ETFDH encodes electron-transfer flavoprotein-ubiquinone oxidoreductase, an iron-sulfur flavoprotein associated with the mitochondrial inner membrane. It oxidizes reduced electron-transfer flavoprotein, the soluble ETFA–ETFB heterodimer, and reduces ubiquinone to ubiquinol. This reaction connects fatty-acid beta-oxidation and amino-acid/choline catabolism to the respiratory ubiquinone pool. Each mature enzyme contains one FAD and one 4Fe–4S cluster as redox cofactors. The canonical 617-residue precursor contains an N-terminal mitochondrial targeting sequence; the alternative 570-residue product lacks canonical residues 12–58. Biallelic pathogenic variants cause multiple acyl-CoA dehydrogenase deficiency, also called glutaric aciduria type II, and can be associated with secondary coenzyme Q10 deficiency.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005743 mitochondrial inner membrane | IBA GO_REF:0000033 | ACCEPT | Summary: ETFDH acts at the mitochondrial inner membrane. Reason: The actual inner-membrane IBD at PTN000065332 is ancestral to human leaf PTN002472061, whose alignment is identical to canonical Q16134. Its human self-WITH reflects the experimental descendant evidence used by PAINT; it is not circular. Human cDNA expression in yeast (PMID:8306995, Results pages 283–284) supports mitochondrial import/processing and active submitochondrial membrane association, including succinate/ubiquinone-dependent reverse electron transfer reported without displayed data. The current human Reactome participant and UniProt location agree. This does not assert the same processing or localization for the internally deleted product. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000065332 SUPPORTS TRANSFER Exact target ancestry and current inner-membrane IBD recovered; human self-WITH is valid experimental grounding. Supporting Evidence: PMID:8306995 Electron-transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) in the inner mitochondrial membrane accepts electrons from electron-transfer flavoprotein PMID:17050691 Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a 4Fe4S flavoprotein located in the inner mitochondrial membrane. Reactome:R-HSA-169270 |
| GO:0004174 electron-transferring-flavoprotein dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: ETFDH catalyses electron transfer from reduced ETF to ubiquinone. Reason: The actual PTHR10617 target leaf PTN002472061 descends from PTN000835262. Its ungapped alignment exactly matches human canonical Q16134 (617 residues); all three positive IBD records on the target path are recovered and no NOT record is present. The current activity IBD donor set matches the captured source, including human Q16134 as valid experimental descendant evidence rather than circular support. Independently, PMID:12049629 assays purified human ETFDH expressed from a full-length cDNA in Sf9 cells: MCAD, ETF and octanoyl-CoA supply electrons for reduction of ubiquinone homologues (Experimental, Enzyme assays; Results, Figure 7 and Table 2). This is ETFDH catalysis, distinct from the ETF alpha/beta carrier. These experiments do not establish activity of the 570-residue splice product. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000835262 SUPPORTS TRANSFER Actual IBD placement and exact target descent are valid. Human self-WITH is expected; the underlying human activity is independently supported by the original enzyme assay. Supporting Evidence: PMID:12049629 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. |
| GO:0022900 electron transport chain | IBA GO_REF:0000033 | MODIFY | Summary: The inherited electron-transport role is supported and can be specified as respiratory electron transport. Reason: Human Q16134 descends from the actual GO:0022900 IBD at PTN000835262, with exact canonical alignment and no target-path NOT. The current donor list matches captured GOA; human self-WITH is valid. Refine to the current child GO:0022904, already carried by row 29: ETFDH catalyses the ETF-to-ubiquinone entry step in human respiratory pathway R-HSA-611105 through reaction 169270 and catalyst 169271. PMID:12049629 directly establishes the human electron-transfer chemistry. This is executed redox work in the respiratory chain, not a claim that ETFDH itself pumps protons, synthesizes ATP, or that a soluble assay reconstitutes complete respiration. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: PANTHER:PTN000835262 SUPPORTS TRANSFER Valid electron-transport IBD and exact target descent; human respiratory context supports a more specific existing descendant, without challenging node placement. Proposed replacements: respiratory electron transport chain Supporting Evidence: PMID:18037314 Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a membrane-bound electron transfer protein that links primary flavoprotein dehydrogenases with the main respiratory chain. Reactome:R-HSA-611105 Reactome:R-HSA-169270 |
