Understanding cerebral L-lysine metabolism: the role of L-pipecolate metabolism in Gcdh-deficient mice as a model for glutaric aciduria type I

作者：Posset Roland; Opp Silvana; Struys Eduard A; Voelkl Alfred; Mohr Heribert; Hoffmann Georg F; Koelker Stefan; Sauer Sven W; Okun Juergen G^*

来源：Journal of Inherited Metabolic Disease, 2015, 38(2): 265-272.

DOI：10.1007/s10545-014-9762-z

Inherited deficiencies of the L-lysine catabolic pathway cause glutaric aciduria type I and pyridoxine-dependent epilepsy. Dietary modulation of cerebral L-lysine metabolism is thought to be an important therapeutic intervention for these diseases. To better understand cerebral L-lysine degradation, we studied in mice the two known catabolic routes - pipecolate and saccharopine pathways - using labeled stable L-lysine and brain peroxisomes purified according to a newly established protocol. Experiments with labeled stable L-lysine show that cerebral L-pipecolate is generated along two pathways: i) a minor proportion retrograde after epsilon-deamination of L-lysine along the saccharopine pathway, and ii) a major proportion anterograde after alpha-deamination of L-lysine along the pipecolate pathway. In line with these findings, we observed only little production of saccharopine in the murine brain. L-pipecolate oxidation was only detectable in brain peroxisomes, but L-pipecolate oxidase activity was low (7 +/- 2 mu U/mg protein). In conclusion, L-pipecolate is a major degradation product from L-lysine in murine brain generated by alpha-deamination of this amino acid.

• 出版日期2015-3