CARNITINE PALMITOYLTRANSFERASE AND FATTY ACID METABOLISM

线粒体肉碱棕榈酰转移酶(CPT)酶系 (由CPT I、CPT II和转位酶组成)起着举足轻重的作用 在哺乳动物组织中调节脂肪酸代谢的作用。 最近，它作为一个潜在的网站受到了越来越多的关注 对高血糖状态的药物干预，现已得到承认 作为人类突变的基因座，其中一些会带来严重的后果。为. 多年来，我们一直试图解开CPT的复杂性 同工酶，在过去的赠款期间，发现了一些新的和 围绕其生化和功能的意想不到的特征 属性。使用克隆技术，我们现在已经达到了 一个激动人心的时代，有望在一年中为这个主题带来新的曙光 分子水平(例如，我们第一次获得了完整的 CPT酶的氨基酸序列)。 延续这一脉络，我们的总体目标是阐明 大鼠和人CPT蛋白的结构，它们的调节特性， 他们的基因的组织，以及遗传缺陷的性质 酶活性。将提出四个主要问题：(1)小学生如何 CPT I和CPT II在不同组织中的氨基酸序列比较(2) CPT I和CPT II如何与各自的膜相互作用， 底物和抑制剂？(3)大鼠CPT I和CPT II基因是如何 在数量和结构上的比较？(4)人类CPT基因和基因是如何 这些产品与它们的老鼠同行有关，其遗传基础是什么？ 对于遗传性CPT缺乏综合征？ 这些问题的答案将改变目前对 线粒体脂肪酸的运输来自模糊的、可操作的领域 具体的生物化学原理之一的定义。此外， 获得的信息可能会导致诊断，并可能导致治疗， 以过度或过度为特征的疾病状态的进展 脂肪酸氧化速率不足。

The mitochondrial carnitine palmitoyltransferase (CPT) enzyme system (composed of CPT I, CPT II and a translocase component) plays a pivotal role in the regulation of fatty acid metabolism in mammalian tissues. Recently it has received increasing attention as a potential site for pharmacological intervention in hyperglycemic states, and is now recognized as a locus of human mutations, some with serious consequences. For a number of years we have sought to unravel the complexities of the CPT isozymes, and during the past grant period have uncovered some novel and unexpected features surrounding their biochemical and functional properties. Using cloning techniques we have now reached the threshold of an exciting era that promises to shed new light on the subject at a molecular level (e.g., for the first time we have obtained the complete amino acid sequence of a CPT enzyme). Continuing in this vein our overall objectives are to elucidate the actual structures of the rat and human CPT proteins, their regulatory properties, the organization of their genes, and the nature of inherited defects in enzyme activity. Four main questions will be posed: (1) How do the primary amino acid sequences of CPT I and CPT II compare in different tissues? (2) How do CPT I and CPT II interact with their respective membranes, substrates and inhibitors? (3) How do the rat genes for CPT I and CPT II compare in number and structure? (4) How do the human CPT genes and gene products relate to their rat counterparts, and what is the genetic basis for the inherited CPT deficiency syndromes? Answers to these questions would transform current understanding of mitochondrial fatty acid transport from the realm of vague, operational definitions to one of concrete, biochemical principles. In addition, the information gained could lead to diagnostic, and possibly therapeutic, advances in the arena of disease states characterized by excessive or inadequate rates of fatty acid oxidation.