| GO:0004174 electron-transferring-flavoprotein dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: The family, reaction and EC mappings specify the experimentally established ETF-to-ubiquinone oxidoreductase. Reason: Actual InterPro IPR040156 matches human Q16134 residues 13–617 and explicitly maps to GO:0004174. Current RHEA:24052 and EC 1.5.5.1 specify ubiquinone plus reduced ETF yielding ubiquinol plus oxidized ETF and a proton, matching the current GO definition. The Rhea equation was recovered through its official SPARQL service after direct page access failed. The human enzyme assay in PMID:12049629 independently establishes this chemistry; no catalytic activity is inferred merely from an FAD-binding fold. The mapping concerns canonical ETFDH and does not establish equivalent processing of Q16134-3. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR040156 SUPPORTS TRANSFER Actual target family match and explicit activity mapping. RHEA:24052 SUPPORTS TRANSFER Official approved reaction equation and GO/EC links match ETF oxidation coupled to ubiquinone reduction. EC:1.5.5.1 SUPPORTS TRANSFER Official ENZYME entry gives the same reaction and explicitly includes human Q16134. Supporting Evidence: PMID:12049629 a component of an electron-transfer system that links 10 different mitochondrial flavoprotein dehydrogenases to the mitochondrial bc1 complex |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | MODIFY | Summary: The target-matching mitochondrial rule is valid but less specific than the established inner-membrane compartment. Reason: Current ARBA00026962 has two target-matching disjuncts: zero-based set 23 requires IPR007859, IPR017896, IPR040156 and Eukaryota, and set 79 requires FunFam 3.30.70.20:FF:000088 and Eukaryota. All conditions are present in the official human Q16134 record, and the rule outputs mitochondrion. Refine to GO:0005743 using the explicit human Reactome 448210 compartment, SL-0168 and the human-protein expression/fractionation results in PMID:8306995. The broad rule is not erroneous; the replacement matches the already-present inner-membrane contexts 16–19. Processing of the 570-residue product remains unestablished. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: ARBA:ARBA00026962 SUPPORTS TRANSFER Actual current disjuncts 23/79 match ETFDH and support mitochondrion; independent target evidence provides inner-membrane specificity. Proposed replacements: mitochondrial inner membrane |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt subcellular-location mapping correctly identifies the mitochondrial inner membrane. Reason: The target UniProt record explicitly carries SL-0168, and the current official location vocabulary maps it to GO:0005743. Human Reactome entity 448210/Q16134 independently has the same compartment for residues 34–617. PMID:8306995 supplies human-protein evidence in yeast, while the native porcine structure in PMID:17050691 supports a monotopic membrane-associated architecture rather than requiring a transmembrane helix. The porcine structural inference is not represented as a human crystal or an assay of Q16134-3. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB-SubCell:SL-0168 SUPPORTS TRANSFER Actual target location and exact vocabulary-to-GO mapping agree with the explicitly modeled human participant. Supporting Evidence: PMID:17050691 ETF-QO is a monotopic integral membrane protein. Reactome:R-HSA-169270 |
