Alpha-aminoadipic semialdehyde synthase (AASS)

Alpha-aminoadipic semialdehyde synthase is a bifunctional mitochondrial enzyme encoded by the AASS gene, responsible for catalyzing the first two steps of the lysine degradation (saccharopine) pathway in mammals[1][2][4]. It possesses two distinct enzymatic activities: an N-terminal lysine-2-oxoglutarate reductase (LOR) domain that condenses lysine and 2-oxoglutarate to form saccharopine, and a C-terminal saccharopine dehydrogenase (SDH) domain that oxidizes saccharopine to yield alpha-aminoadipic semialdehyde and glutamate[1][4]. This metabolic pathway regulates lysine levels, influences hepatic lysine catabolism, and connects to broader amino acid and energy metabolism. Deficiency or mutations in AASS cause hyperlysinemia, an autosomal recessive metabolic disorder with highly variable clinical outcomes, often asymptomatic but occasionally associated with neurological symptoms[1][3]. AASS is under investigation as a unique therapeutic target for disorders caused by defective downstream lysine degradation such as glutaric aciduria type 1, with emerging efforts to discover small molecule inhibitors of its domains[4].

Other names

Aminoadipate semialdehyde synthaseLysine ketoglutarate reductaseSaccharopine dehydrogenaseLKRLORSDHLKR/SDHLysine-2-oxoglutarate reductaseLysine-ketoglutarate reductase/saccharopine dehydrogenaseAlpha-aminoadipate semialdehyde synthaseSaccharopine dehydrogenase (NAD(+), L-glutamate-forming)Saccharopine dehydrogenase (NADP(+), L-lysine-forming)LORSDHLKRSDH

Inhibition of AASS or its lysine ketoglutarate reductase domain would reduce lysine degradation, potentially modulating lysine levels for metabolic disorders[4]