OpenScientist function-assignment hypothesis: ACAD9 (Q9H845) very-long-chain acyl-CoA dehydrogenase activity (GO:0017099)
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The generated report proposes a substrate-channel explanation for preferring long-chain over very-long-chain substrates. This is a computational hypothesis, not primary experimental verification of exclusion of substrates longer than C22.
"larger than VLCAD's glycines (which maximally open the channel) but smaller than MCAD's glutamine and glutamate (which fully block it)"
Gene Ontology annotation through association of InterPro records with GO terms
Annotation inferences using phylogenetic trees
Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping, accompanied by conservative changes to GO terms applied by UniProt
Gene Ontology annotation based on curation of immunofluorescence data
Gene Ontology annotation based on curation of intracellular localizations of expressed fusion proteins in living cells
Electronic Gene Ontology annotations created by ARBA machine learning models
Combined Automated Annotation using Multiple IEA Methods
Human acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial beta-oxidation of unsaturated fatty acids.
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ACAD9 is a mitochondrial membrane-associated homodimer with long-chain acyl-CoA dehydrogenase activity, maximal toward unsaturated C16-C22 substrates.
"Purified mature ACAD-9 had maximal activity with long-chain unsaturated acyl-CoAs as substrates (C16:1-, C18:1-, C18:2-, C22:6-CoA)."
Acyl-CoA dehydrogenase 9 is required for the biogenesis of oxidative phosphorylation complex I.
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The study establishes ACAD9 association with complex I assembly factors and a requirement for assembly. It reported no disturbed long-chain FAO in its tested disease models; this is not a universal exclusion of FAO involvement.
"ACAD9 binds complex I assembly factors NDUFAF1 and Ecsit and is specifically required for the assembly of complex I. Furthermore, ACAD9 mutations result in complex I deficiency and not in disturbed long-chain fatty acid oxidation."
Identification and characterization of new long chain acyl-CoA dehydrogenases.
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The abstract reports ACAD9 enrichment in the human cerebellar granular layer. Primary section 3.8 additionally resolves dendritic staining; the exact cellular-nucleus annotation remains unresolved.
"ACAD9 was most highly expressed in the granular layer, ACAD11 in the white matter, and MCAD in the molecular layer and axons of specific neurons."
ACAD9, a complex I assembly factor with a moonlighting function in fatty acid oxidation deficiencies.
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Catalytically inactive ACAD9 produced partial-to-complete rescue of complex I biogenesis in ACAD9-deficient cells, supporting separation of the catalytic and assembly roles under those conditions.
"Catalytically inactive ACAD9 gave partial-to-complete rescue of complex I biogenesis in ACAD9-deficient cells"
Dissecting the Roles of Mitochondrial Complex I Intermediate Assembly Complex Factors in the Biogenesis of Complex I.
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ACAD9 is a core member of the MCIA complex (with NDUFAF1, ECSIT, TMEM126B) required for ND2-module assembly. A hierarchy of stability exists centered on ACAD9. TMEM186 and COA1 are additional MCIA components.
"while each MCIA component is critical for complex I assembly, a hierarchy of stability exists centered on ACAD9."
Assembly of The Mitochondrial Complex I Assembly Complex Suggests a Regulatory Role for Deflavination.
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ECSIT C-terminal domain binds the vestigial dehydrogenase domain of ACAD9 and induces deflavination, switching ACAD9 from an FAO enzyme to a CI assembly factor. Cryo-EM confirmed the FAD binding site is empty in the ECSIT-bound state.
"interaction with ECSIT induces ACAD9 to eject its FAD cofactor from the catalytic site."
TMEM70 and TMEM242 help to assemble the rotor ring of human ATP synthase and interact with assembly factors for complex I.
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TMEM70 and TMEM242 interact with MCIA complex components including ACAD9, ECSIT, NDUFAF1, and TMEM126B.
"When TMEM242-t and similarly tagged TMEM70 (TMEM70-t) were expressed separately in HEK293 cells, the most significantly associated proteins were ACAD9 (acyl-CoA dehydrogenase family member 9), ECSIT (evolutionarily conserved signaling intermediate in Toll pathway), and NDUFAF1 (NADH:ubiquinone oxidoreductase complex assembly factor 1)"
Molecular mechanism of interactions between ACAD9 and binding partners in mitochondrial respiratory complex I assembly.
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The study reconstitutes an ACAD9/ECSIT/NDUFAF1 ternary complex and measures FAD-dependent activity with palmitoyl-CoA. The quoted 18% comparison is assay-specific, not a universal activity ratio or evidence excluding very-long-chain substrates.
"this activity is only 18% of VLCAD activity"
Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
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The study defines a high-confidence mitochondrial proteome. This general passage does not by itself identify ACAD9; its HTP annotation is retained with curator deference and independent localization evidence.
"We classified >8,000 proteins in mitochondrial preparations of human cells and defined a mitochondrial high-confidence proteome of >1,100 proteins (MitoCoP)."
The assembly of the Mitochondrial Complex I Assembly complex uncovers a redox pathway coordination.
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3.0 A cryo-EM structure of ACAD9-ECSIT complex revealed a 15-residue ECSIT peptide (res 320-334) that inserts at the junction of ACAD9 dehydrogenase and vestigial domains. ECSIT binding induces a 10 A gatekeeper loop movement in ACAD9, releasing FAD. ECSIT phosphorylation downregulates its association with ACAD9 and is reduced upon amyloid-beta exposure.
"ECSIT binding induces a major conformational change in the FAD-binding loop of ACAD9, releasing the FAD cofactor and converting ACAD9 from a fatty acid beta-oxidation (FAO) enzyme to a CI assembly factor."
Peripheral arm subunits bind the 815kDa complex to form a 980kDa complex
The MCIA complex, NDUFAF2-7 all dissociate from the 980kDa complex, resulting in Complex I
ND4, ND5 bind the 550kDa complex to form the 815kDa complex
COA1:MT-ND2, TMEM186:MT-ND3, MT-ND6, NDUFB6 bind the MCIA complex to form a 370kDa subcomplex
The 315kDa subcomplex binds the 370kDa subcomplex to form the 550kDa complex
Complex I assembly function and fatty acid oxidation enzyme activity of ACAD9 both contribute to disease severity in ACAD9 deficiency.
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ACAD9 knockout in two human HEK293 clones reduced palmitate oxidation and palmitoyl-CoA activity by 35-40%, with preserved octanoate oxidation and rescue by wild-type ACAD9. Residual recombinant mutant activity correlated with severity in a patient series; this does not establish every tissue-specific causal contribution.
"both cell lines exhibited a 35–40% decrease in whole-cell palmitate oxidation and palmitoyl-CoA ACAD activity"
Falcon deep research report for human ACAD9
Catalytic and FAD-binding residues of mitochondrial very long chain acyl-coenzyme A dehydrogenase.
UniProtKB P49748: human ACADVL curated protein record