| GO:0022900 electron transport chain | IEA GO_REF:0000002 | MODIFY | Summary: The family-wide electron-chain mapping can be refined to the human respiratory context. Reason: Actual IPR040156 matches canonical Q16134 residues 13–617 and maps to GO:0022900. Its family includes bacterial homologs, making the family-wide term appropriately broad. For human ETFDH, the explicit R-HSA-611105→169270→169271→448210 catalyst chain and measured human ETF-to-ubiquinone chemistry support the descendant respiratory electron transport chain, GO:0022904. The refinement does not assign electron transport across a membrane, proton pumping or ETF carrier-subunit function to ETFDH. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR040156 SUPPORTS TRANSFER Actual target family match and broad GO mapping are valid; the human reaction context establishes respiratory specificity. Proposed replacements: respiratory electron transport chain Supporting Evidence: PMID:18037314 a membrane-bound electron transfer protein that links primary flavoprotein dehydrogenases with the main respiratory chain Reactome:R-HSA-611105 Reactome:R-HSA-169270 |
| GO:0051536 iron-sulfur cluster binding | IEA GO_REF:0000002 | MODIFY | Summary: The mapped iron-sulfur-binding domain supports the specific 4Fe–4S cofactor. Reason: Actual IPR007859 matches canonical residues 512–615 and explicitly maps to iron-sulfur cluster binding. Its PF05187 domain and the neighboring IPR017896 match identify the 4Fe–4S-binding region; the family mapping is not rejected. Refine to GO:0051539, already supported by human IDA row 36. PMID:18037314 independently examines human ETFDH expressed in Sf9 cells: Methods 2.1–2.3, Tables 1/3 and Results 3.1–3.3 directly characterize its reduced 4Fe–4S center by EPR. The native porcine structure in PMID:17050691, Results/Figure 3B and Methods, resolves the cluster and cysteine coordination. Porcine residue numbering is not asserted as newly aligned human numbering, and the shorter natural product was not assayed. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR007859 SUPPORTS TRANSFER Actual target domain match and broad Fe-S mapping are valid; independently measured human 4Fe–4S cofactor supports the specific descendant. Proposed replacements: 4 iron, 4 sulfur cluster binding Supporting Evidence: PMID:8306995 The two redox centers in the protein, FAD and a [4Fe4S]+2,+1 cluster, are present in a 64-kDa monomer. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The HuRI association with A7E2Y1-2 is supported but not a defined core function. Reason: The archived HuRI PSI records link human ETFDH ORF 7047 to partner ORF 13817 in screen 6, including the validated two-hybrid record. This supports the reported association, without establishing a specific enzymatic or adaptor role. The assay uses human ORFs in yeast; it is not an endogenous mitochondrial complex assay. The archived partner A0A087X0T3 maps to the MYH7B gene, matching the imported A7E2Y1-2 gene identity, but its 1,982-residue archived sequence differs from the current 176-residue A7E2Y1-2 sequence. The literal imported partner is preserved; current-product equivalence is not asserted. The inherited paper-title quotation is retained as citation context only; it identifies no partner and does not establish the MYH7B pair or equivalence of the archived clone to current A7E2Y1-2. This context occupies the original position by deterministic first-fresh ordering. Supporting Evidence: PMID:32296183 A reference map of the human binary protein interactome. |
| GO:0006979 response to oxidative stress | IEA GO_REF:0000107 | UNDECIDED | Summary: The oxidative-stress transfer has an identified mouse source, but its functional participation remains unresolved. Reason: Both human transfers trace to mouse Etfdh/Q921G7 IDA PMID:17023274. Its verified abstract and limited publisher-indexed Materials/Results/Discussion describe redox proteomics after adriamycin, identifying increased carbonylation of cardiac ETF-QO. The complete operative Methods/Results and Table 1 were not accessible. Oxidative modification establishes that ETFDH is a target of the insult; it does not by itself show that ETFDH executes an oxidative-stress response step. The GO definition concerns a cellular or organismal change in response to oxidative stress, and the available excerpts do not resolve that participation boundary. Retain uncertainty rather than overrule the experimental source from incomplete text or reinterpret it as a human assay. Official mouse UniProt cross-references identify ENSMUSP00000029386.8; the Ensembl lookup and Q921G7 both report 616 residues. The independent Ensembl sequence retrieval failed, so exact present-version sequence identity is not asserted from matching lengths. The inherited GO_REF quotation describes the transfer method, not a newly verified oxidative-stress experiment. