ACAD8

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005739 mitochondrion	IBA GO_REF:0000033	ACCEPT	Summary: Accept mitochondrial localization at the resolution of the original evidence. Reason: The PAINT node PTN000097535 supports the original mitochondrial localization; independent human import experiments agree with that broad ancestral assertion. Target self-inclusion among descendant evidence is expected and is not circular. Matrix residence is supported separately by the accepted Reactome annotations and retained in core_functions; it is not substituted into this source assertion. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN000097535 SUPPORTS TRANSFER PAINT node PTN000097535 supports mitochondrial localization, consistent with human ACAD8 import experiments. Accept the original scope; no objection is based on donor count or target self-inclusion. Supporting Evidence: PMID:11013134 both wild-type proteins are imported into mitochondria and form tetramers Reactome:R-HSA-70859 Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction
GO:0003853 short-chain 2-methyl fatty acyl-CoA dehydrogenase activity	IEA GO_REF:0000120	ACCEPT	Summary: ACAD8 catalyzes short-chain 2-methyl acyl-CoA dehydrogenation in valine degradation. Reason: The Rhea/EC mapping includes isobutyryl-CoA and (S)-2-methylbutyryl-CoA reactions, both measured for recombinant human ACAD8. Isobutyryl-CoA is preferred by catalytic efficiency and corresponds to its established physiological valine-catabolic role. GO:0003853 is the substrate-class term covering these measured reactions. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:44180 SUPPORTS TRANSFER Fetched UniProt identifies isobutyryl-CoA oxidation with electron-transfer flavoprotein as acceptor, linked to primary human ACAD8 enzymology. This is the valine-pathway reaction. RHEA:48256 SUPPORTS TRANSFER Fetched UniProt identifies oxidation of (2S)-2-methylbutanoyl-CoA, supported by measured recombinant ACAD8 activity. Its lower efficiency does not invalidate the encompassing short-chain 2-methyl substrate-class term. EC:1.3.8.5 SUPPORTS TRANSFER The fetched UniProt EC assignment and live GO0003853 EC cross-reference agree with direct human short-chain 2-methyl acyl-CoA dehydrogenation. Supporting Evidence: PMID:12359132 Thus, this enzyme is an isobutyryl-CoA dehydrogenase.
GO:0003995 acyl-CoA dehydrogenase activity	IEA GO_REF:0000120	MODIFY	Summary: Specify the experimentally established short-chain 2-methyl acyl-CoA dehydrogenase activity. Reason: The conserved acyl-CoA dehydrogenase features support the generic activity, and direct human substrate measurements support a more specific term. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: ARBA:ARBA00026877 UNRESOLVED The GOA rule identifier is preserved, but its learned predicates/training support were not inspected. The annotation decision rests on independent target-specific literature rather than a claim to have validated the rule internals. InterPro:IPR006089 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. InterPro:IPR034178 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. Proposed replacements: short-chain 2-methyl fatty acyl-CoA dehydrogenase activity Supporting Evidence: PMID:12359132 Thus, this enzyme is an isobutyryl-CoA dehydrogenase.
GO:0005739 mitochondrion	IEA GO_REF:0000120	ACCEPT	Summary: Accept mitochondrial localization at the resolution of the original evidence. Reason: The recorded UniProt subcellular-location mapping supports mitochondrion and agrees with human import assays. The ARBA rule predicates were not independently inspected. Matrix residence is supported separately by the accepted Reactome annotations and retained in core_functions; it is not substituted into this source assertion. Propagation Review Root cause: NO FAILURE CORE Sources checked: ARBA:ARBA00026962 UNRESOLVED The GOA rule identifier is preserved, but its learned predicates/training support were not inspected. The annotation decision rests on independent target-specific literature rather than a claim to have validated the rule internals. UniProtKB-SubCell:SL-0173 SUPPORTS TRANSFER SL-0173 is the mitochondrial location recorded in GOA and cached UniProt. Human import experiments corroborate this scope; the separate matrix annotation is not imputed to this mapping. Supporting Evidence: PMID:11013134 both wild-type proteins are imported into mitochondria and form tetramers Reactome:R-HSA-70859 Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction
GO:0006629 lipid metabolic process	IEA GO_REF:0000002	MODIFY	Summary: Correct the lipid-metabolism assignment to the directly established L-valine catabolic pathway. Reason: The InterPro IBD-family mapping identifies the enzyme family but does not establish a separate physiological lipid pathway. Later human enzymology identifies ACAD8 as the isobutyryl-CoA dehydrogenase of L-valine catabolism. GO:0006574 is a different pathway branch from GO:0006629, so this proposed replacement is a biological pathway correction rather than an ontology-descendant refinement. The measured propionyl side activity does not by itself establish fatty-acid beta-oxidation flux. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR034178 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. Proposed replacements: L-valine catabolic process Supporting Evidence: PMID:11013134 indicate that ACAD-8 is a mitochondrial enzyme that functions in valine catabolism.
