythrocytes: demonstra...	ACCEPT	Summary: Direct demonstration of triokinase activity in human erythrocytes (phosphorylation of D-glyceraldehyde) with kinetic characterization. Core molecular function. Reason: Classic biochemical demonstration of human triokinase activity. Supporting Evidence: PMID:4688871 demonstration of triokinase activity and its characterization.

Gene Description

Existing Annotations Review

Core Functions

ATP-dependent triokinase / dihydroxyacetone kinase that phosphorylates D-glyceraldehyde (and dihydroxyacetone) to the triose phosphates glyceraldehyde 3-phosphate and dihydroxyacetone phosphate, acting in the cytosol during hepatic fructose catabolism to return fructose-derived carbon to glycolysis.

Glycerone (dihydroxyacetone) kinase activity phosphorylating dihydroxyacetone to dihydroxyacetone phosphate using ATP, feeding trioses into central carbohydrate metabolism in the cytosol.

FAD-AMP lyase (cyclizing), or FMN cyclase, activity that splits FAD into riboflavin 4',5'-cyclic phosphate (cyclic FMN) plus AMP; TKFC is the only known enzymatic source of cyclic FMN and this activity requires Mn2+ or Co2+.

References

📚 Additional Documentation

Notes

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