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q921G7 UNRESOLVED Actual mouse IDA source PMID:17023274 recovered; only abstract/limited original preview accessible, leaving damage-target versus response-participant interpretation unresolved. ensembl:ENSMUSP00000029386 UNRESOLVED Official cross-reference and mouse translation identity recovered; independent sequence retrieval was unavailable, and the incomplete source experiment is explicitly bounded. Supporting Evidence: GO_REF:0000107 Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl Compara |
| GO:0022904 respiratory electron transport chain | TAS Reactome:R-HSA-611105 | ACCEPT | Summary: ETFDH executes a ubiquinone-reducing step of the human respiratory electron transport chain. Reason: The actual human pathway R-HSA-611105 contains reaction R-HSA-169270. Its catalystActivity 169271 explicitly identifies ETFDH entity 448210/Q16134, not merely a pathway-associated protein. Human ETFDH-dependent reduction of ubiquinone homologues is directly demonstrated in PMID:12049629. This mechanistic role links ETF-supplied reducing equivalents to the ubiquinone pool; it does not make ETFDH a proton pump or establish equivalent function of the untested shorter product. Supporting Evidence: PMID:17050691 It catalyzes ubiquinone (UQ) reduction by ETF, linking oxidation of fatty acids and some amino acids to the mitochondrial respiratory chain. Reactome:R-HSA-611105 Reactome:R-HSA-169270 |
| GO:0004174 electron-transferring-flavoprotein dehydrogenase activity | TAS Reactome:R-HSA-169270 | ACCEPT | Summary: The human Reactome reaction assigns the ETF-to-ubiquinone step to ETFDH itself. Reason: The actual source chain is R-HSA-169270 → catalystActivity 169271 → physicalEntity 448210 → referenceEntity 405899/Q16134. The human participant has its own inner-membrane compartment and modeled mature-chain coordinates 34–617; catalyst activity is GO:0004174. Reduced and oxidized ETF complexes 169268/169267 are separate input/output carriers, so the reaction is not incorrectly attributed to an ETF subunit. PMID:12049629 independently measures human ETFDH-dependent ubiquinone reduction. Supporting Evidence: PMID:12049629 The steady-state kinetic constants of human ETF-QO were determined with ubiquinone homologues, a ubiquinone analogue, and with human wild-type ETF Reactome:R-HSA-169270 |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | MODIFY | Summary: HPA supports mitochondrial localization; independent human evidence supports the inner-membrane refinement. Reason: The actual HPA058140 HEK293 assay and inspected selected image support mitochondrial signal, without resolving the inner membrane. The immunogen is shared by both products (canonical residues 206–299; alternative residues 159–252), so it is not an isoform-specific localization test. The XML also records mitochondrial, nucleoplasmic and cytosolic signal in OE19; these additional signals are not erased. Refine the established mitochondrial location using human Reactome participant 448210/Q16134 and UniProt SL-0168, corroborated by the human cDNA expressed in yeast in PMID:8306995: mitochondrial fractionation, processing and active submitochondrial particles (Results, pages 283–284; Figures 8–10). This is independent inner-membrane support, not greater resolution attributed to HPA microscopy or a claim that both products have identical targeting. Proposed replacements: mitochondrial inner membrane |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | MODIFY | Summary: Refine mitochondrial localization to the mitochondrial inner membrane. Reason: MitoCoP identifies the ETFDH protein group in subtractive, spatial and importomics assays; its carbonate/sonication experiment supports membrane association. Those measurements alone do not distinguish the inner membrane. Independent human ETFDH expressed in yeast is functionally incorporated into that membrane (PMID:8306995, Results p. 284). Protein-group evidence does not resolve the two current products separately. Proposed replacements: mitochondrial inner membrane Supporting Evidence: PMID:34800366 Quantitative