id: Q3LXA3
gene_symbol: TKFC
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  TKFC (triokinase/FMN cyclase; also called DAK) is a cytosolic, homodimeric bifunctional
  enzyme of the dihydroxyacetone kinase (DAK) family, built from an N-terminal DhaK domain and a
  C-terminal DhaL domain. Its first activity is an ATP-dependent triokinase / dihydroxyacetone
  kinase that phosphorylates D-glyceraldehyde to D-glyceraldehyde 3-phosphate (EC 2.7.1.28) and
  dihydroxyacetone to dihydroxyacetone phosphate (EC 2.7.1.29). By phosphorylating the
  D-glyceraldehyde generated by aldolase B during hepatic fructolysis, it returns fructose-derived
  carbon to glycolysis, and it likewise salvages free dihydroxyacetone; both triose phosphate
  products feed central carbohydrate metabolism. Its second activity is an FAD-AMP lyase
  (cyclizing), or FMN cyclase (EC 4.6.1.15), which splits FAD into riboflavin 4',5'-cyclic phosphate
  (cyclic FMN) plus AMP and is the only known enzymatic source of this unusual flavin nucleotide;
  the FMN-cyclase activity requires Mn2+ or Co2+, and the kinase and cyclase activities are each
  inhibited by the substrate(s) of the other, consistent with shared/overlapping catalytic
  chemistry across the two domains. Beyond metabolism, TKFC has a moonlighting regulatory role in
  innate immunity: it binds the cytoplasmic viral RNA sensor MDA5 (IFIH1) via its CARD domains and
  negatively regulates MDA5- (but not RIG-I-) mediated type I interferon signaling, an interaction
  relieved upon viral infection. In humans, bi-allelic loss-of-function variants cause an autosomal
  recessive multisystem disorder (TKFC deficiency) characterized by cataracts and developmental
  delay, variably with cerebellar hypoplasia, liver dysfunction, microcytic anemia, and lactic
  acidosis with cardiomyopathy.
alternative_products:
- name: '1'
  id: Q3LXA3-1
- name: '2'
  id: Q3LXA3-2
  sequence_note: VSP_057181
existing_annotations:
- term:
    id: GO:0004371
    label: glycerone kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Human TKFC phosphorylates dihydroxyacetone (glycerone) using ATP; this activity is
      biochemically established and consistent with the DAK-family phylogeny.
    supported_by:
    - reference_id: PMID:32004446
      supporting_text: >-
        TKFC encodes a bifunctional enzyme involved in fructose metabolism through its
        glyceraldehyde kinase activity and in the generation of riboflavin cyclic 4',5'-phosphate
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "Reaction=dihydroxyacetone + ATP = dihydroxyacetone phosphate + ADP +"
- term:
    id: GO:0019563
    label: glycerol catabolic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    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.
    action: MODIFY
    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.
    proposed_replacement_terms:
    - id: GO:0061624
      label: fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate
    propagation_review:
      root_cause: TERM_SCOPING_PROBLEM
      failure_modes:
      - FUNCTIONAL_DIVERGENCE
    supported_by:
    - reference_id: PMID:32004446
      supporting_text: "TKFC encodes a bifunctional enzyme involved in fructose metabolism through its"
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: >-
        Reaction=D-glyceraldehyde + ATP = D-glyceraldehyde 3-phosphate + ADP +
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      Phylogenetic assignment of cytosolic localization, consistent with the soluble cytosolic
      nature of DAK-family triokinases and with the cytosolic fructolysis pathway.
    action: ACCEPT
    reason: >-
      TKFC is a soluble cytosolic enzyme; cytosol is corroborated by Reactome curation and is the
      compartment where fructolysis and triose phosphorylation occur.
    supported_by:
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "GO:0005829; C:cytosol; IBA:GO_Central."
