id: Q16134
gene_symbol: ETFDH
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO / ETF dehydrogenase;
  EC 1.5.5.1), a monotopic iron-sulfur flavoprotein of the mitochondrial inner membrane.
  It accepts electrons from reduced electron-transfer flavoprotein (ETF, the matrix
  ETFA/ETFB heterodimer) and passes them to ubiquinone in the respiratory chain. This is
  the terminal step of an electron-transfer relay that couples the FAD-dependent flavoprotein
  dehydrogenases of fatty-acid beta-oxidation and amino-acid/choline catabolism to oxidative
  phosphorylation, reducing the ubiquinone pool. Each mature monomer carries one FAD and one
  [4Fe-4S] cluster. Loss of function causes glutaric aciduria type II / multiple acyl-CoA
  dehydrogenase deficiency (MADD), which in its late-onset myopathic form is frequently
  riboflavin-responsive and associated with a secondary coenzyme Q10 deficiency.
alternative_products:
- name: '1'
  id: Q16134-1
- name: '2'
  id: Q16134-3
  sequence_note: VSP_055158
existing_annotations:
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: >-
      ETF-QO is an integral (monotopic) protein of the mitochondrial inner membrane, where
      it acts. This is the core subcellular location and is directly supported by experiment.
    action: ACCEPT
    reason: >-
      Direct experimental evidence and structural data localize ETF-QO to the inner
      mitochondrial membrane; the IBA annotation is at the correct level of specificity and
      matches the human IDA below (PMID:8306995).
    supported_by:
    - reference_id: PMID:8306995
      supporting_text: >-
        Electron-transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) in the inner
        mitochondrial membrane accepts electrons from electron-transfer flavoprotein
    - reference_id: PMID:17050691
      supporting_text: >-
        Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a 4Fe4S
        flavoprotein located in the inner mitochondrial membrane.
- term:
    id: GO:0004174
    label: electron-transferring-flavoprotein dehydrogenase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      This is the defining molecular function of ETFDH (EC 1.5.5.1): oxidation of reduced ETF
      with reduction of ubiquinone. Strongly supported by direct human enzymology.
    action: ACCEPT
    reason: >-
      The IBA annotation matches the multiple human IDA annotations (PMID:12049629,
      PMID:8306995) and the UniProt catalytic activity. It is the core function of the gene.
    supported_by:
    - reference_id: PMID:12049629
      supporting_text: >-
        Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is an iron-sulphur
        flavoprotein and a component of an electron-transfer system that links 10 different
        mitochondrial flavoprotein dehydrogenases to the mitochondrial bc1 complex via
        electron transfer flavoprotein (ETF) and ubiquinone.
- term:
    id: GO:0022900
    label: electron transport chain
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      ETF-QO participates in mitochondrial electron transport by reducing the ubiquinone pool,
      feeding electrons from primary flavoprotein dehydrogenases into the respiratory chain.
    action: ACCEPT
    reason: >-
      Correct and appropriately general biological process; concordant with the human IDA
      annotations to this term and with the Reactome respiratory-electron-transport annotation.
    supported_by:
    - reference_id: PMID:18037314
      supporting_text: >-
        Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a membrane-bound
        electron transfer protein that links primary flavoprotein dehydrogenases with the main
        respiratory chain.
- term:
    id: GO:0004174
    label: electron-transferring-flavoprotein dehydrogenase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic assignment of the core catalytic activity via InterPro/RHEA/EC mapping
      (EC 1.5.5.1, RHEA:24052). Consistent with experimental data.
    action: ACCEPT
    reason: >-
      The IEA maps IPR040156 (ETF-QO) and EC 1.5.5.1 to GO:0004174, the experimentally
      established function; correct and specific.
    supported_by:
    - reference_id: PMID:12049629
      supporting_text: >-
        a component of an electron-transfer system that links 10 different mitochondrial
        flavoprotein dehydrogenases to the mitochondrial bc1 complex
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: located_in
  review:
    summary: >-
      Broad mitochondrial localization (ARBA electronic). Correct but less specific than the
      experimentally supported inner-membrane location.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but a general parent of the inner-membrane annotation; retained as a broader,
      non-core localization statement.
    supported_by:
    - reference_id: PMID:8306995
      supporting_text: >-
        which targets the protein to mitochondria
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: >-
      Inner-membrane localization from UniProt Subcellular Location mapping (SL-0168).