high-confidence human mitochondrial proteome and its dynamics |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-169270 | ACCEPT | Summary: The human reaction places its ETFDH catalyst in the inner mitochondrial membrane. Reason: R-HSA-169270 identifies catalyst 169271, whose physicalEntity 448210 is human Q16134 with coordinates 34–617 and its own compartment GO:0005743. The location is therefore traced to the target protein rather than inferred from a pathway title or an ETF carrier location. The canonical processed-chain model does not resolve targeting of the 570-residue alternative product. Supporting Evidence: PMID:17050691 Electron transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) is a 4Fe4S flavoprotein located in the inner mitochondrial membrane. Reactome:R-HSA-169270 |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IMP PMID:17412732 The myopathic form of coenzyme Q10 deficiency is caused by m... | ACCEPT | Summary: ETFDH performs the respiratory redox step coupled to acyl-CoA dehydrogenase beta-oxidation. Reason: The patient study links ETFDH variants to lipid-storage myopathy and abnormal acylcarnitines; it does not isolate enzyme chemistry. Independent human reconstitution transfers electrons from octanoyl-CoA through MCAD and ETF to quinone, establishing ETFDH’s own redox work in the pathway defined by GO:0033539. ETFDH does not perform the acyl-CoA dehydrogenase or CoQ-biosynthesis reactions. Supporting Evidence: PMID:17412732 All of our patients carried autosomal recessive mutations in ETFDH, suggesting that ETFDH deficiency leads to a secondary CoQ10 deficiency. PMID:17050691 linking oxidation of fatty acids and some amino acids to the mitochondrial respiratory chain |
| GO:0004174 electron-transferring-flavoprotein dehydrogenase activity | IDA PMID:14640977 Alternative quinone substrates and inhibitors of human elect... | ACCEPT | Summary: Human ETFDH has directly measured ETF-dependent quinone reductase activity. Reason: PMID:14640977 uses purified human ETFDH, human MCAD and ETF to measure octanoyl-CoA-dependent quinone reduction. The recovered Immediate Publication manuscript provides the enzyme preparation, assay and substrate-kinetic Results. This is ETFDH catalysis, distinct from the soluble ETFA–ETFB carrier. Supporting Evidence: PMID:14640977 a membrane-bound iron-sulphur flavoprotein that participates in an electron-transport pathway between eleven mitochondrial flavoprotein dehydrogenases and the ubiquinone pool |
| GO:0006979 response to oxidative stress | ISS GO_REF:0000024 | UNDECIDED | Summary: The curator-mediated mouse transfer remains unresolved at the source-experiment level. Reason: Both human transfers trace to mouse Etfdh/Q921G7 IDA PMID:17023274. Its verified abstract and limited publisher-indexed Materials/Results/Discussion describe redox proteomics after adriamycin, identifying increased carbonylation of cardiac ETF-QO. The complete operative Methods/Results and Table 1 were not accessible. Oxidative modification establishes that ETFDH is a target of the insult; it does not by itself show that ETFDH executes an oxidative-stress response step. The GO definition concerns a cellular or organismal change in response to oxidative stress, and the available excerpts do not resolve that participation boundary. Retain uncertainty rather than overrule the experimental source from incomplete text or reinterpret it as a human assay. The source is not claimed to be absent, incorrectly identified, or contradicted. The inherited GO_REF quotation describes the transfer method, not a newly verified oxidative-stress experiment. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:Q921G7 UNRESOLVED Positive source annotation and exact original identity are recovered; complete assay evidence is unavailable, so the transfer is not adversely overruled. Supporting Evidence: GO_REF:0000024 Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity |
| GO:0016491 oxidoreductase activity | IDA PMID:14640977 Alternative quinone substrates and inhibitors of human elect... | MODIFY | Summary: Refine broad oxidoreductase activity to ETF-dependent ubiquinone reduction. Reason: The recovered 2004 author manuscript measures the human ETFDH reaction with ETF and quinone substrates. GO:0004174 provides the demonstrated donor/acceptor specificity within oxidoreductase activity. The alternate-quinone experiments do not turn ETFDH into a general NAD(P)H quinone reductase. Proposed replacements: electron-transferring-flavoprotein dehydrogenase activity Supporting Evidence: PMID:14640977 The steady-state kinetic constants of human ETF-QO were determined with ubiquinone homologues and analogues |
