OpenScientist function-assignment hypothesis: CG4860 (Q9VGC2) short-chain acyl-CoA dehydrogenase activity (GO:0016937)
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Independent AI-scientist analysis (run blinded to our MODIFY action) concludes the short-chain assignment is over-specific and should be generalized to GO:0003995, independently re-deriving the Arc42-vs-CG4860 disambiguation and adding a binding-pocket determinant (a Leu-to-Thr substitution at the RIGIA+8 substrate-specificity position; CG4860 has small polar Thr where ACADS and Arc42 have bulky hydrophobic Leu).
"The smaller, polar threonine could accommodate longer or differently branched substrates, potentially shifting CG4860's substrate preference away from strict short-chain specificity."
Gene Ontology annotation through association of InterPro records with GO terms
Gene Ontology annotation based on Enzyme Commission mapping
Annotation inferences using phylogenetic trees
Combined Automated Annotation using Multiple IEA Methods
An inventory of peroxisomal proteins and pathways in Drosophila melanogaster.
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A proteome-wide inventory of Drosophila peroxisomal proteins and metabolic pathways; the associated reference protein (Q709F0) underlies the FlyBase ISS transfer of general acyl-CoA dehydrogenase activity and fatty acid beta-oxidation to CG4860.
"metabolic enzymes that function within the organelle"
Characterizing fatty acid oxidation genes in Drosophila.
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CG4860 and its paralog Arc42 are both DIOPT-predicted Drosophila orthologs of human ACADS, with CG4860 receiving the lower prediction score.
"Two different fly genes were predicted by DIOPT to be orthologs of human ACADS: Arc42 and CG4860"
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A CRISPR-Cas9 knockout of CG4860 does NOT reproduce the elevated-C4 (butyrylcarnitine) acylcarnitine profile of human short-chain acyl-CoA dehydrogenase (SCAD/ACADS) deficiency; instead C4 is lower and C2 (acetylcarnitine) is elevated. The paralog Arc42 knockout does reproduce the elevated-C4 SCAD profile.
"In contrast, we did not observe an elevation of acylcarnitine C4 in the homozygous CG4860 mutant flies as compared to controls in either condition"
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Overall, loss of Arc42 - not CG4860 - mirrors human ACADS loss of function.
"the acylcarnitine profile for Arc42 loss of function mimics that of ACADS loss of function, while that of CG4860 does not"