GO:0016627 oxidoreductase activity, acting on the CH-CH group of donors	IEA GO_REF:0000002	MODIFY	Summary: Specify the experimentally established short-chain 2-methyl acyl-CoA dehydrogenase activity. Reason: The InterPro family/domain annotations correctly identify CH-CH oxidoreduction but do not describe ACAD8 substrate specificity. A broader catalytic term is not a separate non-core function. Propagation Review Root cause: TERM SCOPING PROBLEM Sources checked: InterPro:IPR006091 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. InterPro:IPR009075 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. InterPro:IPR009100 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. InterPro:IPR013786 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. InterPro:IPR036250 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. InterPro:IPR037069 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. InterPro:IPR046373 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. Proposed replacements: short-chain 2-methyl fatty acyl-CoA dehydrogenase activity Supporting Evidence: PMID:12359132 Thus, this enzyme is an isobutyryl-CoA dehydrogenase.
GO:0016937 short-chain fatty acyl-CoA dehydrogenase activity	IEA GO_REF:0000116	ACCEPT	Summary: The broad short-chain dehydrogenase GO activity includes the core branched reaction; its particular Rhea source documents a measured secondary propionyl reaction. Reason: The action evaluates the asserted GO term: live AmiGO places GO:0003853 directly under GO:0016937, so the latter includes ACAD8's core isobutyryl-CoA dehydrogenation. This does not make every covered substrate a core physiological reaction. The exact IEA source is RHEA:31287, propanoyl-CoA to acryloyl-CoA, supported by the measured 0.04 microM(-1)s(-1) catalytic efficiency compared with 0.8 for isobutyryl-CoA. Preserve this valid mapping and its source scope. Modifying this Rhea-derived row to GO:0003853 would incorrectly replace its unbranched C3 reaction with 2-methyl chemistry; the core-specific term is already represented independently. Propagation Review Root cause: NO FAILURE CORE Sources checked: RHEA:31287 SUPPORTS TRANSFER RHEA:31287 directly supports propanoyl-CoA oxidation, a measured secondary reaction. That chemistry maps correctly to the broad short-chain GO activity; independent human isobutyryl evidence establishes that this encompassing GO term also covers the core function. Source reaction and core-reaction scope remain distinct. Supporting Evidence: PMID:12359132 Purified recombinant enzyme had a k(cat)/K(m) of 0.8, 0.23, and 0.04 (microM(-1)s(-1)) with isobutyryl-CoA, (S) 2-methylbutyryl-CoA, and n-propionyl-CoA, respectively, as substrates.
GO:0050660 flavin adenine dinucleotide binding	IEA GO_REF:0000002	ACCEPT	Summary: Bound FAD is an intrinsic cofactor of ACAD8 catalysis. Reason: The cached UniProt record explicitly assigns FAD as cofactor and records a structure determined with FAD and a substrate analogue. This supports the annotation through the available curated cofactor/structure cross-reference; it does not claim a newly cached or fully inspected underlying structural publication. FAD binding is part of the dehydrogenase mechanism and is incorporated into the same core function rather than listed as a second independent biological activity. Propagation Review Root cause: NO FAILURE CORE Sources checked: InterPro:IPR013786 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. InterPro:IPR037069 UNRESOLVED The domain/family identifier is present in the untouched GOA and UniProt records, but its precise InterPro-to-GO rule was not independently inspected. The annotation-level decision is supported by the target-specific catalytic/cofactor evidence described in review.reason; it is not a claim to have reconstructed the mapping internals. Supporting Evidence: file:human/ACAD8/ACAD8-uniprot.txt Name=FAD; Xref=ChEBI:CHEBI:57692;
GO:0005515 protein binding	IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling...	REMOVE	Summary: The BioPlex association does not specify an informative molecular function for ACAD8. Reason: The seeded BioPlex IPI row and fetched UniProt interaction record identify VSTM2A/Q8TAG5 as the partner, with two experiments recorded by IntAct. Remove generic protein binding from the functional summary because this association does not identify a substrate, electron-transfer partner or established mechanistic activity. This is not a judgment that the reported physical association is false, and the cached BioPlex narrative does not independently expose the ACAD8-specific supplementary evidence. No more specific binding function is inferred from it. Supporting Evidence: file:human/ACAD8/ACAD8-uniprot.txt Q9UKU7; Q8TAG5: VSTM2A; NbExp=2; IntAct=EBI-2339304, EBI-8994042;
GO:0006574 L-valine catabolic process	IEA GO_REF:0000041	ACCEPT	Summary: ACAD8 directly performs the isobutyryl-CoA dehydrogenation step of valine catabolism. Reason: The UniPathway assignment agrees with recombinant human enzyme specificity, mitochondrial import and the valine-oxidation defect associated with ACAD8 deficiency. This is direct enzymatic participation in the pathway. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniPathway:UPA00362 SUPPORTS TRANSFER UPA00362 is the fetched UniProt L-valine degradation pathway cross-reference and agrees with direct ACAD8 substrate/catabolic experiments. Supporting Evidence: PMID:11013134 indicate that ACAD-8 is a mitochondrial enzyme that functions in valine catabolism. PMID:12359132 Thus, this enzyme is an isobutyryl-CoA dehydrogenase.
