Disorders of purine nucleotide degradation include immunodeficiency, myopathy, renal calculi, hyperuricemia and gout, anemia, central nervous system dysfunction, and tissue hypoxia. Disease processes range from rare inborn errors of metabolism to common clinical abnormalities associated with tissue hypoxia and depletion of ATP. Two major types of disorders occur in this pathway: blocks of purine nucleotide degradation and increased activity of this pathway. In the present proposal, we will test the hypothesis that accelerated ATP degradation in humans accounts for the formation of increased purine nucleotide degradation products in specific disorders. We will approach this study by (a) Establishing whether accelerated ATP degradation is involved in the pathophysiology of ethanol-induced alterations of purine metabolism, carbohydrate-induced alterations of purine metabolism, elevated body fluid purines in acute illness and metabolic myopathies; (b) Studying a cell culture model to elucidate mechanisms regulating ATP degradation at the cellular level using a model of purine nucleotide degradation; and (c) Determining whether cytoplasmic 5'-nucleotidase has an important regulatory role in purine nucleotide degradation. This integrated approach involves a study on three levels, the patient, the cell and an enzyme and should provide a unique opportunity to test the hypothesis and its implications. The laboratory will continue to be a resource by providing assays of enzymes of purine metabolism for diagnosing inborn errors and by assisting investigators with studies of disorders of purine metabolism. The methods of procedure will include affinity techniques, high pressure liquid chromatography, cell culture, and new methods which we have developed to study purine nucleotide degradation in humans. By elucidating the role of accelerated ATP degradation in human disease, we may facilitate the design of innovative therapeutic approaches for stimulating adenine nucleotide synthesis in these disorders.
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