Therapeutic modulation of cerebral l-lysine metabolism in a mouse model for glutaric aciduria type I

Sven W. Sauer, Silvana Opp, Georg F. Hoffmann, David M. Koeller, Jürgen G. Okun, Stefan Kölker

Research output: Contribution to journalArticlepeer-review

93 Scopus citations


Glutaric aciduria type I, an inherited deficiency of glutaryl-coenzyme A dehydrogenase localized in the final common catabolic pathway of l-lysine, l-hydroxylysine and l-tryptophan, leads to accumulation of neurotoxic glutaric and 3-hydroxyglutaric acid, as well as non-toxic glutarylcarnitine. Most untreated patients develop irreversible brain damage during infancy that can be prevented in the majority of cases if metabolic treatment with a low l-lysine diet and l-carnitine supplementation is started in the newborn period. The biochemical effect of this treatment remains uncertain, since cerebral concentrations of neurotoxic metabolites can only be determined by invasive techniques. Therefore, we studied the biochemical effect and mechanism of metabolic treatment in glutaryl-coenzyme A dehydrogenase-deficient mice, an animal model with complete loss of glutaryl-coenzyme A dehydrogenase activity, focusing on the tissue-specific changes of neurotoxic metabolites and key enzymes of l-lysine metabolism. Here, we demonstrate that low l-lysine diet, but not l-carnitine supplementation, lowered the concentration of glutaric acid in brain, liver, kidney and serum. l-carnitine supplementation restored the free l-carnitine pool and enhanced the formation of glutarylcarnitine. The effect of low l-lysine diet was amplified by add-on therapy with l-arginine, which we propose to result from competition with l-lysine at system y+ of the blood-brain barrier and the mitochondrial l-ornithine carriers. l-Lysine can be catabolized in the mitochondrial saccharopine or the peroxisomal pipecolate pathway. We detected high activity of mitochondrial 2-aminoadipate semialdehyde synthase, the rate-limiting enzyme of the saccharopine pathway, in the liver, whereas it was absent in the brain. Since we found activity of the subsequent enzymes of l-lysine oxidation, 2-aminoadipate semialdehyde dehydrogenase, 2-aminoadipate aminotransferase and 2-oxoglutarate dehydrogenase complex as well as peroxisomal pipecolic acid oxidase in brain tissue, we postulate that the pipecolate pathway is the major route of l-lysine degradation in the brain and the saccharopine pathway is the major route in the liver. Interestingly, treatment with clofibrate decreased cerebral and hepatic concentrations of glutaric acid in glutaryl-coenzyme A dehydrogenase-deficient mice. This finding opens new therapeutic perspectives such as pharmacological stimulation of alternative l-lysine oxidation in peroxisomes. In conclusion, this study gives insight into the discrepancies between cerebral and hepatic l-lysine metabolism, provides for the first time a biochemical proof of principle for metabolic treatment in glutaric aciduria type I and suggests that further optimization of treatment could be achieved by exploitation of competition between l-lysine and l-arginine at physiological barriers and enhancement of peroxisomal l-lysine oxidation and glutaric acid breakdown.

Original languageEnglish (US)
Pages (from-to)157-170
Number of pages14
Issue number1
StatePublished - Jan 2011


  • basic amino acid transporter
  • dicarboxylic acids
  • lysine metabolism
  • pipecolic acid
  • saccharopine

ASJC Scopus subject areas

  • Clinical Neurology


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