title: Understanding cerebral L-lysine metabolism: the role of L-pipecolate metabolism in Gcdh-deficient mice as a model for glutaric aciduria type I.
abstract: 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.
authors.affiliation: Division of Inherited Metabolic Diseases, University Children's Hospital, Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Posset
authors.forename: Silvana
authors.initials: S
authors.lastname: Opp
authors.forename: Eduard A
authors.initials: EA
authors.lastname: Struys
authors.forename: Alfred
authors.initials: A
authors.lastname: Völkl
authors.forename: Heribert
authors.initials: H
authors.lastname: Mohr
authors.forename: Georg F
authors.initials: GF
authors.lastname: Hoffmann
authors.forename: Stefan
authors.initials: S
authors.lastname: Kölker
authors.forename: Sven W
authors.initials: SW
authors.lastname: Sauer
authors.forename: Jürgen G
authors.initials: JG
authors.lastname: Okun
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics*; D000818:Animals; D001921:Brain / Q000201:enzymology*; D001928:Brain Diseases, Metabolic / Q000201:enzymology* / Q000235:genetics*; D003641:Deamination; D004195:Disease Models, Animal; D020022:Genetic Predisposition to Disease; D050770:Glutaryl-CoA Dehydrogenase / Q000172:deficiency* / Q000235:genetics*; D008099:Liver / Q000201:enzymology; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism*; D018345:Mice, Knockout; D010084:Oxidation-Reduction; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000378:metabolism; D020675:Peroxisomes / Q000201:enzymology; D010641:Phenotype; D010875:Pipecolic Acids / Q000378:metabolism*
chemical_list: D010875:Pipecolic Acids; D050770:Glutaryl-CoA Dehydrogenase; D000587:Oxidoreductases Acting on CH-NH Group Donors; C032771:L-pipecolate dehydrogenase; C031345:pipecolic acid; D008239:Lysine; C100169:saccharopine