GO:0003853 short-chain 2-methyl fatty acyl-CoA dehydrogenase activity	EXP PMID:11013134 Isolated 2-methylbutyrylglycinuria caused by short/branched-...	ACCEPT	Summary: Experimental human ACAD8 evidence supports isobutyryl-CoA dehydrogenase activity. Reason: PMID:11013134 directly tests ACAD8 as well as ACADSB and identifies ACAD8 as mitochondrial isobutyryl-CoA dehydrogenase; the paper title is not a paralog-misattribution problem. Supporting Evidence: PMID:11013134 indicate that ACAD-8 is a mitochondrial enzyme that functions in valine catabolism.
GO:0003853 short-chain 2-methyl fatty acyl-CoA dehydrogenase activity	EXP PMID:12359132 Identification of isobutyryl-CoA dehydrogenase and its defic...	ACCEPT	Summary: Experimental human ACAD8 evidence supports isobutyryl-CoA dehydrogenase activity. Reason: PMID:12359132 measures purified recombinant human ACAD8 specificity, with kcat/Km values 0.8 for isobutyryl-CoA, 0.23 for (S)-2-methylbutyryl-CoA and 0.04 microM(-1)s(-1) for propionyl-CoA. The approximately 3.5-fold efficiency preference over the alternate branched substrate is distinct from the 20-fold comparison with propionyl-CoA. Supporting Evidence: PMID:12359132 Thus, this enzyme is an isobutyryl-CoA dehydrogenase.
GO:0003853 short-chain 2-methyl fatty acyl-CoA dehydrogenase activity	EXP PMID:16857760 Variations in IBD (ACAD8) in children with elevated C4-carni...	ACCEPT	Summary: Experimental human ACAD8 evidence supports isobutyryl-CoA dehydrogenase activity. Reason: PMID:16857760 reports variant effects on imported tetramer folding and residual IBD activity in Chang cells, together with patient-fibroblast defects. These observations corroborate the established normal enzymatic activity; they do not define a separate disease-state molecular function. Supporting Evidence: PMID:16857760 low/no IBD residual enzyme activity was detectable when the variant IBD proteins were overexpressed in Chang cells.
GO:0005739 mitochondrion	EXP PMID:11013134 Isolated 2-methylbutyrylglycinuria caused by short/branched-...	ACCEPT	Summary: Accept mitochondrial localization at the resolution of the original evidence. Reason: The source directly assays human wild-type ACAD8 import into mitochondria and tetramer formation; it does not resolve the submitochondrial compartment in the accessible passage. Matrix residence is supported separately by the accepted Reactome annotations and retained in core_functions; it is not substituted into this source assertion. Supporting Evidence: PMID:11013134 both wild-type proteins are imported into mitochondria and form tetramers Reactome:R-HSA-70859 Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction
GO:0005739 mitochondrion	EXP PMID:12359132 Identification of isobutyryl-CoA dehydrogenase and its defic...	ACCEPT	Summary: Accept mitochondrial localization at the resolution of the original evidence. Reason: The accessible abstract reports that inactive Arg302Gln retains mitochondrial targeting; wild-type import is independently demonstrated in PMID:11013134. Preserve the curator's mitochondrial assignment without presenting this passage as a matrix-localization assay. Matrix residence is supported separately by the accepted Reactome annotations and retained in core_functions; it is not substituted into this source assertion. Supporting Evidence: PMID:11013134 both wild-type proteins are imported into mitochondria and form tetramers Reactome:R-HSA-70859 Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction
GO:0005739 mitochondrion	HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an...	ACCEPT	Summary: Accept mitochondrial localization at the resolution of the original evidence. Reason: MitoCoP supports mitochondrial membership. Its cached main text does not expose the ACAD8-specific supplementary entry or establish a submitochondrial compartment; the assignment agrees with independent human import evidence. Matrix residence is supported separately by the accepted Reactome annotations and retained in core_functions; it is not substituted into this source assertion. Supporting Evidence: PMID:11013134 both wild-type proteins are imported into mitochondria and form tetramers Reactome:R-HSA-70859 Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-70859	ACCEPT	Summary: The mitochondrial matrix is the core functional location of ACAD8. Reason: The cached Reactome reaction explicitly identifies mitochondrial ACAD8-catalyzed isobutyryl-CoA dehydrogenation and its mature tetramer. This is the functional matrix location. Supporting Evidence: Reactome:R-HSA-70859 Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction PMID:11013134 both wild-type proteins are imported into mitochondria and form tetramers
