L-lysine catabolism (saccharopine pathway to glutaryl-CoA; glutaric aciduria type 1)

The main (saccharopine) pathway of L-lysine degradation in humans, a mitochondrial route that also handles L-hydroxylysine and the final steps of L-tryptophan catabolism, converging on glutaryl-CoA and ultimately acetyl-CoA. The bifunctional alpha-aminoadipic semialdehyde synthase (AASS) catalyses the first two committed steps: its lysine-2-oxoglutarate reductase (saccharopine dehydrogenase, NADP+) activity condenses L-lysine with 2-oxoglutarate to saccharopine, and its saccharopine dehydrogenase (NAD+) activity then oxidises saccharopine to L-2-aminoadipate-6-semialdehyde + L-glutamate. Downstream (semialdehyde -> L-2-aminoadipate by ALDH7A1; L-2-aminoadipate -> 2-oxoadipate by the aminotransferase AADAT — not modelled here) yields 2-oxoadipate, which the 2-oxoadipate dehydrogenase complex (OADHC) oxidatively decarboxylates to glutaryl-CoA. The OADHC is a paralogous sibling of the 2-oxoglutarate dehydrogenase complex: a dedicated E1 (DHTKD1, TPP-dependent) plus the shared E2 succinyltransferase core (DLST, acting as a glutaryltransferase here) and the shared E3 (DLD). Finally the FAD-dependent glutaryl-CoA dehydrogenase (GCDH) oxidatively decarboxylates glutaryl-CoA to crotonyl-CoA + CO2, passing electrons to the electron-transfer flavoprotein system (ETF -> ETFDH -> respiratory chain). Inherited defects: AASS deficiency causes (largely benign) hyperlysinemia / saccharopinuria; DHTKD1 deficiency causes 2-aminoadipic/2-oxoadipic aciduria (and is linked to Charcot-Marie-Tooth 2Q); and GCDH deficiency causes glutaric aciduria type 1 (GA1), a serious encephalopathy with striatal injury.