RECYCLING DEFECTS OF COVALENTLY-BOUND VITAMINS

对维生素反应性酶病的生化和遗传学研究 结果阐明了一组成功治疗的遗传性疾病 代谢紊乱，并为营养作用提供了新的见解 各种维生素。我们最近证明了一种这样的疾病， 迟发性生物素反应性多重羧基酶缺乏症是由 生物素酶活性缺乏。这种酶催化脱除 来自各种辅酶依赖的羧基酶的共价结合的生物素， 从而使维他命再生以供再利用。要充分了解 共价结合维生素的营养意义现在很清楚了 他们的新陈代谢和他们的行动模式必须是 重新考虑。我们计划研究人类的生物化学和免疫学 生物素酶与生物素酶缺乏症的临床和遗传学方面。我们 将尝试解释在受影响儿童中观察到的临床变异 并确定这些患者是否积聚了血清 和尿液生物细胞素，它是羧基酶降解的产物和底物 生物素酶。我们将开发更快速、更灵敏的检测方法 研究生物素酶与生物素在成纤维细胞中的相互作用， 白细胞和肝细胞。我们将研究这种酶在 正常、生物素缺乏和生物素补充状态。此外，我们 将评估各种肝、胃肠道和肾脏的影响 紊乱，导致肝脏蛋白质合成或蛋白质减少 损失，对生物素酶活性和生物素代谢，并将检查 生物素酶在雷氏综合征和婴儿猝死中的可能作用 综合症。最后，我们将对这种酶进行平行研究， 脂酰胺酶，释放另一种共价结合的维生素--硫辛酸。 因为丙酮酸脱氢酶是硫辛酸依赖的酶， 这种酶的缺乏已知会导致乳酸中毒，这是一种主要的 脂酰胺酶缺陷可能是一些无法解释的疾病的原因 乳酸代谢。拟议的研究将提供更完整的 了解循环维生素和蛋白质的酶的代谢作用 它们对正常营养的贡献以及各种已知和可能的 维生素缺乏症。

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.