ACADVL encodes very-long-chain acyl-CoA dehydrogenase (VLCAD), a mitochondrial FAD-dependent enzyme (EC 1.3.8.9 and EC 1.3.8.8) that catalyzes the initial dehydrogenation step of fatty acid beta-oxidation. It converts long-chain and very-long-chain acyl-CoA thioesters to trans-2-enoyl-CoAs, transferring reducing equivalents to electron-transfer flavoprotein. Its substrate range extends approximately from C12 to C24, with strong activity toward long-chain substrates such as palmitoyl-CoA. The mature enzyme is a homodimer associated peripherally with the matrix face of the inner mitochondrial membrane. This membrane-associated homodimer differs in organization from the soluble matrix tetramers SCAD, MCAD and LCAD. Membrane association contributes to dimer assembly, while bound FAD supports catalysis and protein stability. VLCAD-dependent fatty acid oxidation supplies energy particularly in heart and skeletal muscle. Loss of activity causes VLCAD deficiency, which can present with cardiomyopathy, hypoketotic hypoglycemia, or exercise-associated myopathy and rhabdomyolysis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0017099 very-long-chain fatty acyl-CoA dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT infers very-long-chain acyl-CoA dehydrogenase activity from ancestral node PTN000856877. Reason: The cached PAINT IBD includes experimental human VLCAD evidence, which legitimately grounds the ancestral assertion. UniProt records C24-CoA oxidation with PMID:21237683; the human structure supports a cavity accommodating long acyl chains. GO:0017099 covers the very-long-chain range and is a sibling of the long-chain activity term, not its parent. The palmitoyl-CoA assay in PMID:9461620 alone does not demonstrate the entire range. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000856877 SUPPORTS TRANSFER PTHR43884-paint.tsv contains the GO:0017099 IBD at this node, supported by rat and human experimental descendants. Human occurrence among descendant evidence is not circularity; no target-specific loss is evident. Supporting Evidence: PMID:9461620 Replacing Glu-422 with glutamine (E422Q) caused a loss of enzyme activity file:human/ACADVL/ACADVL-uniprot.txt Reaction=tetracosanoyl-CoA + oxidized [electron-transfer flavoprotein] CC + H(+) = (2E)-tetracosenoyl-CoA + reduced [electron-transfer CC flavoprotein]; Xref=Rhea:RHEA:47232, Rhea:RHEA-COMP:10685, Rhea:RHEA- CC COMP:10686, ChEBI:CHEBI:15378, ChEBI:CHEBI:57692, ChEBI:CHEBI:58307, CC ChEBI:CHEBI:65052, ChEBI:CHEBI:74693; CC Evidence={ECO:0000269|PubMed:21237683}; |
| GO:0000062 fatty-acyl-CoA binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetically inferred binding of the acyl-CoA substrate. VLCAD necessarily binds fatty-acyl-CoA substrates to perform dehydrogenation; the formation of a charge-transfer complex between VLCAD and palmitoyl-CoA has been observed (PMID:9461620). This is a correct but ancillary (substrate-binding) annotation. Reason: Substrate binding is a prerequisite of the catalytic activity rather than a separate core function; the catalytic dehydrogenase terms better represent VLCAD's role. The binding itself is supported by the observed VLCAD-palmitoyl-CoA charge-transfer complex (PMID:9461620). Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000856877 SUPPORTS TRANSFER The cached node carries the GO:0000062 IBD with rat experimental support. Human palmitoyl-CoA binding independently agrees; binding is a catalytic property rather than a separate physiological function. Supporting Evidence: PMID:9461620 preventing the formation of a charge transfer complex between VLCAD and palmitoyl-CoA |
| GO:0003995 acyl-CoA dehydrogenase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro IPR006089 correctly identifies the acyl-CoA dehydrogenase catalytic family. Reason: The family-level function is core but underspecified. Human long-chain substrate assays support refinement to long-chain fatty acyl-CoA dehydrogenase activity. The existing separate very-long-chain annotation captures the additional substrate range. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR006089 SUPPORTS TRANSFER The ACAD active-site family supports the parent reaction; the proposed refinement uses independent human substrate evidence, not a claim that every family member has VLCAD specificity. Proposed replacements: long-chain fatty acyl-CoA dehydrogenase activity Supporting Evidence: PMID:9461620 preventing the formation of a charge transfer complex between VLCAD and palmitoyl-CoA PMID:7668252 raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts |