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838035	ACCEPT	Summary: The mitochondrial matrix is the core functional location of ACAD8. Reason: GOA assigns matrix localization through this Reactome protein-quality-control event. The cached event narrative discusses matrix substrates but does not individually name ACAD8, so it is not treated as a direct ACAD8 turnover experiment. The matrix location itself is independently supported by its curated valine-degradation reaction and mitochondrial import evidence and remains core regardless of the event used to record it. Being a candidate protease substrate does not make ACAD8 a protease or an executor of protein degradation. Supporting Evidence: Reactome:R-HSA-70859 Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction PMID:11013134 both wild-type proteins are imported into mitochondria and form tetramers
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838081	ACCEPT	Summary: The mitochondrial matrix is the core functional location of ACAD8. Reason: GOA assigns matrix localization through this Reactome protein-quality-control event. The cached event narrative discusses matrix substrates but does not individually name ACAD8, so it is not treated as a direct ACAD8 turnover experiment. The matrix location itself is independently supported by its curated valine-degradation reaction and mitochondrial import evidence and remains core regardless of the event used to record it. Being a candidate protease substrate does not make ACAD8 a protease or an executor of protein degradation. Supporting Evidence: Reactome:R-HSA-70859 Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction PMID:11013134 both wild-type proteins are imported into mitochondria and form tetramers
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838093	ACCEPT	Summary: The mitochondrial matrix is the core functional location of ACAD8. Reason: GOA assigns matrix localization through this Reactome protein-quality-control event. The cached event narrative discusses matrix substrates but does not individually name ACAD8, so it is not treated as a direct ACAD8 turnover experiment. The matrix location itself is independently supported by its curated valine-degradation reaction and mitochondrial import evidence and remains core regardless of the event used to record it. Being a candidate protease substrate does not make ACAD8 a protease or an executor of protein degradation. Supporting Evidence: Reactome:R-HSA-70859 Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction PMID:11013134 both wild-type proteins are imported into mitochondria and form tetramers
GO:0005759 mitochondrial matrix	TAS Reactome:R-HSA-9838289	ACCEPT	Summary: The mitochondrial matrix is the core functional location of ACAD8. Reason: GOA assigns matrix localization through this Reactome protein-quality-control event. The cached event narrative discusses matrix substrates but does not individually name ACAD8, so it is not treated as a direct ACAD8 turnover experiment. The matrix location itself is independently supported by its curated valine-degradation reaction and mitochondrial import evidence and remains core regardless of the event used to record it. Being a candidate protease substrate does not make ACAD8 a protease or an executor of protein degradation. Supporting Evidence: Reactome:R-HSA-70859 Mitochondrial isobutyryl-CoA dehydrogenase (ACAD8) catalyzes the reaction PMID:11013134 both wild-type proteins are imported into mitochondria and form tetramers
GO:0003995 acyl-CoA dehydrogenase activity	TAS PMID:10524212 Isolation and characterisation of a cDNA encoding the precur...	MODIFY	Summary: Specify the experimentally established short-chain 2-methyl acyl-CoA dehydrogenase activity. Reason: The PMID:10524212 abstract establishes a cloned acyl-CoA dehydrogenase-family sequence, without experimentally resolving substrate specificity. Later recombinant-enzyme work identifies the isobutyryl-CoA reaction; the replacement rests on that later evidence, not on an assay attributed to the cloning study. Proposed replacements: short-chain 2-methyl fatty acyl-CoA dehydrogenase activity Supporting Evidence: PMID:12359132 Thus, this enzyme is an isobutyryl-CoA dehydrogenase.
GO:0006629 lipid metabolic process	TAS PMID:10524212 Isolation and characterisation of a cDNA encoding the precur...	MODIFY	Summary: Correct the lipid-metabolism assignment to the directly established L-valine catabolic pathway. Reason: The early cloning paper established family membership before ACAD8 substrate specificity was defined. Later human enzymology identifies ACAD8 as the isobutyryl-CoA dehydrogenase of L-valine catabolism. GO:0006574 is a different pathway branch from GO:0006629, so this proposed replacement is a biological pathway correction rather than an ontology-descendant refinement. The measured propionyl side activity does not by itself establish fatty-acid beta-oxidation flux. Proposed replacements: L-valine catabolic process Supporting Evidence: PMID:11013134 indicate that ACAD-8 is a mitochondrial enzyme that functions in valine catabolism.

Gene Description

Existing Annotations Review

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