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

Abstract

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-N) or nitrogen alpha (α-N). Analysis of ε-N and α-N 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.

Disorders affecting vitamin B6 metabolism

“…When a formula low in lysine and tryptophan (as manufactured for treatment of glutaric aciduria type I) is used there is a potential risk of low plasma tryptophan leading to central serotonin deficiency. Other therapeutic strategies currently being investigated, although still some way from clinical translation, include antisense therapy and substrate reduction therapy …”

“…The contribution of each pathway to lysine catabolism depends on the age of the individual and cell-type studied; studies in mice suggest that the saccharopine pathway is primarly reponsible for AASA/P6C prodcution. 80,81 POX, L-pipecolate oxidase; PYRC, pyrroline-5-carboxylate reductase (three homologous genes exist; PYCR1 and PYCR2 localize to mitochondria and possibly with the outer mitochondrial membrane and PYCRL (aka PYCR3) is cytosolic 122,123 deficiency. An overview of the clinical features of patients with ALDH7A1 deficiency is as detailed in Figure 5 (adapted from Karnebeek et al 69 ).…”

“…Other therapeutic strategies currently being investigated, although still some way from clinical translation, include antisense therapy and substrate reduction therapy. 80,81 11 | PYRIDOX(AM)INE PHOSPHATE OXIDASE DEFICIENCY Kuo and Wang 82 described a neonate whose seizures were not controlled by pyridoxine but were well controlled by PLP. Clayton et al 83 described the same phenomenon in an infant whose pre-PLP biochemistry suggested deficient PLP-dependent enzyme activities: low CSF concentrations of HVA and 5HIAA with raised CSF 3-methoxytyrosine and urinary vanillactate (indicating aromatic amino acid decarboxylase deficiency) and raised plasma threonine and glycine indicating defects in the PLP-dependent pathways for catabolism of these amino acids.…”

New insights into human lysine degradation pathways with relevance to pyridoxine‐dependent epilepsy due to antiquitin deficiency

“…13,14 Development of inhibitors of α-aminoadipic semialdehyde synthase (AASS), the enzyme which converts lysine to saccharopine, was proposed as a possible new treatment strategy in patients with ATQ deficiency. 13,14 As any activity through the PA pathway could result in accumulation of AASA/P6C even if AASS is inhibited, it is important to determine whether the saccharopine pathway is also the major lysine degradation pathway in human brain, as the lysine degradation pathways appear to show species-specific activities. [15][16][17][18][19]33 In this study, we used isotopic tracing studies to examine whether in human brain cells, AAA is formed by the PA pathway as has been deduced from previous studies, or by the saccharopine pathway as was recently demonstrated in mouse brain.…”

C/D-Box Snord105b Promotes Tumorigenesis in Gastric Cancer via ALDOA/C-Myc Pathway

“…Based on conserved sequence elements, snoRNAs are classified as C/D box snoRNAs or H/ACA box snoRNAs. The best-understood function of snoRNAs is to define the target sites of rRNAs for 2'-O-ribose methylation and pseudouridylation [3, 4]. Thus, snoRNAs play a vital role in the genesis and processing of the ribosome.…”