      Matches the experimental IDA.
    action: ACCEPT
    reason: >-
      Correct and specific; equivalent to the experimentally supported location.
    supported_by:
    - reference_id: PMID:17050691
      supporting_text: >-
        ETF-QO is a monotopic integral membrane protein.
- term:
    id: GO:0022900
    label: electron transport chain
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: involved_in
  review:
    summary: >-
      InterPro2GO electronic assignment of electron transport chain involvement; matches the
      experimentally supported process.
    action: ACCEPT
    reason: >-
      Consistent with IBA and human IDA annotations to the same term; correct.
    supported_by:
    - reference_id: PMID:18037314
      supporting_text: >-
        a membrane-bound electron transfer protein that links primary flavoprotein
        dehydrogenases with the main respiratory chain
- term:
    id: GO:0051536
    label: iron-sulfur cluster binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: >-
      ETF-QO binds one [4Fe-4S] cluster; this InterPro-derived term is the broader parent of
      the more specific IDA-supported GO:0051539.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct but less specific than 4 iron, 4 sulfur cluster binding (GO:0051539); retained as
      a broader cofactor-binding statement.
    supported_by:
    - reference_id: PMID:8306995
      supporting_text: >-
        The two redox centers in the protein, FAD and a [4Fe4S]+2,+1 cluster, are present in a
        64-kDa monomer.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Seven high-throughput yeast two-hybrid interactions (HuRI) with keratin-associated
      proteins, transcription factors (OTX1, GSC2, ZNF581) and other proteins (MYH7B, TRIM69,
      KRTAP11-1/13-2) that share no compartment or pathway with this mitochondrial
      inner-membrane oxidoreductase. The bare "protein binding" term is also uninformative.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      These are large-scale binary-interactome (Y2H) hits from a reference interactome map with
      no functional context; the partners are cytoplasmic/nuclear and biologically implausible
      for an inner-membrane enzyme, and the generic term conveys no molecular function. Marked as
      over-annotated per policy rather than removed.
    supported_by:
    - reference_id: PMID:32296183
      supporting_text: A reference map of the human binary protein interactome.
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: >-
      Ortholog-transferred (Ensembl Compara, from mouse Etfdh) association with oxidative-stress
      response. This is a downstream/phenotypic consequence rather than a direct molecular
      function of the electron-transfer reaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The term is electronically transferred from the mouse ortholog and reflects a secondary
      phenotype (impaired electron flux increases electron leak/ROS) rather than a core activity
      of ETF-QO; retained but flagged as over-annotated.
    supported_by:
    - reference_id: GO_REF:0000107
      supporting_text: >-
        Automatic transfer of experimentally verified manual GO annotation data to
        orthologs using Ensembl Compara
- term:
    id: GO:0022904
    label: respiratory electron transport chain
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-611105
  qualifier: involved_in
  review:
    summary: >-
      Reactome places ETFDH in respiratory electron transport, reducing coenzyme Q; a correct,
      specific process for this enzyme.
    action: ACCEPT
    reason: >-
      Traceable author statement (Reactome) consistent with the enzyme's role of feeding
      electrons into the ubiquinone pool of the respiratory chain.
    supported_by:
    - reference_id: PMID:17050691
      supporting_text: >-
        It catalyzes ubiquinone (UQ) reduction by ETF, linking oxidation of fatty acids and
        some amino acids to the mitochondrial respiratory chain.