| GO:0048038 quinone binding | IDA PMID:14640977 Alternative quinone substrates and inhibitors of human elect... | ACCEPT | Summary: Quinone binding is supported across a tested substrate and inhibitor class. Reason: The human-enzyme study tests ubiquinone analogues, menadione and duroquinone, and measures binding of the inhibitor DBMIB by fluorescence titration. Thus the broader quinone-binding term has positive support beyond ubiquinone alone; it is not merely an uninformative parent that should be narrowed away. These in-vitro analogues do not establish additional physiological electron acceptors. Supporting Evidence: PMID:14640977 consistent with one ubiquinone-binding site per ETF-QO monomer |
| GO:0048039 ubiquinone binding | IDA PMID:14640977 Alternative quinone substrates and inhibitors of human elect... | ACCEPT | Summary: Human ETFDH binds ubiquinone substrates for reduction. Reason: The human-enzyme substrate-kinetic experiments directly use ubiquinone homologues and examine the contribution of their side chains. This supports ubiquinone binding as part of the enzyme’s established reaction. The binding claim is separate from assigning physiological roles to every tested synthetic analogue. Supporting Evidence: PMID:14640977 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 PMID:17050691 The UQ-binding pocket consists mainly of hydrophobic residues |
| GO:0051539 4 iron, 4 sulfur cluster binding | IDA PMID:18037314 Electron spin relaxation enhancement measurements of intersp... | ACCEPT | Summary: Human ETFDH contains a bound 4Fe–4S redox cluster. Reason: PMID:18037314 prepares human ETFDH in Sf9 cells and measures its iron–sulfur EPR signal and relaxation properties alongside separate porcine and bacterial preparations (Methods sections 2.1–2.4; human entries in Tables 1 and 3). This is target-specific cofactor evidence, not a structural claim based only on another species. Supporting Evidence: PMID:18037314 Human, porcine, and Rhodobacter sphaeroides ETF-QO each contain a single [4Fe-4S](2+,1+) cluster and one equivalent of FAD |
| GO:0004174 electron-transferring-flavoprotein dehydrogenase activity | IDA PMID:12049629 Expression of human electron transfer flavoprotein-ubiquinon... | ACCEPT | Summary: Human ETFDH catalyzes electron transfer from reduced ETF to ubiquinone. Reason: The recombinant human enzyme purified from Sf9 cells reduces quinone in the coupled MCAD–ETF assay (PMID:12049629, Methods pp. 660–661 and Results pp. 662–664). This is the reaction defined by GO:0004174. The experiment tests the processed long precursor; it does not establish equivalent activity or processing of the 570-residue product. Supporting Evidence: PMID:12049629 The steady-state kinetic constants of human ETF-QO were determined with ubiquinone homologues, a ubiquinone analogue, and with human wild-type ETF |
| GO:0004174 electron-transferring-flavoprotein dehydrogenase activity | IDA PMID:8306995 Molecular cloning and expression of a cDNA encoding human el... | ACCEPT | Summary: The expressed human enzyme catalyzes ETF-dependent ubiquinone reduction. Reason: The actual 1994 Methods (p. 280) and Results (p. 284) assay human ETFDH expressed in yeast using detergent-extracted submitochondrial particles, MCAD, ETF and Q1. The empty-vector cells lacked detectable activity. Later purified human enzyme experiments independently establish the same reaction. Supporting Evidence: PMID:8306995 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 |
| GO:0005743 mitochondrial inner membrane | IDA PMID:8306995 Molecular cloning and expression of a cDNA encoding human el... | ACCEPT | Summary: Human ETFDH is associated with the mitochondrial inner membrane. Reason: PMID:8306995 reports mitochondrial fractionation of the expressed human protein (Figure 8), active submitochondrial extracts, and succinate/ubiquinone-dependent reduction of ETF (Results p. 284; the latter spectral observation is reported as data not shown). This supports functional inner-membrane incorporation in the yeast host. It does not imply a transmembrane helix or equivalent targeting of the shorter product. Supporting Evidence: PMID:8306995 Electron-transfer flavoprotein-ubiquinone oxidoreductase (ETF-QO) in the inner mitochondrial membrane accepts electrons from electron-transfer flavoprotein |