| GO:0004466 long-chain fatty acyl-CoA dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation from ARBA/Rhea mapping based on EC 1.3.8.8. VLCAD has well-documented long-chain acyl-CoA dehydrogenase activity (classically assayed with palmitoyl-CoA, C16) in addition to its very-long-chain activity, so this is a valid and biologically accurate term. Reason: VLCAD catalyzes dehydrogenation of long-chain acyl-CoA substrates (EC 1.3.8.8), demonstrated directly for the human enzyme (PMID:7668252 measures palmitic-acid beta-oxidation flux driven by VLCAD activity). Consistent with the IDA and TAS annotations to this same term. Supporting Evidence: PMID:7668252 raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation from UniProt subcellular-location mapping. VLCAD is experimentally localized as a peripheral protein of the mitochondrial inner membrane, distinguishing it from the soluble matrix ACADs. This is the core cellular localization. Reason: Inner-membrane association of VLCAD is directly demonstrated and is required for dimer assembly (PMID:9599005); UniProt lists "Mitochondrion inner membrane; Peripheral membrane protein". Supporting Evidence: PMID:9599005 association of VLCAD protein with mitochondrial inner membrane is necessary for dimer assembly and formation of mature VLCAD |
| GO:0006635 fatty acid beta-oxidation | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA electronic annotation placing VLCAD in fatty acid beta-oxidation. VLCAD catalyzes the first step of this pathway, so the annotation is correct and represents a core biological process. Reason: VLCAD catalyzes the initial step of the mitochondrial beta-oxidation spiral (PMID:9461620); loss of VLCAD impairs long-chain fatty acid beta-oxidation (PMID:7668252). Consistent with the IDA/IMP annotations to beta-oxidation. Supporting Evidence: PMID:9461620 Very long-chain acyl-CoA dehydrogenase (VLCAD) is one of four flavoproteins which catalyze the initial step of the mitochondrial beta-oxidation spiral |
| GO:0016627 oxidoreductase activity, acting on the CH-CH group of donors | IEA GO_REF:0000002 | MODIFY | Summary: InterPro domains correctly identify CH-CH oxidoreductase chemistry. Reason: VLCAD catalyzes acyl-CoA alpha,beta-dehydrogenation. Refine this broad catalytic term to the long-chain acyl-CoA activity directly supported by human palmitoyl-CoA assays; no loss of the broader chemistry is implied. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: InterPro:IPR006091 SUPPORTS TRANSFER The GOA also cites IPR009075, IPR009100, IPR013786, IPR036250, IPR037069 and IPR046373. These ACAD-domain mappings establish the enzyme class; human assays supply the narrower substrate specificity. Proposed replacements: long-chain fatty acyl-CoA dehydrogenase activity Supporting Evidence: PMID:9461620 preventing the formation of a charge transfer complex between VLCAD and palmitoyl-CoA |
| GO:0017099 very-long-chain fatty acyl-CoA dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: ARBA/Rhea annotation captures VLCAD activity on very-long-chain acyl-CoA substrates. Reason: The source includes ARBA00096922 and the curated C24-CoA reaction RHEA:47232 in UniProt, supported there by PMID:21237683. This is distinct from the C16 long-chain activity and is compatible with the substrate cavity characterized in PMID:18227065. The enzyme name and the older palmitoyl-CoA experiment are not alone proof of the C24 reaction. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:47232 SUPPORTS TRANSFER The machine-fetched UniProt record assigns tetracosanoyl-CoA dehydrogenation to human VLCAD with experimental evidence from PMID:21237683. The reaction falls in the current GO very-long-chain range; its kinetics were not re-extracted from the figure. Supporting Evidence: PMID:18227065 permitting substrate acyl chain lengths as long as 24 carbons to bind file:human/ACADVL/ACADVL-uniprot.txt Reaction=tetracosanoyl-CoA + oxidized [electron-transfer flavoprotein] CC + H(+) = (2E)-tetracosenoyl-CoA + reduced [electron-transfer CC flavoprotein]; Xref=Rhea:RHEA:47232, Rhea:RHEA-COMP:10685, Rhea:RHEA- CC COMP:10686, ChEBI:CHEBI:15378, ChEBI:CHEBI:57692, ChEBI:CHEBI:58307, CC ChEBI:CHEBI:65052, ChEBI:CHEBI:74693; CC Evidence={ECO:0000269|PubMed:21237683}; |
| GO:0031966 mitochondrial membrane | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA places VLCAD at a mitochondrial membrane. Reason: The membrane-level assertion correctly describes its core location. Preserve the mapping at its original resolution; separate inner-membrane evidence supplies the precise topology. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026364 SUPPORTS TRANSFER The GOA rule produces mitochondrial membrane. Targeted human import/assembly data support this location without requiring an inferred compartment upgrade. Supporting Evidence: PMID:9599005 association of VLCAD protein with mitochondrial inner membrane is necessary for dimer assembly and formation of mature VLCAD |