- term:
    id: GO:0004371
    label: glycerone kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Consistent with the demonstrated dihydroxyacetone kinase activity (EC 2.7.1.29) and DAK-family
      domain content.
    supported_by:
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "EC=2.7.1.29; Evidence={ECO:0000269|PubMed:32004446,"
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      TKFC is an ATP-dependent kinase with mapped ATP-binding sites; ATP binding is a well-supported
      supporting molecular function.
    supported_by:
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "/ligand=\"ATP\""
- term:
    id: GO:0006071
    label: glycerol metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:32004446
      supporting_text: "TKFC encodes a bifunctional enzyme involved in fructose metabolism through its"
- term:
    id: GO:0034012
    label: FAD-AMP lyase (cyclizing) activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    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.
    supported_by:
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "Reaction=FAD = riboflavin cyclic-4',5'-phosphate + AMP + H(+);"
    - reference_id: PMID:16289032
      supporting_text: >-
        yielded a protein active both as FMN cyclase and ATP-dependent Dha kinase
- term:
    id: GO:0050354
    label: triokinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Human TKFC phosphorylates D-glyceraldehyde (EC 2.7.1.28); this IEA is correctly mapped.
    supported_by:
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "EC=2.7.1.28; Evidence={ECO:0000269|PubMed:32004446,"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:17600090
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bare protein binding is not an informative molecular function. The specific IFIH1 interaction
      and its functional consequence are better represented by GO:0039534.
    supported_by:
    - reference_id: PMID:17600090
      supporting_text: >-
        we identified DAK, a functionally unknown
        dihydroacetone kinase, as a specific MDA5-interacting protein
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:25416956
  qualifier: enables
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      High-throughput binary interaction; the uninformative protein binding term does not describe a
      molecular function and lacks functional context for this gene.
    supported_by:
    - reference_id: PMID:25416956
      supporting_text: A proteome-scale map of the human interactome network.
- term:
    id: GO:0006001
    label: fructose catabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ensembl-Compara transfer (from mouse ortholog) of a fructose catabolic role. This is the
      physiologically correct process for human TKFC, and a more specific child term describing the
      triose-phosphate products is available.
    action: MODIFY
    reason: >-
      The role is correct but can be made more precise: TKFC's triokinase activity operates in the
      terminal step of fructolysis producing glyceraldehyde 3-phosphate (and DHAP). The more
      specific term better captures the biochemistry.
    proposed_replacement_terms:
    - id: GO:0061624
      label: fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate
    supported_by:
    - reference_id: PMID:32004446
      supporting_text: "TKFC encodes a bifunctional enzyme involved in fructose metabolism through its"
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate"
- term:
    id: GO:0004371
    label: glycerone kinase activity
  evidence_type: IDA
  original_reference_id: PMID:32004446
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Experimentally demonstrated dihydroxyacetone (glycerone) kinase activity of the human enzyme.
    supported_by:
    - reference_id: PMID:32004446
      supporting_text: >-
        TKFC encodes a
        bifunctional enzyme involved in fructose metabolism through its glyceraldehyde
        kinase activity
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "very severe decrease of triokinase\n                   and glycerone kinase activities"
- term:
    id: GO:0050354
    label: triokinase activity
  evidence_type: IDA
  original_reference_id: PMID:32004446
  qualifier: enables
  review:
    summary: >-
      Direct assay (IDA) of triokinase activity (D-glyceraldehyde phosphorylation) for human TKFC;
      TKFCD patient variants very severely decrease triokinase activity. Core function.
    action: ACCEPT
    reason: >-
      Experimentally demonstrated triokinase activity; loss of this activity underlies the human
      TKFC deficiency phenotype.
    supported_by:
    - reference_id: PMID:32004446
      supporting_text: >-
        We report an inborn error of metabolism caused by TKFC deficiency
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "very severe decrease of triokinase\n                   and glycerone kinase activities"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70349
  qualifier: located_in
  review:
    summary: >-
      Reactome-curated cytosolic localization associated with the fructose-catabolism reaction in
      which the DAK dimer phosphorylates D-glyceraldehyde to glyceraldehyde 3-phosphate.
