RECYCLING DEFECTS OF COVALENTLY-BOUND VITAMINS

共价结合维生素缺陷的回收

• 批准号: 3231418
• 负责人: BARRY WOLF
• 金额: $ 11.09万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-07-01 至 1987-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3231418
• 关键词: amidohydrolases; bioassay; biotin; cellular immunity; covalent bond; decarboxylases; enzyme substrate; fibroblasts; high performance liquid chromatography; human subject; human tissue; inborn metabolism disorder; lactates; lactic acidosis; leukocytes; liver cells; nutrition related tag; orphan disease /drug; vitamin metabolism

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.

维生素反应性酶病的生化和遗传研究 结果阐明了一组成功治疗的遗传性 代谢紊乱，并提供了新的见解的营养作用， 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发性羧化酶缺乏症，由以下原因引起： 缺乏生物素酶活性。 这种酶催化去除 来自各种辅酶依赖性卡巴氨酶的共价结合的生物素， 从而使维生素再生再利用。 全面了解 共价结合维生素的营养意义现在已经很清楚了 它们的新陈代谢和作用方式必须 重新考虑 我们计划研究人类的生物化学和免疫学 生物素酶和生物素酶缺乏症的临床和遗传方面。 我们 将试图解释在受影响的儿童中观察到的临床变化 并确定这些患者是否有血清 和尿生物胞素，羧化酶降解的产物和底物 生物素酶 我们将开发更快速和灵敏的检测方法， 研究成纤维细胞中生物素酶和生物素的相互作用， 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 将评估各种肝脏、胃肠道和肾脏 导致肝脏蛋白质合成或蛋白质合成减少的疾病 损失，对生物素酶活性和生物素代谢，并将检查 生物素酶在Reye综合征和婴儿猝死中的作用 综合征 最后，我们将进行酶的平行研究， 脂酰胺酶，其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一种硫辛酸依赖性酶， 已知这种酶的缺乏会导致乳酸性酸中毒， 脂酰胺酶的缺陷可能导致一些无法解释的疾病， 乳酸代谢 这项研究将提供一个更完整的 了解酶的代谢作用，回收维生素和 它们对正常营养的贡献以及各种已知的和可能的 维生素缺乏症