Mouse lysine catabolism to aminoadipate occurs primarily through the saccharopine pathway; implications for pyridoxine dependent epilepsy (PDE).

Lysine is catabolized in mammals through the saccharopine and pipecolate pathways - the former is mainly hepatic and renal, and the latter is believed to play a role in the cerebral lysine oxidation. Both pathways lead to the formation of aminoadipic semialdehyde (AASA) that is then oxidized to aminoadipate (AAA) by antiquitin (ALDH7A1). Mutations in the ALDH7A1 gene result in the accumulation of AASA and its cyclic form, piperideine-6-carboxylate (P6C), which causes pyridoxine-dependent epilepsy (PDE). P6C reacts with pyridoxal 5'-phosphate (PLP) causing its inactivation. Here, we used liquid chromatography-mass spectrometry to investigate lysine catabolism in mice injected with lysine labelled at either its nitrogen epsilon (ε-15N) or nitrogen alpha (α-15N). Analysis of ε-15N and α-15N lysine catabolites in plasma, liver and brain suggested the saccharopine as the main pathway for AAA biosynthesis. Although there was evidence for upstream cerebral pipecolate pathway activity, the resulting pipecolate does not appear to be further oxidized into AASA/P6C/AAA. By far the bulk of lysine degradation and therefore, the primary source of lysine catabolites are hepatic and renal. The results indicate that the saccharopine pathway is primarily responsible for body's production of AASA/P6C. The centrality of the saccharopine pathway in whole body lysine catabolism opens new possibilities of therapeutic targets for PDE. We suggest that inhibition of this pathway upstream of AASA/P6C synthesis may be used to prevent its accumulation benefiting PDE patients. Inhibition of the enzyme aminoadipic semialdehyde synthase, for example, could constitute a new strategy to treat PDE and other inherited diseases of lysine catabolism.

The saccharopine pathway in seed development and stress response of maize.

Lysine is catabolized in developing plant tissues through the saccharopine pathway. In this pathway, lysine is converted into α-aminoadipic semialdehyde (AASA) by the bifunctional enzyme lysine-ketoglutarate reductase/saccharopine dehydrogenase (LKR/SDH). AASA is then converted into aminoadipic acid (AAA) by aminoadipic semialdehyde dehydrogenase (AASADH). Here, we show that LKR/SDH and AASADH are co-expressed in the sub-aleurone cell layers of the developing endosperm; however, although AASADH protein is produced in reproductive and vegetative tissues, the LKR/SDH protein is detectable only in the developing endosperm. AASADH showed an optimum pH of 7.4 and Kms for AASA and NAD(+) in the micromolar range. In the developing endosperm, the saccharopine pathway is induced by exogenous lysine and repressed by salt stress, whereas proline and pipecolic acid synthesis are significantly repressed by lysine. In young coleoptiles, the LKR/SDH and AASADH transcriptions are induced by abiotic stress, but while the AASADH protein accumulates in the stressed tissues, the LKR/SDH protein is not produced. In the developing seeds, the saccharopine pathway is used for pipecolic acid synthesis although proline may play a major role in abiotic stress response. The results indicate that the saccharopine pathway in maize seed development and stress responses significantly differ from that observed for dicot plants.

Current knowledge for pyridoxine-dependent epilepsy: a 2016 update.

Pyridoxine-dependent epilepsy (PDE) is a rare genetic condition characterized by intractable and recurrent neonatal seizures that are uniquely alleviated by high doses of pyridoxine (vitamin B6). This recessive disease is caused by mutations in ALDH7A1, a gene encoding Antiquitin, an enzyme central to lysine degradation. This results in the pathogenic accumulation of the lysine intermediates Aminoadipate Semialdehyde (AASA) and its cyclic equilibrium form Piperideine-6-carboxylate (P6C) in body fluids; P6C reacts with pyridoxal-5'-phosphate (PLP, the active form of vitamin B6) causing its inactivation and leading to pyridoxine-dependent seizures. While PDE is responsive to pharmacological dosages of pyridoxine, despite lifelong supplementation, neurodevelopment delays are observed in >75% of PDE cases. Thus, adjunct treatment strategies are emerging to both improve seizure control and moderate the delays in cognition. These adjunctive therapies, lysine restriction and arginine supplementation, separately or in combination (with pyridoxine thus termed 'triple therapy'), have shown promising results and are recommended in all PDE patients. Other new therapeutic strategies currently in preclinical phase of study include antisense therapy and substrate reduction therapy. We present here a comprehensive review of current treatment options as well as PDE phenotype, differential diagnosis, current management and views upon the future of PDE research.