    action: ACCEPT
    reason: >-
      Consistent with the cytosolic localization of TKFC and its role in cytosolic fructolysis.
    supported_by:
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "GO:0005829; C:cytosol; IBA:GO_Central."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-913725
  qualifier: located_in
  review:
    summary: >-
      Reactome-curated cytosolic localization associated with the IFIH1:TKFC / viral dsRNA sensing
      context; consistent with cytosolic TKFC.
    action: ACCEPT
    reason: >-
      TKFC is cytosolic; the MDA5 (IFIH1) interaction occurs in the cytoplasm.
    supported_by:
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "GO:0005829; C:cytosol; IBA:GO_Central."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9754745
  qualifier: located_in
  review:
    summary: >-
      Reactome-curated cytosolic localization in the SARS-CoV-2 innate-immune module (IFIH1:TKFC
      binding dsRNA intermediates); consistent with cytosolic TKFC.
    action: ACCEPT
    reason: >-
      Cytosolic localization corroborated across multiple Reactome curations.
    supported_by:
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "GO:0005829; C:cytosol; IBA:GO_Central."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-9755244
  qualifier: located_in
  review:
    summary: >-
      Reactome-curated cytosolic localization in a SARS-CoV-2 innate-immune deISGylation module;
      consistent with cytosolic TKFC.
    action: ACCEPT
    reason: >-
      Cytosolic localization corroborated across multiple Reactome curations.
    supported_by:
    - reference_id: file:human/TKFC/TKFC-uniprot.txt
      supporting_text: "GO:0005829; C:cytosol; IBA:GO_Central."
- term:
    id: GO:0039534
    label: negative regulation of MDA-5 signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:17600090
  qualifier: involved_in
  review:
    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.
    action: ACCEPT
    reason: >-
      Precisely matches the experimental findings of PMID:17600090; TKFC binds MDA5 and negatively
      regulates its signaling.
    supported_by:
    - reference_id: PMID:17600090
      supporting_text: >-
        These findings
        suggest that DAK is a physiological suppressor of MDA5 and specifically inhibits
        MDA5- but not RIG-I-mediated innate antiviral signaling.
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:23533145
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Abundant cytosolic enzymes are common background in exosome proteomics; there is no functional
      evidence for an extracellular-exosome role for TKFC.
    supported_by:
    - reference_id: PMID:23533145
      supporting_text: "In pooled EPS-urine exosome \n samples, ~900 proteins were detected."
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: HDA
  original_reference_id: PMID:21630459
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    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.
    supported_by:
    - reference_id: PMID:21630459
      supporting_text: "403 \n different proteins have been identified from the isolated sperm nuclei."
- term:
    id: GO:0070062
    label: extracellular exosome
  evidence_type: HDA
  original_reference_id: PMID:19056867
  qualifier: located_in
  review:
    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.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Bulk urinary-exosome proteomics; no functional evidence for an extracellular-exosome role.
    supported_by:
    - reference_id: PMID:19056867
      supporting_text: "the \n analysis identified 1132 proteins unambiguously"
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:16289032
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      The essence is correct but the term is a broad parent; the specific triokinase/fructose
      catabolic role is the informative core function.
    supported_by:
    - reference_id: PMID:16289032
      supporting_text: >-
        yielded a protein active both as FMN cyclase and ATP-dependent Dha kinase
- term:
    id: GO:0005975
    label: carbohydrate metabolic process
  evidence_type: IDA
  original_reference_id: PMID:4688871
  qualifier: involved_in
  review:
    summary: >-
      General carbohydrate metabolic process annotation from the erythrocyte triokinase
      characterization. Correct but high-level relative to the specific triokinase function.
    action: KEEP_AS_NON_CORE
    reason: >-
      Broad parent term; retained as non-core with the specific triokinase MF representing the core
      function.
    supported_by:
    - reference_id: PMID:4688871
      supporting_text: "demonstration of triokinase \n activity and its characterization."