- term:
    id: GO:0004174
    label: electron-transferring-flavoprotein dehydrogenase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-169270
  qualifier: enables
  review:
    summary: >-
      Reactome reaction (ETFDH oxidises reduced ETF, reduces CoQ to CoQH2) assigning the core
      catalytic activity. Correct.
    action: ACCEPT
    reason: >-
      Concordant with experimental IDA and the enzyme's EC 1.5.5.1 catalytic activity.
    supported_by:
    - reference_id: PMID:12049629
      supporting_text: >-
        The steady-state kinetic constants of human ETF-QO were determined with ubiquinone
        homologues, a ubiquinone analogue, and with human wild-type ETF
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: GO_REF:0000052
  qualifier: located_in
  review:
    summary: >-
      Immunofluorescence (HPA) localizes ETFDH to mitochondria. Correct but a broad parent of
      the specific inner-membrane location.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate general localization; less specific than the inner-membrane annotation, so kept
      as a non-core broader term.
    supported_by:
    - reference_id: PMID:8306995
      supporting_text: >-
        which targets the protein to mitochondria
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: HTP
  original_reference_id: PMID:34800366
  qualifier: located_in
  review:
    summary: >-
      High-throughput mitochondrial proteomics identifies ETFDH as a mitochondrial protein.
      Correct but broad.
    action: KEEP_AS_NON_CORE
    reason: >-
      Supports mitochondrial localization at low specificity; consistent with the experimentally
      established inner-membrane location, kept as non-core.
    supported_by:
    - reference_id: PMID:34800366
      supporting_text: Quantitative high-confidence human mitochondrial proteome and its dynamics
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-169270
  qualifier: located_in
  review:
    summary: >-
      Reactome asserts inner-membrane localization for the ETFDH reaction; matches experimental
      data.
    action: ACCEPT
    reason: >-
      Correct, specific location concordant with the IDA and structural evidence.
    supported_by:
    - reference_id: PMID:17050691
      supporting_text: >-
        Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a 4Fe4S
        flavoprotein located in the inner mitochondrial membrane.
- term:
    id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  evidence_type: IMP
  original_reference_id: PMID:17412732
  qualifier: involved_in
  review:
    summary: >-
      ETFDH mutations cause multiple acyl-CoA dehydrogenase deficiency with impaired fatty-acid
      beta-oxidation flux; ETF-QO is the electron acceptor for the acyl-CoA dehydrogenation step,
      so its loss blocks beta-oxidation.
    action: ACCEPT
    reason: >-
      IMP evidence from patients with ETFDH mutations demonstrates the gene's required role in
      the acyl-CoA dehydrogenase branch of fatty-acid beta-oxidation (electron sink); this is the
      biologically central metabolic process that ETF-QO enables.
    supported_by:
    - reference_id: PMID:17412732
      supporting_text: >-
        All of our patients carried autosomal recessive mutations in ETFDH, suggesting that
        ETFDH deficiency leads to a secondary CoQ10 deficiency.
    - reference_id: PMID:17050691
      supporting_text: >-
        linking oxidation of fatty acids and some amino acids to the mitochondrial respiratory
        chain
- term:
    id: GO:0004174
    label: electron-transferring-flavoprotein dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:14640977
  qualifier: enables
  review:
    summary: >-
      Direct kinetic characterization of human ETF-QO catalyzing electron transfer from ETF to
      the ubiquinone pool. Core molecular function.
    action: ACCEPT
    reason: >-
      Steady-state kinetics of purified human enzyme with ETF and ubiquinone substrates directly
      demonstrate the EC 1.5.5.1 activity.
    supported_by:
    - reference_id: PMID:14640977
      supporting_text: >-
        a membrane-bound iron-sulphur flavoprotein that participates in an electron-transport
        pathway between eleven mitochondrial flavoprotein dehydrogenases and the ubiquinone pool
- term:
    id: GO:0006979
    label: response to oxidative stress
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: >-
      Sequence-similarity transfer from the mouse ortholog (Q921G7) of an oxidative-stress
      response role; a secondary/phenotypic association rather than a direct function of the
      electron-transfer reaction.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      As with the Ensembl IEA to the same term, this is transferred from mouse and reflects a
      downstream phenotype of impaired electron flux (increased ROS/electron leak), not a core
      molecular function; flagged as over-annotated.
