OpenScientist function-assignment hypothesis: Echs1 (Q7JR58) enoyl-CoA hydratase activity / substrate breadth (GO:0004300)
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Independent AI-scientist analysis (blinded to our review action, focused on substrate breadth) strongly supports enoyl-CoA hydratase activity for fly Echs1 and indicates the broad short/branched-chain substrate range of human ECHS1 is conserved - both catalytic glutamates and the active-site/substrate-binding residues are 100% conserved, and Echs1-deficient flies accumulate the valine-pathway substrate methacrylyl-CoA (elevated lysine methacrylation).
"the enzymatic activity framework that is expected to be shared by the Drosophila ortholog based on the complete conservation of catalytic and substrate-binding residues"
Gene Ontology annotation through association of InterPro records with GO terms
Combined Automated Annotation using Multiple IEA Methods
Clinical, biochemical and metabolic characterisation of a mild form of human short-chain enoyl-CoA hydratase deficiency: significance of increased N-acetyl-S-(2-carboxypropyl)cysteine excretion.
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Purified human ECHS1 (the ortholog of fly Echs1) hydrates five enoyl-CoA substrates across different metabolic pathways, with highest specificity for crotonyl-CoA and lowest for tiglyl-CoA, spanning fatty acid beta-oxidation and branched-chain amino acid catabolism.
"Human ECHS1 catalyses the hydration of five substrates via different metabolic pathways, with the highest specificity for crotonyl-CoA and the lowest specificity for tiglyl-CoA."
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ECHS1 catalyses mitochondrial short-chain fatty acid beta-oxidation and branched-chain amino acid catabolic pathways; its deficiency reflects defective valine catabolic and beta-oxidation pathways.
"harbouring defective valine catabolic and β-oxidation pathways"
Ectopic protein lysine methacrylation contributes to defects caused by loss of HIBCH or ECHS1.
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Loss of ECHS1 (or downstream HIBCH) in Drosophila and in cells elevates lysine methacrylation and causes abnormal mitochondrial morphology, respiratory defects, and age-dependent fly eye degeneration, consistent with accumulation of the valine-pathway intermediate methacrylyl-CoA that Echs1 normally hydrates.
"Elevated lysine methacrylation (Kmea) is observed in both HIBCH- and ECHS1-deficient cells and fly tissues."
Manual transfer of experimentally-verified manual GO annotation data to orthologs by curator judgment of sequence similarity
Annotation inferences using phylogenetic trees
Mapping organelle proteins and protein complexes in Drosophila melanogaster.
Valine Restriction Extends Survival in a Drosophila Model of Short-Chain Enoyl-CoA Hydratase 1 (ECHS1) Deficiency.