- term:
    id: GO:0045088
    label: regulation of innate immune response
  evidence_type: IDA
  original_reference_id: PMID:16289032
  qualifier: involved_in
  review:
    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).
    action: KEEP_AS_NON_CORE
    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.
    supported_by:
    - reference_id: PMID:17600090
      supporting_text: >-
        DAK is a physiological suppressor of MDA5 and specifically inhibits
        MDA5- but not RIG-I-mediated innate antiviral signaling.
- term:
    id: GO:0046835
    label: carbohydrate phosphorylation
  evidence_type: IDA
  original_reference_id: PMID:4688871
  qualifier: involved_in
  review:
    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.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct process directly reflecting TKFC's ATP-dependent triose phosphorylation; kept as
      non-core alongside the specific triokinase MF and fructose catabolic process.
    supported_by:
    - reference_id: PMID:4688871
      supporting_text: "demonstration of triokinase \n activity and its characterization."
- term:
    id: GO:0004371
    label: glycerone kinase activity
  evidence_type: IDA
  original_reference_id: PMID:16289032
  qualifier: enables
  review:
    summary: >-
      Direct demonstration that the heterologously expressed human protein is active as an ATP-
      dependent dihydroxyacetone (glycerone) kinase. Core molecular function.
    action: ACCEPT
    reason: >-
      Experimentally established dihydroxyacetone kinase activity of human TKFC.
    supported_by:
    - reference_id: PMID:16289032
      supporting_text: >-
        yielded a protein active both as FMN cyclase and ATP-dependent Dha kinase
- term:
    id: GO:0004371
    label: glycerone kinase activity
  evidence_type: IDA
  original_reference_id: PMID:4688871
  qualifier: enables
  review:
    summary: >-
      Direct demonstration of triokinase (dihydroxyacetone/glycerone kinase) activity in human
      erythrocytes with kinetic characterization. Core molecular function.
    action: ACCEPT
    reason: >-
      Classic biochemical demonstration of the human triokinase/DHA kinase activity.
    supported_by:
    - reference_id: PMID:4688871
      supporting_text: "demonstration of triokinase \n activity and its characterization."
- term:
    id: GO:0034012
    label: FAD-AMP lyase (cyclizing) activity
  evidence_type: IDA
  original_reference_id: PMID:16289032
  qualifier: enables
  review:
    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.
    action: ACCEPT
    reason: >-
      Experimentally established FAD-AMP lyase (cyclizing)/FMN cyclase activity of human TKFC.
    supported_by:
    - reference_id: PMID:16289032
      supporting_text: >-
        yielded a protein active both as FMN cyclase and ATP-dependent Dha kinase, each
        activity being inhibited by the substrate(s) of the other.
- term:
    id: GO:0050354
    label: triokinase activity
  evidence_type: IDA
  original_reference_id: PMID:4688871
  qualifier: enables
  review:
    summary: >-
      Direct demonstration of triokinase activity in human erythrocytes (phosphorylation of
      D-glyceraldehyde) with kinetic characterization. Core molecular function.
    action: ACCEPT
    reason: >-
      Classic biochemical demonstration of human triokinase activity.
    supported_by:
    - reference_id: PMID:4688871
      supporting_text: "demonstration of triokinase \n activity and its characterization."
core_functions:
- description: >-
    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.
  molecular_function:
    id: GO:0050354
    label: triokinase activity
  directly_involved_in:
  - id: GO:0061624
    label: fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:32004446
    supporting_text: "TKFC encodes a bifunctional enzyme involved in fructose metabolism through its"
  - reference_id: PMID:4688871
    supporting_text: "demonstration of triokinase \n activity and its characterization."
