Mammalian tissues synthesize four Beta-amino carboxylic acids: 1) Beta-alanine, a catabolite of uracil, 2) R-Beta-amino-iso-butyrate (R-Beta-AiB), a catabolite of thymine, 3) S-Beta-amino-iso-butyrate (S-Beta-AiB), a catabolite of valine, and 4) Beta-leucine, reportedly a precursor of a small amount of L-leucine. Although the overall metabolism of these compounds is fairly well established, there are several reactions in their putative catabolic pathways for which no mammalian enzyme is yet identified. Factors controlling the cellular levels of Beta-amino acids or regulating the enzymes of their metabolism are also not yet well defined. In addition, relatively little is known of the extent to which mammals are able to metabolize the variety of other Beta-amino carboxylic acids which are produced by plants and microorganisms. Derangements and anomalies of Beta-amino acid metabolism and transport have received considerable attention. Increased urinary excretion of Beta-amino acids is, for example, associated with some cancers, pregnancy, anemia, stress, Down's syndrome, surgery, radiation, glucose infusion and inherited deficiency of R-Beta-AiB transaminase. There is also substantial evidence that Beta-alanine is a mammalian neurotransmitter, a finding which may explain the clinical severity of inherited deficiencies affecting the catabolism of Beta-alanine or carnosine (Beta-alanyl-histidine). The investigations proposed here will elucidate the mammalian metabolism of both endogenous and exogenous Beta-amino carboxylic acids and will develop methodologies for the in vivo manipulation of the enzymes and pathways involved in their metabolism. Specific goals include (i) the development of general methodologies for the analysis and preparation of enantiomeric Beta-amino acids, (ii) the elucidation of the mammalian pathways of Beta-alanine and R-Beta-AiB catabolism, (iii) the design and synthesis of inhibitors of R-Beta-AiB metabolism and their use in vivo to study thymine and nucleic acid turnover, (iv) an evaluation of the biochemical interconversion of R- and S-Beta-AiB, and (v) an investigation of the mammalian metabolism of Beta-substituted-Beta-amino acids. It is anticipated that these studies will help to resolve several uncertainties about the basic biochemistry of the Beta-amino acids and will provide enzyme inhibitors facilitating the in vivo study of pyrimidine turnover.
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