The broad objectives of this research project are to study the metabolism of lysine in the rat brain, to measure the endogenous contents of lysine mtabolites in the whole brain, to examine the subcellular distribution of lysine metabolites and their metabolizing enzymes in the brain tissues, and to synthesize the non-commercially available lysine metabolites for research use. A study is proposed to test the hypothesis that piperidine is formed from L-lysine via Delta1-piperideine 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. The endogenous contents of lysine metabolites and their metabolizing enzymes will be studied in the whole brain as well as subcellular cortical fractions. Examination of the possible association of lysine metabolites and/or their enzymes with the nerve endings and synaptic vesicles will be performed with the technique of density gradient centrifugation. Isotopically labeled lysine metabolites will be used for the study of uptake and distribution of these metabolites into the subcellular fractions in order to augment results obtained from the endogenous distribution study. 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, and other neuronal functions related to neurological disorders.
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