| GO:0009055 electron transfer activity | IDA PMID:12049629 Expression of human electron transfer flavoprotein-ubiquinon... | MODIFY | Summary: Use the specific ETF-to-ubiquinone oxidoreductase activity. Reason: The broad electron-transfer activity is correct, but the human enzyme experiment directly identifies ETF-dependent quinone reduction. Current GO:0004174 is a descendant of GO:0009055 and captures the measured catalytic reaction without confusing ETFDH with the soluble ETF carrier. Proposed replacements: electron-transferring-flavoprotein dehydrogenase activity Supporting Evidence: PMID:12049629 a component of an electron-transfer system that links 10 different mitochondrial flavoprotein dehydrogenases to the mitochondrial bc1 complex |
| GO:0009055 electron transfer activity | IDA PMID:8306995 Molecular cloning and expression of a cDNA encoding human el... | MODIFY | Summary: Refine the electron-transfer annotation to the measured quinone reductase activity. Reason: Human ETFDH expressed in yeast supports MCAD/ETF-dependent Q1 reduction in submitochondrial extracts (PMID:8306995, Methods p. 280; Results p. 284). GO:0004174 specifies this reaction within electron-transfer activity; purified human enzyme independently confirms it. Proposed replacements: electron-transferring-flavoprotein dehydrogenase activity Supporting Evidence: PMID:8306995 The detergent-solubilized protein transfers electrons from ETF to the ubiquinone homolog, Q1 |
| GO:0022900 electron transport chain | IDA PMID:12049629 Expression of human electron transfer flavoprotein-ubiquinon... | MODIFY | Summary: Specify participation in the respiratory electron transport chain. Reason: The human enzyme carries out the ETF-to-quinone redox step (PMID:12049629, coupled assay and substrate-reduction Results), rather than merely being necessary for the pathway. GO:0022904 is the respiratory descendant of GO:0022900, and current GO:0004174 is linked to it by part_of. ETFDH itself is not asserted to pump protons; the assay does not reconstitute complete respiratory flux. Proposed replacements: respiratory electron transport chain Supporting Evidence: PMID:12049629 links 10 different mitochondrial flavoprotein dehydrogenases to the mitochondrial bc1 complex via electron transfer flavoprotein (ETF) and ubiquinone |
| GO:0022900 electron transport chain | IDA PMID:8306995 Molecular cloning and expression of a cDNA encoding human el... | MODIFY | Summary: Specify respiratory electron transport rather than an unspecified electron transport chain. Reason: The 1994 human-expression study measures ETF-dependent quinone reduction and reports reverse transfer from succinate through endogenous ubiquinone in yeast submitochondrial particles (Results p. 284). Together with the independently purified human enzyme, this identifies the respiratory redox step. It does not demonstrate proton pumping by ETFDH. Proposed replacements: respiratory electron transport chain |
| GO:0031966 mitochondrial membrane | IDA PMID:12049629 Expression of human electron transfer flavoprotein-ubiquinon... | MODIFY | Summary: Specify the mitochondrial inner membrane. Reason: The 2002 human enzyme study recovers a processed, detergent-solubilized enzyme but explicitly treats its exact membrane localization as an inference. Independent human-expression fractionation and submitochondrial electron transfer in PMID:8306995 support the more precise inner-membrane location. Neither experiment establishes the shorter product’s targeting. Proposed replacements: mitochondrial inner membrane |
