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Understanding cerebral L‐lysine metabolism: the role of L‐pipecolate metabolism in Gcdh‐deficient mice as a model for glutaric aciduria type I
Author(s) -
Posset Roland,
Opp Silvana,
Struys Eduard A.,
Völkl Alfred,
Mohr Heribert,
Hoffmann Georg F.,
Kölker Stefan,
Sauer Sven W.,
Okun Jürgen G.
Publication year - 2015
Publication title -
journal of inherited metabolic disease
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 102
eISSN - 1573-2665
pISSN - 0141-8955
DOI - 10.1007/s10545-014-9762-z
Subject(s) - lysine , catabolism , glutaric acid , deamination , endocrinology , medicine , metabolism , biochemistry , chemistry , amino acid , enzyme
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 ε‐deamination of L‐lysine along the saccharopine pathway, and ii) a major proportion anterograde after α‐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 ± 2μU/mg protein). In conclusion, L‐pipecolate is a major degradation product from L‐lysine in murine brain generated by α‐deamination of this amino acid.