| GO:0050660 flavin adenine dinucleotide binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro-based annotation for FAD binding. VLCAD is an FAD-containing flavoprotein; FAD is the obligate redox cofactor and FAD-binding residues (e.g. Phe-418) have been mapped. The term is correct and corresponds to a core feature of the enzyme. Reason: FAD is the essential cofactor of VLCAD (UniProt COFACTOR: FAD; PMID:18227065, PMID:9461620); FAD-binding mutants lose bound FAD and activity (PMID:9461620). Consistent with the IDA annotation to this term. Supporting Evidence: PMID:9461620 These data suggest that Phe-418 is involved in the binding and subsequent reduction of FAD |
| GO:0070991 medium-chain fatty acyl-CoA dehydrogenase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Rhea captures activity on medium-chain substrates at the lower end of VLCAD substrate specificity. Reason: GO:0070991 defines a substrate range, not exclusive membership in the protein named MCAD. The source includes dodecanoyl-CoA reaction RHEA:47296 and additional unsaturated medium-chain reactions. UniProt records these activities, and PMID:18227065 describes little activity below C12 rather than none. Retain this secondary substrate activity; it does not establish that VLCAD replaces MCAD as the principal medium-chain enzyme. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: RHEA:47296 SUPPORTS TRANSFER UniProt assigns dodecanoyl-CoA dehydrogenation with PMID:21237683 and an additional legacy substrate-study citation; GO:0070991 includes this chain length. Other mapped reactions are RHEA:82951, RHEA:84471, RHEA:84475, RHEA:84607 and RHEA:84611. Their individual kinetic panels were not all re-extracted. Supporting Evidence: PMID:18227065 VLCAD shows little activity for substrates with chain lengths of less than 12 carbons |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: HuRI supplies an ACADVL-TAF1B interaction underlying a generic protein-binding annotation. Reason: Remove the uninformative molecular-function term rather than treating the interaction as disproven. GOA identifies TAF1B/Q53T94, and UniProt records three experiments, not a single observation. The full HuRI methods describe repeated screening and validation; different annotated compartments do not establish a false positive. No specific binding function is established for this pair by the material inspected. Supporting Evidence: PMID:32296183 a human 'all-by-all' reference interactome map of human binary protein interactions |
| GO:0001659 temperature homeostasis | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: Temperature-homeostasis annotation transferred from mouse Acadvl/VLCAD (P50544). Reason: P50544 is mouse Acadvl (MGI:895149). MGI records a mouse IMP temperature-homeostasis annotation, and PMID:15639194 explicitly reports cold intolerance in VLCAD-deficient mice. Retain this organismal consequence of fatty acid oxidation as non-core; it does not make VLCAD a temperature sensor or directly demonstrate the phenotype in humans. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P50544 SUPPORTS TRANSFER NCBI Gene11370 links P50544 to mouse Acadvl (MGI:895149). MGI lists GO:0001659 IMP/J:95532. PMID:15639194 independently verifies the VLCAD-deficient cold phenotype; the exact J-number-to-PMID link was not recovered. Supporting Evidence: PMID:15639194 neither mouse model can maintain core body temperature when exposed to cold |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IEA GO_REF:0000107 | ACCEPT | Summary: Mouse Acadvl/VLCAD supports conserved participation in dehydrogenase-dependent fatty acid beta-oxidation. Reason: P50544 is mouse Acadvl, whose conserved catalytic activity initiates mitochondrial fatty acid beta-oxidation. Human mutant and rescue experiments independently support the same catalytic contribution, so both the biological assertion and the orthology transfer are sound. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P50544 SUPPORTS TRANSFER NCBI Gene11370 identifies the donor as Acadvl. MGI records the dehydrogenase-dependent beta-oxidation process on this gene; direct human enzyme and flux evidence agree. Supporting Evidence: PMID:9461620 the initial step of the mitochondrial beta-oxidation spiral PMID:7668252 raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts |
| GO:0045717 negative regulation of fatty acid biosynthetic process | IEA GO_REF:0000107 | UNDECIDED | Summary: A regulatory process is transferred from mouse Acadvl/VLCAD (P50544). Reason: P50544 is mouse Acadvl (MGI:895149). MGI lists this term with IMP/J:95532, but the original gene-specific result has not been verified in full. The available abstract foregrounds elevated lipogenic transcripts in LCAD-deficient mice; the VLCAD-specific supporting experiment and conservation of this regulatory effect remain unresolved. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P50544 UNRESOLVED Donor identity is verified by NCBI Gene11370/MGI895149. The MGI graph lists GO:0045717 with IMP/J:95532. PMID:15639194 is relevant and cached abstract-only, but the exact J-number linkage and full supporting results remain unresolved. |
| GO:0046322 negative regulation of fatty acid oxidation | IEA GO_REF:0000107 | UNDECIDED | Summary: A regulatory process is transferred from mouse Acadvl/VLCAD (P50544). Reason: P50544 is mouse Acadvl (MGI:895149). MGI lists this term with IMP/J:95532, but the original gene-specific result has not been verified in full. The available abstract reports elevated hepatic oxidation-gene expression in VLCAD-deficient mice. Compensatory transcription is not itself an oxidation-flux measurement. Direct catalytic participation and indirect negative feedback can coexist, so the regulatory sign is not intrinsically contradictory. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P50544 UNRESOLVED Donor identity is verified by NCBI Gene11370/MGI895149. The MGI graph lists GO:0046322 with IMP/J:95532. PMID:15639194 is relevant and cached abstract-only, but the exact J-number linkage and full supporting results remain unresolved. |
| GO:0090181 regulation of cholesterol metabolic process | IEA GO_REF:0000107 | UNDECIDED | Summary: A regulatory process is transferred from mouse Acadvl/VLCAD (P50544). Reason: P50544 is mouse Acadvl (MGI:895149). MGI lists this term with IMP/J:95532, but the original gene-specific result has not been verified in full. The available abstract does not resolve the VLCAD-specific cholesterol measurements or regulatory mechanism. Other lipid phenotypes cannot substitute for the supporting experiment. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P50544 UNRESOLVED Donor identity is verified by NCBI Gene11370/MGI895149. The MGI graph lists GO:0090181 with IMP/J:95532. PMID:15639194 is relevant and cached abstract-only, but the exact J-number linkage and full supporting results remain unresolved. |
| GO:0005739 mitochondrion | IDA GO_REF:0000052 | ACCEPT | Summary: HPA immunofluorescence supports mitochondrial localization. Reason: The live HPA page reports mitochondria as supported, with antibodies HPA019006 and HPA020595. Preserve this organelle-level observation; microscopy does not resolve the matrix-facing inner-membrane topology. Supporting Evidence: PMID:9599005 association of VLCAD protein with mitochondrial inner membrane is necessary for dimer assembly and formation of mature VLCAD |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: The MitoCoP HTP row supports mitochondrion as the core organelle. Reason: The full MitoCoP main study was inspected, while its ACADVL-specific supplementary entry was not independently re-extracted. Defer to the curated protein assignment, corroborated by targeted human localization evidence. Do not upgrade the source to a submitochondrial compartment. Supporting Evidence: PMID:9599005 association of VLCAD protein with mitochondrial inner membrane is necessary for dimer assembly and formation of mature VLCAD |
| GO:0003995 acyl-CoA dehydrogenase activity | IMP PMID:9599005 Very-long-chain acyl-CoA dehydrogenase subunit assembles to ... | MODIFY | Summary: The assembly-mutant study supports VLCAD acyl-CoA dehydrogenase function. Reason: The S583W mutant connects defective membrane association and dimer assembly to VLCAD deficiency. Refine the broad enzyme-family term to long-chain fatty acyl-CoA dehydrogenase activity, using the independent human palmitoyl-CoA and flux experiments for substrate specificity rather than attributing new kinetics to the assembly paper. Proposed replacements: long-chain fatty acyl-CoA dehydrogenase activity Supporting Evidence: PMID:9599005 association of VLCAD protein with mitochondrial inner membrane is necessary for dimer assembly and formation of mature VLCAD PMID:7668252 raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IMP PMID:9599005 Very-long-chain acyl-CoA dehydrogenase subunit assembles to ... | ACCEPT | Summary: IMP annotation linking the VLCAD assembly/function defect (S583W) to its role in fatty acid beta-oxidation. This is a core biological process and is supported by patient-derived mutation data demonstrating that defective VLCAD impairs the pathway. Reason: VLCAD is required for the acyl-CoA dehydrogenase step of beta-oxidation; the disease-causing monomeric mutant connects loss of VLCAD function to the pathway (PMID:9599005), corroborated by flux restoration in PMID:7668252. Supporting Evidence: PMID:9599005 a VLCAD monomeric mutant S583W, a novel mutation identified from a patient with VLCAD deficiency |