    supported_by:
    - reference_id: GO_REF:0000024
      supporting_text: >-
        Manual transfer of experimentally-verified manual GO annotation data to orthologs
        by curator judgment of sequence similarity
- term:
    id: GO:0016491
    label: oxidoreductase activity
  evidence_type: IDA
  original_reference_id: PMID:14640977
  qualifier: enables
  review:
    summary: >-
      ETF-QO is an oxidoreductase, but this is the very general parent of the specific
      GO:0004174 activity established in the same study.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      Correct in essence but far too general given that the specific dehydrogenase activity
      (GO:0004174) is annotated with the same experimental evidence; retained as an
      over-annotation rather than as a core function.
    supported_by:
    - reference_id: PMID:14640977
      supporting_text: >-
        The steady-state kinetic constants of human ETF-QO were determined with ubiquinone
        homologues and analogues
- term:
    id: GO:0048038
    label: quinone binding
  evidence_type: IDA
  original_reference_id: PMID:14640977
  qualifier: enables
  review:
    summary: >-
      Fluorescence titrations demonstrate a single quinone-binding site per ETF-QO monomer.
      Correct; the parent of the more specific ubiquinone binding.
    action: KEEP_AS_NON_CORE
    reason: >-
      Directly supported but broader than the specific ubiquinone binding annotation
      (GO:0048039); kept as a non-core broader term.
    supported_by:
    - reference_id: PMID:14640977
      supporting_text: >-
        consistent with one ubiquinone-binding site per ETF-QO monomer
- term:
    id: GO:0048039
    label: ubiquinone binding
  evidence_type: IDA
  original_reference_id: PMID:14640977
  qualifier: enables
  review:
    summary: >-
      ETF-QO binds ubiquinone at a single site per monomer and reduces it; the physiological
      electron acceptor. Core function-related binding.
    action: ACCEPT
    reason: >-
      Direct biophysical evidence (fluorescence titration, kinetics) for a specific
      ubiquinone-binding site; structurally corroborated. Specific and correct.
    supported_by:
    - reference_id: PMID:14640977
      supporting_text: >-
        determined by fluorescence titrations of the protein with DBMIB and
        6-(10-bromodecyl)ubiquinone, are consistent with one ubiquinone-binding site per ETF-QO
        monomer
    - reference_id: PMID:17050691
      supporting_text: >-
        The UQ-binding pocket consists mainly of hydrophobic residues
- term:
    id: GO:0051539
    label: 4 iron, 4 sulfur cluster binding
  evidence_type: IDA
  original_reference_id: PMID:18037314
  qualifier: enables
  review:
    summary: >-
      EPR/electron-spin-relaxation measurements confirm a single [4Fe-4S] cluster in human
      ETF-QO. Core cofactor binding.
    action: ACCEPT
    reason: >-
      Direct spectroscopic evidence for one [4Fe-4S] cluster per monomer; specific and correct.
    supported_by:
    - reference_id: PMID:18037314
      supporting_text: >-
        Human, porcine, and Rhodobacter sphaeroides ETF-QO each contain a single
        [4Fe-4S](2+,1+) cluster and one equivalent of FAD
- term:
    id: GO:0004174
    label: electron-transferring-flavoprotein dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:12049629
  qualifier: enables
  review:
    summary: >-
      Kinetic and spectral characterization of recombinant human ETF-QO establishes the core
      EC 1.5.5.1 activity with ETF and ubiquinone substrates.
    action: ACCEPT
    reason: >-
      Direct enzymology of the human protein; the defining molecular function.
