Valine and isoleucine distal catabolism (acyl-CoA dehydrogenase -> propionyl-CoA)

After the shared, mitochondrial branched-chain aminotransferase (BCAT2) and branched-chain alpha-ketoacid dehydrogenase (BCKDH) steps deaminate and oxidatively decarboxylate the three branched-chain amino acids to their acyl-CoA thioesters, valine and isoleucine follow their own distal degradation routes in the mitochondrial matrix that converge on propionyl-CoA. In the VALINE route, isobutyryl-CoA is dehydrogenated by isobutyryl-CoA dehydrogenase (ACAD8, an FAD enzyme feeding electrons to ETF) to methacrylyl-CoA; the crotonase ECHS1 (curated elsewhere) hydrates this to (S)-3-hydroxyisobutyryl-CoA, which the crotonase-superfamily hydrolase HIBCH deacylates to free 3-hydroxyisobutyrate + CoA (a step thought to detoxify the reactive methacrylyl-CoA). 3-Hydroxy- isobutyrate dehydrogenase (HIBADH, NAD+) then oxidises it to (S)-methylmalonate semialdehyde, and the CoA-acylating aldehyde dehydrogenase ALDH6A1 (methylmalonate-semialdehyde dehydrogenase) oxidatively decarboxylates that to propionyl-CoA. In the ISOLEUCINE route, 2-methylbutyryl-CoA is dehydrogenated by the short/branched-chain acyl-CoA dehydrogenase ACADSB (FAD -> ETF) to tiglyl-CoA; ECHS1 hydrates it, and HSD17B10 (the moonlighting SDR protein MRPP2/HADH2, in its 2-methyl-3-hydroxybutyryl-CoA dehydrogenase role, NAD+) oxidises 2-methyl-3-hydroxybutyryl-CoA to 2-methylacetoacetyl-CoA, which the thiolase ACAT1 (curated elsewhere) cleaves to propionyl-CoA + acetyl-CoA. The propionyl-CoA produced by both routes enters the propionyl-CoA -> methylmalonyl-CoA -> succinyl-CoA anaplerotic pathway (PCC/MUT). Inherited defects at each step cause distinct organic acidurias (ACAD8: isobutyryl-CoA dehydrogenase deficiency; ACADSB: 2-methylbutyryl-CoA dehydrogenase deficiency; HIBCH and ALDH6A1: valine-pathway neurometabolic disease; HSD17B10: X-linked MHBD deficiency, which also impairs the protein's separate mitochondrial RNase P role).