| GO:0042802 identical protein binding | IDA PMID:9599005 Very-long-chain acyl-CoA dehydrogenase subunit assembles to ... | KEEP AS NON CORE | Summary: IDA annotation capturing VLCAD homodimerization. PMID:9599005 directly demonstrated that mature VLCAD is a homodimer and characterized the membrane-dependent dimer-assembly process. Unlike generic "protein binding", this term is informative about the functional quaternary structure, though "identical protein binding" describes self-association rather than a catalytic molecular function. Reason: Homodimerization is a genuine structural requirement of mature VLCAD, supported by PMID:9599005 and the human crystal structure. Keep this self-association property as non-core rather than presenting it as an independent physiological binding function. This does not dispute the experimental interaction. Supporting Evidence: PMID:9599005 Mature VLCAD is a homodimer of a 70-kDa protein associated with the mitochondrial membrane |
| GO:0003995 acyl-CoA dehydrogenase activity | IMP PMID:9461620 Catalytic and FAD-binding residues of mitochondrial very lon... | MODIFY | Summary: Catalytic and FAD-binding mutagenesis directly establishes VLCAD dehydrogenase chemistry. Reason: The accessible study reports palmitoyl-CoA charge-transfer and maximal-velocity effects. Refine the broad acyl-CoA dehydrogenase term to the long-chain activity matching that substrate, without treating C16 as proof of the distinct very-long-chain GO range. Proposed replacements: long-chain fatty acyl-CoA dehydrogenase activity Supporting Evidence: PMID:9461620 Replacing Glu-422 with glutamine (E422Q) caused a loss of enzyme activity PMID:9461620 preventing the formation of a charge transfer complex between VLCAD and palmitoyl-CoA |
| GO:0005739 mitochondrion | IDA PMID:9461620 Catalytic and FAD-binding residues of mitochondrial very lon... | ACCEPT | Summary: The mitochondrial IDA assertion is consistent with targeted VLCAD characterization. Reason: Retain the original organelle resolution and curator assignment. The cached PMID:9461620 abstract foregrounds catalysis rather than a detailed localization protocol; independent import and assembly evidence in PMID:9599005 confirms mitochondria. It does not justify rewriting this source row to matrix or inner membrane. Supporting Evidence: PMID:9599005 association of VLCAD protein with mitochondrial inner membrane is necessary for dimer assembly and formation of mature VLCAD |
| GO:0017099 very-long-chain fatty acyl-CoA dehydrogenase activity | IDA PMID:9461620 Catalytic and FAD-binding residues of mitochondrial very lon... | ACCEPT | Summary: The curator assigns very-long-chain acyl-CoA dehydrogenase activity to the recombinant VLCAD study. Reason: Retain the experimental assertion with curator deference and independent curated C24-CoA evidence in UniProt. The accessible PMID:9461620 abstract specifically describes palmitoyl-CoA assays, so it cannot alone verify the modern GO very-long-chain threshold. This limitation is not grounds to reject a known VLCAD activity or infer that the full paper lacked other assays. Supporting Evidence: PMID:9461620 Replacing Glu-422 with glutamine (E422Q) caused a loss of enzyme activity file:human/ACADVL/ACADVL-uniprot.txt Reaction=tetracosanoyl-CoA + oxidized [electron-transfer flavoprotein] CC + H(+) = (2E)-tetracosenoyl-CoA + reduced [electron-transfer CC flavoprotein]; Xref=Rhea:RHEA:47232, Rhea:RHEA-COMP:10685, Rhea:RHEA- CC COMP:10686, ChEBI:CHEBI:15378, ChEBI:CHEBI:57692, ChEBI:CHEBI:58307, CC ChEBI:CHEBI:65052, ChEBI:CHEBI:74693; CC Evidence={ECO:0000269|PubMed:21237683}; |
| GO:0042802 identical protein binding | IDA PMID:9461620 Catalytic and FAD-binding residues of mitochondrial very lon... | KEEP AS NON CORE | Summary: IDA annotation reflecting VLCAD homodimerization, characterized as part of the recombinant enzyme studies (the protein is a homodimer; PMID:9461620, UniProt SUBUNIT). Informative about quaternary structure rather than a generic interaction. Reason: Homodimerization is a genuine structural requirement of mature VLCAD, supported by PMID:9599005 and the human crystal structure. Keep this self-association property as non-core rather than presenting it as an independent physiological binding function. This does not dispute the experimental interaction. Supporting Evidence: PMID:9599005 Mature VLCAD is a homodimer of a 70-kDa protein associated with the mitochondrial membrane |