    supported_by:
    - reference_id: PMID:12049629
      supporting_text: >-
        The steady-state kinetic constants of human ETF-QO were determined with ubiquinone
        homologues, a ubiquinone analogue, and with human wild-type ETF
- term:
    id: GO:0004174
    label: electron-transferring-flavoprotein dehydrogenase activity
  evidence_type: IDA
  original_reference_id: PMID:8306995
  qualifier: enables
  review:
    summary: >-
      Heterologously expressed human ETF-QO transfers electrons from ETF to ubiquinone,
      demonstrating the core catalytic activity with both cofactors correctly inserted.
    action: ACCEPT
    reason: >-
      Direct functional demonstration of ETF-to-ubiquinone electron transfer by the human
      enzyme; defining molecular function.
    supported_by:
    - reference_id: PMID:8306995
      supporting_text: >-
        The detergent-solubilized protein transfers electrons from ETF to the ubiquinone homolog,
        Q1, indicating that both the FAD and iron-sulfur cluster are properly inserted
- term:
    id: GO:0005743
    label: mitochondrial inner membrane
  evidence_type: IDA
  original_reference_id: PMID:8306995
  qualifier: located_in
  review:
    summary: >-
      Direct evidence that the mature ETF-QO resides in the inner mitochondrial membrane.
      Core location.
    action: ACCEPT
    reason: >-
      Experimental localization of the processed 64-kDa mature protein to the mitochondrial
      (inner) membrane; matches structural data.
    supported_by:
    - reference_id: PMID:8306995
      supporting_text: >-
        Electron-transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) in the inner
        mitochondrial membrane accepts electrons from electron-transfer flavoprotein
- term:
    id: GO:0009055
    label: electron transfer activity
  evidence_type: IDA
  original_reference_id: PMID:12049629
  qualifier: enables
  review:
    summary: >-
      ETF-QO functions as an electron carrier, transferring electrons from ETF to ubiquinone.
      Correct, though broader than the specific dehydrogenase activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate description of the electron-carrier property; kept as a correct but more general
      companion to the specific GO:0004174 core function.
    supported_by:
    - reference_id: PMID:12049629
      supporting_text: >-
        a component of an electron-transfer system that links 10 different mitochondrial
        flavoprotein dehydrogenases to the mitochondrial bc1 complex
- term:
    id: GO:0009055
    label: electron transfer activity
  evidence_type: IDA
  original_reference_id: PMID:8306995
  qualifier: enables
  review:
    summary: >-
      ETF-QO transfers electrons from ETF to ubiquinone, acting as an electron carrier in the
      relay to the respiratory chain.
    action: KEEP_AS_NON_CORE
    reason: >-
      Correct electron-carrier description; retained as a general companion to the specific
      dehydrogenase activity.
    supported_by:
    - reference_id: PMID:8306995
      supporting_text: >-
        The detergent-solubilized protein transfers electrons from ETF to the ubiquinone homolog,
        Q1
- term:
    id: GO:0022900
    label: electron transport chain
  evidence_type: IDA
  original_reference_id: PMID:12049629
  qualifier: involved_in
  review:
    summary: >-
      ETF-QO participates in the mitochondrial electron transport chain, linking flavoprotein
      dehydrogenases to the bc1 complex via ubiquinone.
    action: ACCEPT
    reason: >-
      Direct evidence for the enzyme's role in feeding electrons into the respiratory electron
      transport chain via the ubiquinone pool.
    supported_by:
    - reference_id: PMID:12049629
      supporting_text: >-
        links 10 different mitochondrial flavoprotein dehydrogenases to the mitochondrial bc1
        complex via electron transfer flavoprotein (ETF) and ubiquinone
- term:
    id: GO:0022900
    label: electron transport chain
  evidence_type: IDA
  original_reference_id: PMID:8306995
  qualifier: involved_in
  review:
    summary: >-
      ETF-QO reduces ubiquinone in the mitochondrial membrane, participating in the electron
      transport chain.