| GO:0050660 flavin adenine dinucleotide binding | ISS PMID:17050691 Structure of electron transfer flavoprotein-ubiquinone oxido... | ACCEPT | Summary: FAD is a bound catalytic cofactor of ETFDH. Reason: The source structure is native porcine ETFDH (P55931), with resolved FAD contacts; it is not a human crystal structure. Human recombinant ETFDH independently exhibits the expected flavin spectrum and FAD semiquinone signal. The conserved-cofactor inference is therefore supported without transferring porcine residue numbering or assuming the shorter human product was assayed. Supporting Evidence: PMID:17050691 Three functional regions bind FAD, the 4Fe4S cluster, and UQ PMID:18037314 each contain a single [4Fe-4S](2+,1+) cluster and one equivalent of FAD |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The HuRI association with O15499 is supported but not a defined core function. Reason: The archived HuRI PSI records link human ETFDH ORF 7047 to partner ORF 100080813 in screen 5, including the validated two-hybrid record. This supports the reported association, without establishing a specific enzymatic or adaptor role. The assay uses human ORFs in yeast; it is not an endogenous mitochondrial complex assay. Exact equivalence of the archived ORF sequence to every current product was not established. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The HuRI association with P32242 is supported but not a defined core function. Reason: The archived HuRI PSI records link human ETFDH ORF 7047 to partner ORF 5285 in screen 6, including the validated two-hybrid record. This supports the reported association, without establishing a specific enzymatic or adaptor role. The assay uses human ORFs in yeast; it is not an endogenous mitochondrial complex assay. Exact equivalence of the archived ORF sequence to every current product was not established. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The HuRI association with Q52LG2 is supported but not a defined core function. Reason: The archived HuRI PSI records link human ETFDH ORF 7047 to partner ORF 71745 in screen 4, including the validated two-hybrid record. This supports the reported association, without establishing a specific enzymatic or adaptor role. The assay uses human ORFs in yeast; it is not an endogenous mitochondrial complex assay. Exact equivalence of the archived ORF sequence to every current product was not established. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The HuRI association with Q86WT6-2 is supported but not a defined core function. Reason: The archived HuRI PSI records link human ETFDH ORF 7047 to partner ORF 9383 in screen 2, including the validated two-hybrid record. This supports the reported association, without establishing a specific enzymatic or adaptor role. The assay uses human ORFs in yeast; it is not an endogenous mitochondrial complex assay. Exact equivalence of the archived ORF sequence to every current product was not established. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The HuRI association with Q8IUC1 is supported but not a defined core function. Reason: The archived HuRI PSI records link human ETFDH ORF 7047 to partner ORF 54869 in screen 5, including the validated two-hybrid record. This supports the reported association, without establishing a specific enzymatic or adaptor role. The assay uses human ORFs in yeast; it is not an endogenous mitochondrial complex assay. Exact equivalence of the archived ORF sequence to every current product was not established. Supporting Evidence: |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | KEEP AS NON CORE | Summary: The HuRI association with Q9P0T4 is supported but not a defined core function. Reason: The archived HuRI PSI records link human ETFDH ORF 7047 to partner ORF 6880 in screen 6, including the validated two-hybrid record. This supports the reported association, without establishing a specific enzymatic or adaptor role. The assay uses human ORFs in yeast; it is not an endogenous mitochondrial complex assay. Exact equivalence of the archived ORF sequence to every current product was not established. Supporting Evidence: |
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Download this section (compressed HTML)Q: How is the 570-residue Q16134-3 product imported and processed, and does the resulting protein retain FAD/4Fe–4S binding and ETF-dependent quinone-reduction activity? The deletion of canonical residues 12–58 overlaps the targeting region and beginning of the mature chain.
Q: Does oxidative modification of ETFDH alter its catalytic function or contribute to an adaptive oxidative-stress response, and what experiment distinguishes an executed response role from ETFDH simply being a target of oxidation?
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