| GO:0050660 flavin adenine dinucleotide binding | IDA PMID:9461620 Catalytic and FAD-binding residues of mitochondrial very lon... | ACCEPT | Summary: IDA annotation for FAD binding, directly supported by the demonstration that FAD-binding mutants (F418L/F418V) contain no bound FAD and that Phe-418 is required for FAD binding and reduction (PMID:9461620). FAD is the obligate cofactor. Reason: Direct experimental evidence that VLCAD binds FAD as its redox cofactor and that loss of FAD destabilizes the protein (PMID:9461620). Core molecular function feature. Supporting Evidence: PMID:9461620 F418L and F418V contained no bound FAD when expressed at extremely high levels in the baculovirus expression system |
| GO:0004466 long-chain fatty acyl-CoA dehydrogenase activity | IDA PMID:7668252 Cloning of human very-long-chain acyl-coenzyme A dehydrogena... | ACCEPT | Summary: IDA annotation from the original cloning/characterization paper, which demonstrated that VLCAD drives long-chain (palmitic acid) beta-oxidation flux: restoring VLCAD activity in patient fibroblasts restored palmitate beta-oxidation (PMID:7668252). VLCAD's long-chain acyl-CoA dehydrogenase activity is a core function. Reason: Direct functional evidence that VLCAD provides long-chain acyl-CoA dehydrogenase activity (palmitoyl-CoA, C16) in human cells (PMID:7668252). Supporting Evidence: PMID:7668252 raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts |
| GO:0031966 mitochondrial membrane | IDA PMID:16020546 Human acyl-CoA dehydrogenase-9 plays a novel role in the mit... | ACCEPT | Summary: Human muscle fractionation in the full ACAD9 paper directly includes VLCAD as a mitochondrial-membrane control. Reason: Figure 5 and its Results identify VLCAD in the membrane fraction of human muscle mitochondria using anti-VLCAD immunoblotting, alongside ACAD9 and MCAD comparators. This directly supports the membrane-level IDA. The fractionation does not establish finer membrane topology; separate assembly and structural studies support the inner-membrane placement. The author-uploaded full article was inspected, while the local publication cache remains abstract-only. Supporting Evidence: PMID:9599005 association of VLCAD protein with mitochondrial inner membrane is necessary for dimer assembly and formation of mature VLCAD |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | IDA PMID:7668252 Cloning of human very-long-chain acyl-coenzyme A dehydrogena... | ACCEPT | Summary: IDA annotation linking VLCAD to the acyl-CoA dehydrogenase step of beta-oxidation, supported by the demonstration that VLCAD activity drives long-chain fatty acid beta-oxidation flux in human fibroblasts (PMID:7668252). Core biological process. Reason: VLCAD-dependent restoration of palmitate beta-oxidation directly demonstrates its role in this process (PMID:7668252). Supporting Evidence: PMID:7668252 the deficiency of the normal VLCAD protein causes impaired long-chain fatty acid beta-oxidation activity in the patients' fibroblasts |
| GO:0030855 epithelial cell differentiation | IEP PMID:21492153 Analysis of proteomic changes induced upon cellular differen... | MARK AS OVER ANNOTATED | Summary: Caco-2 proteomics detects increased ACADVL abundance after differentiation. Reason: Full publisher Methods, Table 1 and Discussion were inspected. ACADVL increased 3.25-fold; the authors interpret the lipid-enzyme changes as metabolic adaptation. This establishes a differentiation-associated expression pattern but does not show ACADVL performing a differentiation step. The IEP code accurately records expression evidence; the biological-process inference is broader than the demonstrated role. Supporting Evidence: PMID:21492153 proteins involved in xenobiotic and drug metabolism as well as in lipid metabolism were upregulated upon cellular differentiation |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-1791069 | KEEP AS NON CORE | Summary: This Reactome event describes ACADVL expression, not a beta-oxidation reaction. Reason: The matrix TAS is retained as an imported-protein/expression-context placement. Mature VLCAD assembles at the matrix face of the inner membrane, whereas a soluble matrix pool is most clearly described for the assembly-defective S583W mutant. Do not promote the expression-event compartment to a defining freely soluble localization. Supporting Evidence: Reactome:R-HSA-1791069 The ACADVL gene is transcribed to yield mRNA and the mRNA is translated to yield protein. PMID:9599005 association of VLCAD protein with mitochondrial inner membrane is necessary for dimer assembly and formation of mature VLCAD |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-77299 | KEEP AS NON CORE | Summary: Reactome places the palmitoyl-CoA dehydrogenation reaction in the mitochondrial matrix. Reason: Retain this reaction-compartment context for matrix-facing catalysis, while representing the mature enzyme in core functions at the inner membrane. Matrix is not a synonym or an ancestor of inner membrane; the contextual TAS does not establish a freely soluble mature VLCAD enzyme. Supporting Evidence: Reactome:R-HSA-77299 VLCAD in the mitochondrial matrix dehydrogenates palmitoyl-CoA to form trans-hexadec-2-enoyl-CoA PMID:9599005 association of VLCAD protein with mitochondrial inner membrane is necessary for dimer assembly and formation of mature VLCAD |