    action: ACCEPT
    reason: >-
      Direct evidence that the enzyme reduces ubiquinone, its role in the respiratory electron
      transport chain.
    supported_by:
    - reference_id: PMID:8306995
      supporting_text: >-
        reduces ubiquinone in the mitochondrial membrane
- term:
    id: GO:0031966
    label: mitochondrial membrane
  evidence_type: IDA
  original_reference_id: PMID:12049629
  qualifier: located_in
  review:
    summary: >-
      ETF-QO is an integral mitochondrial membrane protein; correct but a broad parent of the
      specific inner-membrane location.
    action: KEEP_AS_NON_CORE
    reason: >-
      Accurate but less specific than mitochondrial inner membrane (GO:0005743); kept as a
      broader, non-core localization.
    supported_by:
    - reference_id: PMID:12049629
      supporting_text: >-
        ETF-QO is an integral membrane protein
- term:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  evidence_type: ISS
  original_reference_id: PMID:17050691
  qualifier: enables
  review:
    summary: >-
      ETF-QO carries one FAD cofactor essential for electron transfer; supported by the
      structure of the porcine ortholog (source of ISS) and confirmed for the human enzyme.
    action: ACCEPT
    reason: >-
      FAD binding is a core cofactor function; the crystal structure defines the FAD site, and
      the human enzyme is spectroscopically shown to contain one FAD equivalent. Correct and
      specific.
    supported_by:
    - reference_id: PMID:17050691
      supporting_text: >-
        Three functional regions bind FAD, the 4Fe4S cluster, and UQ
    - reference_id: PMID:18037314
      supporting_text: >-
        each contain a single [4Fe-4S](2+,1+) cluster and one equivalent of FAD
core_functions:
- description: >-
    Electron-transferring-flavoprotein dehydrogenase (ETF-QO, EC 1.5.5.1): oxidizes reduced
    electron-transfer flavoprotein and reduces ubiquinone in the mitochondrial inner membrane,
    using bound FAD and a [4Fe-4S] cluster as redox relays.
  molecular_function:
    id: GO:0004174
    label: electron-transferring-flavoprotein dehydrogenase activity
  directly_involved_in:
  - id: GO:0022904
    label: respiratory electron transport chain
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:12049629
    supporting_text: >-
      a component of an electron-transfer system that links 10 different mitochondrial
      flavoprotein dehydrogenases to the mitochondrial bc1 complex via electron transfer
      flavoprotein (ETF) and ubiquinone
  - reference_id: PMID:17050691
    supporting_text: >-
      It catalyzes ubiquinone (UQ) reduction by ETF, linking oxidation of fatty acids and some
      amino acids to the mitochondrial respiratory chain.
- description: >-
    Ubiquinone binding at a single hydrophobic site per monomer, positioning the physiological
    electron acceptor for reduction to ubiquinol.
  molecular_function:
    id: GO:0048039
    label: ubiquinone binding
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:14640977
    supporting_text: >-
      consistent with one ubiquinone-binding site per ETF-QO monomer
- description: >-
    FAD cofactor binding; the flavin is a core redox center that shuttles electrons from reduced
    ETF toward ubiquinone.
  molecular_function:
    id: GO:0050660
    label: flavin adenine dinucleotide binding
  supported_by:
  - reference_id: PMID:18037314
    supporting_text: >-
      each contain a single [4Fe-4S](2+,1+) cluster and one equivalent of FAD
- description: >-
    [4Fe-4S] cluster binding; a single iron-sulfur cluster serves as the second redox center of
    ETF-QO.
  molecular_function:
    id: GO:0051539
    label: 4 iron, 4 sulfur cluster binding
  supported_by:
  - reference_id: PMID:18037314
    supporting_text: >-
      Human, porcine, and Rhodobacter sphaeroides ETF-QO each contain a single
      [4Fe-4S](2+,1+) cluster and one equivalent of FAD
- description: >-
    Links fatty-acid beta-oxidation (acyl-CoA dehydrogenase branch) to the respiratory chain by
    accepting the electrons generated during acyl-CoA dehydrogenation via ETF; loss of ETFDH
    blocks this flux and causes multiple acyl-CoA dehydrogenase deficiency.
