Biochemical and genetic studies of vitamin-responsive enzymopathies have resulted in the elucidation of a group of successfully treatable inherited metabolic disorders and have given new insight into the nutritional role of the various vitamins. We have recently demonstrated that one such disease, late-onset biotin-responsive multiple carboxylase deficiency, is caused by a deficiency of biotinidase activity. This enzyme catalyzes the removal of covalently bound biotin from the various co-enzyme-dependent caboxylases, thus regenerating the vitamin for reutilization. To fully understand the nutritional significance of the covalently bound vitamins it is now clear that their metabolism as well as their mode of action must be reconsidered. We plan to study the biochemistry and immunology of human biotinidase and clinical and genetic aspects of biotinidase deficiency. We will attempt to explain clinical variation observed in children affected with the disorder and to determine if these patients are accumlating serum and urinary biocytin, a product of carboxylase degradation and a substrate of biotinidase. We will develop more rapid and sensitive assays for studying the interaction of biotinidase and biotin in the fibroblasts, leukocytes and hepatocytes. We will investigate the enzyme's role in normal, biotin-deficient and biotin-supplemented states. Furthermore we will evaluate the effect of various hepatic, gastrointestinal and renal disorders, which result in decreased hepatic protein synthesis or protein loss, on biotinidase activity and biotin metabolism, and will examine the possible role of biotinidase in Reye's syndrome and sudden infant death syndrome. Finally we will conduct parallel studies of the enzyme, lipoamidase, which releases another covalently bound vitamin, lipoic acid. Because pyruvate dehydrogenase is a lipoic acid-dependent enzyme and deficiency of this enzyme is known to result in lactic acidosis, a primary defect in lipoamidase may be responsible for some unexplained disorders of lactic acid metabolism. The proposed research will provide a more complete understanding of the metabolic role of enzymes that recycle vitamins and their contribution to normal nutrition and a variety of known and possible vitamin deficiency states.
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