- description: >-
    Glycerone (dihydroxyacetone) kinase activity phosphorylating dihydroxyacetone to
    dihydroxyacetone phosphate using ATP, feeding trioses into central carbohydrate metabolism in
    the cytosol.
  molecular_function:
    id: GO:0004371
    label: glycerone kinase activity
  directly_involved_in:
  - id: GO:0046835
    label: carbohydrate phosphorylation
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:16289032
    supporting_text: >-
      yielded a protein active both as FMN cyclase and ATP-dependent Dha kinase
- description: >-
    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+.
  molecular_function:
    id: GO:0034012
    label: FAD-AMP lyase (cyclizing) activity
  locations:
  - id: GO:0005829
    label: cytosol
  supported_by:
  - reference_id: PMID:16289032
    supporting_text: >-
      yielded a protein active both as FMN cyclase and ATP-dependent Dha kinase
  - reference_id: file:human/TKFC/TKFC-uniprot.txt
    supporting_text: "Reaction=FAD = riboflavin cyclic-4',5'-phosphate + AMP + H(+);"
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:16289032
  title: Identification of human and rat FAD-AMP lyase (cyclic FMN forming) as ATP-dependent
    dihydroxyacetone kinases.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Establishes that a single human protein (LOC26007 cDNA, i.e. TKFC)
      possesses both FMN cyclase (FAD-AMP lyase) and ATP-dependent dihydroxyacetone kinase
      activities, each inhibited by the substrate(s) of the other. Supports the FAD-AMP lyase and
      glycerone kinase MF annotations.
- id: PMID:17600090
  title: Negative regulation of MDA5- but not RIG-I-mediated innate antiviral signaling
    by the dihydroxyacetone kinase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Identifies DAK/TKFC as a specific MDA5 (IFIH1)-interacting protein and a
      physiological suppressor of MDA5- but not RIG-I-mediated antiviral signaling. Supports
      GO:0039534 and the moonlighting immune core function.
- id: PMID:19056867
  title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Bulk urinary-exosome proteomics (1132 proteins); TKFC detection is incidental for a cytosolic
      enzyme. Supports only the (over-annotated) extracellular exosome localization.
- id: PMID:21630459
  title: Proteomic characterization of the human sperm nucleus.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Sperm-nucleus proteome (403 proteins). Detection of a cytosolic enzyme likely reflects
      contamination/non-functional presence; supports only the over-annotated nuclear localization.
- id: PMID:23533145
  title: In-depth proteomic analyses of exosomes isolated from expressed prostatic
    secretions in urine.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Prostatic/urinary exosome proteomics (~900 proteins). Incidental detection of a cytosolic
      enzyme; supports only the over-annotated extracellular exosome localization.
- id: PMID:25416956
  title: A proteome-scale map of the human interactome network.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      Proteome-scale binary interactome map; source of the SDCBP (O00560) protein binding IPI. No
      established functional interpretation for TKFC; supports only the uninformative protein
      binding term.
- id: PMID:32004446
  title: Bi-allelic Variants in TKFC Encoding Triokinase/FMN Cyclase Are Associated
    with Cataracts and Multisystem Disease.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Defines human TKFC deficiency (TKFCD); confirms the bifunctional enzyme
      (glyceraldehyde kinase in fructose metabolism plus FMN lyase generating cyclic FMN); FMN-lyase
      domain variants (G445S, R543I) severely reduce triokinase and glycerone kinase activities.
- id: PMID:4688871
  title: 'Dihydroxyacetone metabolism by human erythrocytes: demonstration of triokinase
    activity and its characterization.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      PubMed-verified. Classic biochemical demonstration and kinetic characterization of human
      triokinase (dihydroxyacetone/glyceraldehyde kinase) activity in erythrocytes. Supports the
      triokinase and glycerone kinase MF annotations.
- id: Reactome:R-HSA-70349
  title: DAK dimer phosphorylates D-glyceraldehyde to form D-glyceraldehyde 3-phosphate
  findings: []
- id: Reactome:R-HSA-913725
  title: viral dsRNA binds IFIH1:TKFC
  findings: []
- id: Reactome:R-HSA-9754745
  title: 'IFIH1:TKFC binds SARS-CoV-2 dsRNA intermediates '
  findings: []
- id: Reactome:R-HSA-9755244
  title: SARS-CoV-2 nsp3 deISGylates ISGylated IFIH1
  findings: []