  molecular_function:
    id: GO:0004174
    label: electron-transferring-flavoprotein dehydrogenase activity
  directly_involved_in:
  - id: GO:0033539
    label: fatty acid beta-oxidation using acyl-CoA dehydrogenase
  locations:
  - id: GO:0005743
    label: mitochondrial inner membrane
  supported_by:
  - reference_id: PMID:17412732
    supporting_text: >-
      All of our patients carried autosomal recessive mutations in ETFDH, suggesting that ETFDH
      deficiency leads to a secondary CoQ10 deficiency.
  - reference_id: PMID:17050691
    supporting_text: >-
      linking oxidation of fatty acids and some amino acids to the mitochondrial respiratory
      chain
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO
    terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
    vocabulary mapping, accompanied by conservative changes to GO terms applied by
    UniProt
  findings: []
- id: GO_REF:0000052
  title: Gene Ontology annotation based on curation of immunofluorescence data
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to
    orthologs using Ensembl Compara
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:12049629
  title: 'Expression of human electron transfer flavoprotein-ubiquinone oxidoreductase
    from a baculovirus vector: kinetic and spectral characterization of the human
    protein.'
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Kinetic and spectral characterization of recombinant human ETF-QO; establishes the core
      EC 1.5.5.1 catalytic activity with ETF and ubiquinone substrates (IDA source).
- id: PMID:14640977
  title: Alternative quinone substrates and inhibitors of human electron-transfer
    flavoprotein-ubiquinone oxidoreductase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Human ETF-QO enzymology; documents a single ubiquinone-binding site per monomer and the
      quinone/oxidoreductase activities (IDA source).
- id: PMID:17050691
  title: Structure of electron transfer flavoprotein-ubiquinone oxidoreductase and
    electron transfer to the mitochondrial ubiquinone pool.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Crystal structure (porcine, basis for human ISS FAD binding); defines FAD, 4Fe-4S and UQ
      sites, inner-membrane monotopic topology, and electron-transfer mechanism.
- id: PMID:17412732
  title: The myopathic form of coenzyme Q10 deficiency is caused by mutations in the
    electron-transferring-flavoprotein dehydrogenase (ETFDH) gene.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Establishes ETFDH mutations as cause of riboflavin-responsive MADD with secondary CoQ10
      deficiency; source of the beta-oxidation IMP annotation.
- id: PMID:18037314
  title: Electron spin relaxation enhancement measurements of interspin distances
    in human, porcine, and Rhodobacter electron transfer flavoprotein-ubiquinone oxidoreductase
    (ETF-QO).
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      EPR study confirming a single [4Fe-4S] cluster and one FAD per human ETF-QO monomer
      (basis for the 4Fe-4S IDA).
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI large-scale yeast two-hybrid reference interactome; the ETFDH IPI hits are generic
      "protein binding" to biologically implausible partners (keratin-associated proteins,
      transcription factors) and are treated as over-annotations.
- id: PMID:34800366
  title: Quantitative high-confidence human mitochondrial proteome and its dynamics
    in cellular context.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      High-throughput mitochondrial proteomics; supports mitochondrial localization at low
      specificity (HTP source).
- id: PMID:8306995
  title: Molecular cloning and expression of a cDNA encoding human electron transfer
    flavoprotein-ubiquinone oxidoreductase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Cloning and heterologous expression of human ETF-QO; demonstrates inner-membrane
      localization, ETF-to-ubiquinone electron transfer, and both FAD and [4Fe-4S] cofactors.
- id: Reactome:R-HSA-169270
  title: ETFDH oxidises ETF (reduced) to ETF, reduces CoQ to CoQH2
  findings: []
- id: Reactome:R-HSA-611105
  title: Respiratory electron transport
  findings: []