ISOLEUCINE METABOLISM IN MAN

人体异亮氨酸代谢

• 批准号: 3152453
• 负责人: MACKENZIE WALSER
• 金额: $ 12.89万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-08-01 至 1986-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3152453
• 关键词: acidosis; aminoacid metabolism; chemical structure function; dietary aminoacid; human subject; human tissue; inborn metabolism disorder; intravenous administration; ion exchange chromatography; isoleucine; ketoacid; liver metabolism; middle childhood (6-11); nutrition related tag; oxidoreductase; preschool child (1-5); radiotracer; renal failure; stereoisomer

The metabolism of isoleucine (Ile) is known to involve transamination to S(+)-Alpha-keto-Beta-methylvalerate (S-KMVA) followed by oxidative decarboxylation to S-Alpha-methylbutyryl CoA and eventually to propionyl CoA. However, S-KMVA is also converted to R(-) Alpha-keto-Beta-methylvalerate (R-KMVA) at an unknown site, giving rise by transamination to alloisoleucine (Ale). The rate of this conversion and the rate at which R-KMVA is decarboxylated (to R-Alpha-methylbutyryl CoA and eventually to butyryl CoA) are unknown, as are several other aspects of Ile metabolism, especially in patients receiving KMVA therapeutically. We propose to pursue this problem by primed continuous infusions of [1-13C] isoleucine, plus two forms of labelled alloisoleucine. Following preliminary studies of whole body Ile flux and oxidation rates in normal man, infusions of [1-13C] isoleucine, [1-14C] alloisoleucine, and [methyl-2H3] alloisoleucine will be conducted first in dogs and then in man. By measuring isotopic enrichment of Ile, Ale, S-KMVA, R-KMVA, and expired CO2, the 4 fluxes (S greater than CO2, S greater than R, R greater than S, and R greater than CO2) can be estimated. I.v. and nasogastric infusions will be compared to assess the role of the splanchnic bed in these reactions. The effect of dietary isoleucine restriction on these fluxes will be studies. Organ homogenates from dogs will be examined for their capacity to catalyze these reactions. Patients with high plasma levels of Ale and KMVA, owing to chronic R,S-KMVA administration, will be infused i.v. with these same isotopes. The time course of circulating levels of Ile, Ale, S-KMVA, and R-KMVA following single loads of Ile, Ale, S-KMVA, or R-KMVA will be measured for two hours in normal subjects. Plasma of children with branched-chain ketoaciduria, treated and untreated, will be analyzed for Ile, Ale, S-KMVA, and R-KMVA to determine the steady-state relationships between these compounds in the presence of BCKA dehydrogenase deficiency. The results should clarify several aspects of Ile metabolism.

已知异亮氨酸 (Ile) 的代谢涉及转氨基作用 S(+)-α-酮基-β-戊酸甲酯 (S-KMVA)，然后进行氧化 脱羧为 S-α-甲基丁酰 CoA，并最终生成丙酰 辅酶A。 然而，S-KMVA 也转换为 R(-) α-酮-β-甲基戊酸 (R-KMVA) 位于未知位点，产生 转氨为别异亮氨酸 (Ale)。 此转换率和 R-KMVA 脱羧（生成 R-α-甲基丁酰 CoA）的速率 并最终形成丁酰辅酶A）尚不清楚，其他几个方面也是未知的 Ile 代谢，尤其是接受 KMVA 治疗的患者。 我们 建议通过启动连续输注[1-13C]来解决这个问题 异亮氨酸，加上两种形式的标记的别异亮氨酸。 下列的 正常人全身 Ile 通量和氧化率的初步研究 男性，输注 [1-13C] 异亮氨酸、[1-14C] 别异亮氨酸，以及 [甲基-2H3]别异亮氨酸将首先在狗中进行，然后在 男人。 通过测量 Ile、Ale、S-KMVA、R-KMVA 和 呼出的CO2，4个通量（S大于CO2，S大于R，R大于 大于 S，且 R 大于 CO2) 可以估计。 静脉注射和鼻胃管 将比较输注以评估内脏床在 这些反应。 膳食异亮氨酸限制对这些的影响 通量将被研究。 将检查狗的器官匀浆 它们催化这些反应的能力。 高血浆患者 由于长期使用 R,S-KMVA，Ale 和 KMVA 的水平将 静脉注射与这些相同的同位素。 流通的时间进程 单次负载 Ile、Ale、S-KMVA 和 R-KMVA 后的 Ile、Ale、S-KMVA 和 R-KMVA 水平 对于正常受试者，将测量 S-KMVA 或 R-KMVA 两个小时。 治疗和未治疗的支链酮酸尿症儿童的血浆， 将分析 Ile、Ale、S-KMVA 和 R-KMVA，以确定 BCKA 存在下这些化合物之间的稳态关系 脱氢酶缺乏。 结果应澄清以下几个方面 胰岛代谢。