| GO:0090181 regulation of cholesterol metabolic process | ISS GO_REF:0000024 | UNDECIDED | Summary: A regulatory process is transferred from mouse Acadvl/VLCAD (P50544). Reason: P50544 is mouse Acadvl (MGI:895149). MGI lists this term with IMP/J:95532, but the original gene-specific result has not been verified in full. The available abstract does not resolve the VLCAD-specific cholesterol measurements or regulatory mechanism. Other lipid phenotypes cannot substitute for the supporting experiment. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P50544 UNRESOLVED Donor identity is verified by NCBI Gene11370/MGI895149. The MGI graph lists GO:0090181 with IMP/J:95532. PMID:15639194 is relevant and cached abstract-only, but the exact J-number linkage and full supporting results remain unresolved. |
| GO:0001659 temperature homeostasis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: Temperature-homeostasis annotation transferred from mouse Acadvl/VLCAD (P50544). Reason: P50544 is mouse Acadvl (MGI:895149). MGI records a mouse IMP temperature-homeostasis annotation, and PMID:15639194 explicitly reports cold intolerance in VLCAD-deficient mice. Retain this organismal consequence of fatty acid oxidation as non-core; it does not make VLCAD a temperature sensor or directly demonstrate the phenotype in humans. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:P50544 SUPPORTS TRANSFER NCBI Gene11370 links P50544 to mouse Acadvl (MGI:895149). MGI lists GO:0001659 IMP/J:95532. PMID:15639194 independently verifies the VLCAD-deficient cold phenotype; the exact J-number-to-PMID link was not recovered. Supporting Evidence: PMID:15639194 neither mouse model can maintain core body temperature when exposed to cold |
| GO:0005739 mitochondrion | ISS GO_REF:0000024 | ACCEPT | Summary: Mitochondrial localization is transferred from the correct mouse Acadvl ortholog. Reason: P50544 is mouse VLCAD, and mitochondrial targeting is conserved. Independent human import and assembly evidence confirms the core organelle. Preserve the source assertion at mitochondrial resolution. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P50544 SUPPORTS TRANSFER Donor identity is verified as mouse Acadvl through NCBI Gene11370. No wrong-paralog or localization-transfer error is supported. Supporting Evidence: PMID:9599005 association of VLCAD protein with mitochondrial inner membrane is necessary for dimer assembly and formation of mature VLCAD |
| GO:0033539 fatty acid beta-oxidation using acyl-CoA dehydrogenase | ISS GO_REF:0000024 | ACCEPT | Summary: Mouse Acadvl/VLCAD supports conserved participation in dehydrogenase-dependent fatty acid beta-oxidation. Reason: P50544 is mouse Acadvl, whose conserved catalytic activity initiates mitochondrial fatty acid beta-oxidation. Human mutant and rescue experiments independently support the same catalytic contribution, so both the biological assertion and the orthology transfer are sound. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:P50544 SUPPORTS TRANSFER NCBI Gene11370 identifies the donor as Acadvl. MGI records the dehydrogenase-dependent beta-oxidation process on this gene; direct human enzyme and flux evidence agree. Supporting Evidence: PMID:9461620 the initial step of the mitochondrial beta-oxidation spiral PMID:7668252 raising VLCAD activity to approximately 20% of normal control fibroblast activity raised palmitic acid beta-oxidation flux to the level found in control fibroblasts |
| GO:0045717 negative regulation of fatty acid biosynthetic process | ISS GO_REF:0000024 | UNDECIDED | Summary: A regulatory process is transferred from mouse Acadvl/VLCAD (P50544). Reason: P50544 is mouse Acadvl (MGI:895149). MGI lists this term with IMP/J:95532, but the original gene-specific result has not been verified in full. The available abstract foregrounds elevated lipogenic transcripts in LCAD-deficient mice; the VLCAD-specific supporting experiment and conservation of this regulatory effect remain unresolved. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P50544 UNRESOLVED Donor identity is verified by NCBI Gene11370/MGI895149. The MGI graph lists GO:0045717 with IMP/J:95532. PMID:15639194 is relevant and cached abstract-only, but the exact J-number linkage and full supporting results remain unresolved. |
