The broad objectives of this research project are to study the metabolism of lysine in the rat brain, to examine the regional and subcellular distribution of lysine metabolizing enzymes in the brain, and to synthesize the non-commercially available lysine metabolites for research use. Attempts will be made to elucidate the reaction mechanism of each metabolic step for lysine in the brain, and to identify the metabolic intermediates involved in each enzymatic reaction. Isotope-labeling, flourometric and spectrophotometric techniques will be used for these studies. A study is also proposed to test the hypothesis that piperidine is formed from L-lysine via delta1-piperidine by """"""""abortive transamination."""""""" Experiments are also proposed to examine the possibility of enzyme-bound intermediates in the metabolism of L-lysine to L-pipecolate. Properties of the enzymes involved in the metabolism of L-lysine in the brain will be studied with the design of new and sensitive assay methods. Affinity chromatography and affinity precipitation will be used to purify lysine oxidase, delta1-piperideine-2-carboxylate reductase and pipecolate oxidase. The metabolizing enzymes will be studied in the subcellular cortical fractions. Examination of the possible association of these enzymes with the nerve endings and other subcellular organelles will be performed with the technique of density gradient centrifugation. Synthesis of lysine metabolites, both labeled and unlabeled, will utilize microbial, enzymatic as well as organic synthesis techniques. It is hoped that the knowledge obtained in this work will help understand the etiology of human genetic disorders related to brain lysine metabolism, and the role of lysine and its metabolites play in sedation, sleep, convulsion and other neuronal function related to neurological disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurological Sciences Subcommittee 1 (NLS)
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University of Maryland Baltimore
Schools of Dentistry
United States
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Chang, Y F; Cauley, R K; Chang, J D et al. (1997) L-alpha-aminoadipate inhibits kynurenate synthesis in rat brain hippocampus and tissue culture. Neurochem Res 22:825-9
Tsai, M J; Chang, Y F; Schwarcz, R et al. (1996) Characterization of L-alpha-aminoadipic acid transport in cultured rat astrocytes. Brain Res 741:166-73
Chang, Y F; Gao, X M (1995) L-lysine is a barbiturate-like anticonvulsant and modulator of the benzodiazepine receptor. Neurochem Res 20:931-7
Chang, Y F; Charles, A K (1995) Uptake and metabolism of delta 1-piperidine-2-carboxylic acid by synaptosomes from rat cerebral cortex. Biochim Biophys Acta 1238:29-33
Chang, Y F; Wang, Y; Cauley, R K et al. (1993) Chronic L-lysine develops anti-pentylenetetrazol tolerance and reduces synaptic GABAergic sensitivity. Eur J Pharmacol 233:209-17
Rao, V V; Pan, X; Chang, Y F (1992) Developmental changes of L-lysine-ketoglutarate reductase in rat brain and liver. Comp Biochem Physiol B 103:221-4
Rao, V V; Chang, Y F (1992) Assay for L-pipecolate oxidase activity in human liver: detection of enzyme deficiency in hyperpipecolic acidaemia. Biochim Biophys Acta 1139:189-95
Chang, Y F; Gao, X M; Chen, J S (1991) Correlation between enhancement of [3H]flunitrazepam binding and suppression of pentylenetetrazol-induced seizures by L-lysine. Eur J Pharmacol 193:239-47
Chang, Y F; Ghosh, P; Rao, V V (1990) L-pipecolic acid metabolism in human liver: L-alpha-aminoadipate delta-semialdehyde oxidoreductase. Biochim Biophys Acta 1038:300-5
Rao, V V; Chang, Y F (1990) L-pipecolic acid metabolism in human liver: detection of L-pipecolate oxidase and identification of its reaction product. Biochim Biophys Acta 1038:295-9

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