Saccharocin

Mutations in the Aminoadipate-Semialdehyde Synthase (AASS) gene encoding α-aminoadipic semialdehyde synthase lead to hyperlysinemia-I, a benign metabolic variant without clinical significance, and hyperlysinemia-II with developmental delay and intellectual disability. Although both forms of hyperlysinemia display biochemical phenotypes of questionable clinical significance, an association between neurologic disorder and a pronounced biochemical abnormality remains a challenging clinical question. Here, we report that Aass mutant male and female mice carrying the R65Q mutation in α-ketoglutarate reductase (LKR) domain have an elevated cerebral lysine level and a normal brain development, whereas the Aass mutant mice carrying the G489E mutation in saccharopine dehydrogenase (SDH) domain exhibit elevations of both cerebral lysine and saccharopine levels and a smaller brain with defective neuronal development. Mechanistically, the accumulated saccharopine, but not lysine, leads to impaired neuronal development by inhibiting the neurotrophic effect of glucose-6-phosphate isomerase (GPI). While extracellular supplementation of GPI restores defective neuronal development caused by G498E mutation in SDH of Aass. Altogether, our findings not only unravel the requirement for saccharopine degradation in neuronal development, but also provide the mechanistic insights for understanding the neurometabolic disorder of hyperlysinemia-II.SIGNIFICANCE STATEMENT The association between neurologic disorder and a pronounced biochemical abnormality in hyperlysinemia remains a challenging clinical question. Here, we report that mice carrying the R65Q mutation in lysine α-ketoglutarate reductase (LKR) domain of aminoadipate-semialdehyde synthase (AASS) have an elevated cerebral lysine levels and a normal brain development, whereas those carrying the G489E mutation in saccharopine dehydrogenase (SDH) domain of AASS exhibit an elevation of both cerebral lysine and saccharopine and a small brain with defective neuronal development. Furthermore, saccharopine impairs neuronal development by inhibiting the neurotrophic effect of glucose-6-phosphate isomerase (GPI). These findings demonstrate saccharopine degradation is essential for neuronal development.

Lysine cannot be synthesized by most higher organisms and, therefore, is an indispensable amino acid (IAA) that must be consumed in adequate amounts to maintain protein synthesis. Although lysine is an abundant amino acid in body proteins, lysine is limited in abundance in many important food sources (e.g. grains). Older observations assigned importance to lysine because animals fed a lysine-deficient diet did not lose weight as fast as animals placed upon other IAA-deficient diets, leading to the theory that there may be a special pool of lysine or metabolites that could be converted to lysine. The first step in the lysine catabolic pathway is the formation of saccharopine and then 2-aminoadipic acid, processes that are mitochondrial. The catabolism of 2-aminoadipic acid proceeds via decarboxylation to a series of CoA esters ending in acetyl-CoA. In mammals, the liver appears to be the primary site of lysine catabolism. In humans, the metabolic and oxidative response of lysine to diets either restricted in protein or in lysine is consistent with what has been measured for other IAAs with isotopically labeled tracers. Intestinal microflora are known to metabolize urea to ammonia and scavenge nitrogen (N) for the synthesis of amino acids. Studies feeding 15N-ammonium chloride or 15N-urea to animals and to humans, demonstrate the appearance of 15N-lysine in gut microbial lysine and in host lysine. However, the amount of 15N-lysine transferred to the host is difficult to assess directly using current methods. It is important to understand the role of the gut microflora in human lysine metabolism, especially in conditions where dietary lysine intake may be limited, but better methods need to be devised.

The saccharopine pathway (SACPATH) involves the conversion of lysine into α-aminoadipate by three enzymatic reactions catalyzed by the bifunctional enzyme lysine-ketoglutarate reductase/saccharopine dehydrogenase (LKR/SDH) and the enzyme α-aminoadipate semialdehyde dehydrogenase (AASADH). The LKR domain condenses lysine and α-ketoglutarate into saccharopine, and the SDH domain hydrolyzes saccharopine to form glutamate and α-aminoadipate semialdehyde, the latter of which is oxidized to α-aminoadipate by AASADH. Glutamate can give rise to proline by the action of the enzymes Δ1-pyrroline-5-carboxylate synthetase (P5CS) and Δ1-pyrroline-5-carboxylate reductase (P5CR), while Δ1-piperideine-6-carboxylate the cyclic form of α-aminoadipate semialdehyde can be used by P5CR to produce pipecolate. The production of proline and pipecolate by the SACPATH can help plants face the damage caused by osmotic, drought, and salt stress. AASADH is a versatile enzyme that converts an array of aldehydes into carboxylates, and thus, its induction within the SACPATH would help alleviate the toxic effects of these compounds produced under stressful conditions. Pipecolate is the priming agent of N-hydroxypipecolate (NHP), the effector of systemic acquired resistance (SAR). In this review, lysine catabolism through the SACPATH is discussed in the context of abiotic stress and its potential role in the induction of the biotic stress response.