| GO:0046322 negative regulation of fatty acid oxidation | ISS GO_REF:0000024 | UNDECIDED | Summary: A regulatory process is transferred from mouse Acadvl/VLCAD (P50544). Reason: P50544 is mouse Acadvl (MGI:895149). MGI lists this term with IMP/J:95532, but the original gene-specific result has not been verified in full. The available abstract reports elevated hepatic oxidation-gene expression in VLCAD-deficient mice. Compensatory transcription is not itself an oxidation-flux measurement. Direct catalytic participation and indirect negative feedback can coexist, so the regulatory sign is not intrinsically contradictory. Propagation Review Root cause: UNRESOLVED Sources checked: UniProtKB:P50544 UNRESOLVED Donor identity is verified by NCBI Gene11370/MGI895149. The MGI graph lists GO:0046322 with IMP/J:95532. PMID:15639194 is relevant and cached abstract-only, but the exact J-number linkage and full supporting results remain unresolved. |
| GO:0042645 mitochondrial nucleoid | IDA PMID:18063578 The layered structure of human mitochondrial DNA nucleoids. | KEEP AS NON CORE | Summary: Table 1 identifies ACADVL in one native and one cross-linked HeLa mitochondrial nucleoid preparation. Reason: Table 1 places ACADVL/NP_000009 in Class I, the study's operational group of core nucleoid proteins. The values count independent LC-MS/MS peptides with confidence above 90%: native anti-TFAM purification 3, native anti-mtSSB purification 0, cross-linked preparation 1 3, and preparation 2 0. Thus ACADVL was detected in one preparation of each category, not every preparation. The abstract's metabolic proteins absent after cross-linking correspond to a different subset, represented by Class II and ATAD3. Retain this biochemical association as non-core. Cross-linking can capture indirect protein contacts, so the result does not establish direct DNA binding, mtDNA maintenance, or a constitutive nucleoid pool. Supporting Evidence: |
| GO:0004466 long-chain fatty acyl-CoA dehydrogenase activity | TAS PMID:8466512 A novel disease with deficiency of mitochondrial very-long-c... | ACCEPT | Summary: TAS annotation from the report that first defined VLCAD deficiency as a disease, using very low palmitoyl-CoA (C16, long-chain) dehydrogenase activity and loss of anti-VLCAD immunoreactivity in patients (PMID:8466512). Supports VLCAD's long-chain acyl-CoA dehydrogenase activity. Reason: Patient deficiency of palmitoyl-CoA dehydrogenase activity attributable to VLCAD directly supports the long-chain acyl-CoA dehydrogenase activity assignment (PMID:8466512). Supporting Evidence: PMID:8466512 found to have a novel disease, VLCAD deficiency, as judged from the results of very low palmitoyl-CoA dehydrogenase activity and the lack of immunoreactivity toward antibody raised to purified VLCAD |
| GO:0015980 energy derivation by oxidation of organic compounds | TAS PMID:7479827 Molecular basis of human mitochondrial very-long-chain acyl-... | KEEP AS NON CORE | Summary: VLCAD supports energy derivation through fatty acid beta-oxidation. Reason: PMID:7479827 explicitly links reduced myocardial fatty acid beta-oxidation in VLCAD deficiency to reduced energy production. Retain this broader bioenergetic role as non-core alongside the precise catalytic pathway annotation. The live AmiGO is_a ancestry displayed for GO:0033539 runs through fatty acid beta-oxidation and fatty acid oxidation/catabolism without including GO:0015980, so replacement by the already annotated pathway would not simply preserve an asserted ancestor relationship. Supporting Evidence: PMID:7479827 VLCAD deficiency reduces myocardial fatty acid beta-oxidation and energy production and is associated with cardiomyopathy and sudden death in childhood |
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Download this section (compressed HTML)Q: Which mouse Acadvl loss-of-function effects on lipid synthesis, oxidation and cholesterol metabolism reflect altered metabolic flux, and which reflect compensatory transcriptional feedback?
Q: What physiological role, if any, accompanies the VLCAD pool detected in biochemical mitochondrial nucleoid preparations, and does it contact DNA directly or associate through other proteins?
Experiment: Measure fatty acid oxidation flux and transcriptional feedback separately in matched Acadvl-deficient and rescued hepatocytes under fasting-like conditions.
Hypothesis: Loss of catalytic flux can increase compensatory oxidation-gene expression without making VLCAD a direct transcriptional repressor.
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