ISOLEUCINE METABOLISM IN MAN

已知异亮氨酸（Ile）的代谢涉及转氨作用， S（+）-α-酮基-β-甲基戊酸酯（S-KMVA），然后氧化 脱羧为S-α-甲基丁酰CoA，最终为丙酰 检验报告。 然而，S-KMVA也转化为R（-） α-酮-β-甲基戊酸（R-KMVA）在未知位点，引起 转氨作用为别异亮氨酸（Ale）。 这种转化率和 R-KMVA脱羧（生成R-α-甲基丁酰CoA）的速率 并最终转化为丁酰辅酶A）是未知的， Ile代谢，尤其是在接受KMVA治疗的患者中。 我们 我建议通过[1- 13 C]的预充连续输注来解决这个问题 异亮氨酸，加上两种形式的标记别异亮氨酸。 以下 正常人全身Ile通量和氧化率的初步研究 人，输注[1- 13 C]异亮氨酸、[1- 14 C]别异亮氨酸，和 [甲基-2H3]别异亮氨酸将首先在犬中进行，然后在 伙计 通过测定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 #21040;，R大于CO2）。 静脉注射和鼻饲 将比较输注以评估内脏床在以下方面的作用： 这些反应。 饮食中限制异亮氨酸对这些 通量将进行研究。 将检查犬的器官匀浆， 它们催化这些反应的能力。 高血浆患者 由于长期R，S-KMVA给药，Ale和KMVA的水平将 静脉注射同样的同位素 循环时间过程 Ile、Ale、S-KMVA和R-KMVA单次负荷后的Ile、Ale、 将在正常受试者中测量S-KMVA或R-KMVA两小时。 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 在BCKA存在下这些化合物之间的稳态关系 脱氢酶缺乏症 研究结果应澄清以下几个方面： 胰岛代谢。

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.