| ECHS1, or mitochondrial short-chain enoyl-CoA hydratase 1, serves as a core enzyme in the fatty acid β-oxidation spiral and branched-chain amino acid catabolism, particularly valine degradation, within the crotonase superfamily. The protein forms a compact barrel-like structure with a Rossmann fold for CoA ester binding and catalytic His-Asp dyad for proton abstraction, enabling stereospecific hydration of trans-2-enoyl-CoA thioesters. It catalyzes the second step of β-oxidation by adding water across the α-β double bond of medium- and short-chain enoyl-CoA (C4-C16) to generate L-3-hydroxyacyl-CoA, feeding downstream hydroxyacyl-CoA dehydrogenase and thiolase for acetyl-CoA production that enters the TCA cycle. High specificity targets methacrylyl-CoA from valine (yielding 2-methyl-3-hydroxybutyryl-CoA) and crotonyl-CoA from isoleucine/butyrate, though tiglyl-CoA binds without efficient turnover; multifunctional activity also handles leucine's 3-methylcrotonyl-CoA. Expressed ubiquitously but enriched in high-energy tissues like heart, muscle, and brain, ECHS1 maintains mitochondrial bioenergetics by linking lipid/amino acid oxidation to OXPHOS, with palmitate loading unmasking short-chain defects via butyrylcarnitine accumulation. Deficiency blocks these pathways, elevating toxic acryloyl-CoA/methacryloyl-CoA and 2-methyl-2,3-dihydroxybutyric acid in urine, secondary OXPHOS complex reductions (I/II/IV), lactate elevation, and Leigh-like basal ganglia lesions with cardiomyopathy, epilepsy, and encephalopathy. Patient fibroblasts show diminished protein/activity, while structural variants disrupt active site or tetramerization, linking to mitochondrial encephalopathy treatable potentially via metabolic interventions. |
