Fig. 1

Schematic representation of lysine degradation pathways in mammals. Lysine can be degraded via pipecolate and saccharopine pathways. In the pipecolate pathway, that is believed to operate mostly in the brain, lysine is deaminated at the alpha nitrogen, and the resulted pipecolic acid is converted to P6C by pipecolate oxidase (PIPOX). In the saccharopine pathway that has been demonstrated in several tissues, lysine is deaminated at the epsilon nitrogen. In the first reaction step, catalyzed by the lysine-ketoglutarate reductase (LKR) domain of the aminoadipic semialdehyde synthase (AASS), lysine is condensed with α-ketoglutarate to form saccharopine. Than the saccharopine dehydrogenase (SDH) domain of AASS hydrolyse saccharopine into glutamic acid and α-aminoadipic-δ-semialdehyde (AASA). AASA is then oxidized to form aminoadipic acid (AAA) by the enzyme aminoadipic semialdehyde dehydrogenase (AASADH). AASA is in equilibrium with its cyclic form P6C. P6C can be used as substrate by the enzyme piperideine-5-carboxilic reductase (P5CR). AAA than proceeds to several enzymatic steps catalyzed by the enzymes AADAT (aminoadipate aminotransferase), DHTKD1 (dehydrogenase E1 and transketolase domain containing 1), GCDH (glutaryl-CoA dehydrogenase), ECHS1 (enoyl-CoA hydratase, short chain, 1), HADH (Hydroxyacyl-coenzyme A dehydrogenase) and ACAA2 (acetyl-CoA acyltransferase 2) to form acetyl-CoA. Mutations in the genes encoding AASADH and GCDH lead to PDE and glutaric aciduria type 1 disease, respectively