CRYSTAL STRUCTURE OF L-3-HYDROXACYL COA DEHYDROGENASE

短链L-3-羟基酰辅酶A脱氢酶(SCHAD)是一种 线粒体酶参与脂肪酸的新陈代谢。它 催化L-3-羟基酰基的羟基氧化 CoA到酮基，伴随着NAD+还原到 不会的。这种酶的缺乏会导致各种疾病状态， 包括肥厚型心肌病，骨骼肌病， 低酮症低血糖和肝功能障碍。建议数 研究利用多方面的方法来理解 结构-功能关系存在于人类SCHAD中。谢哈德遗嘱 从适当的表达系统中纯化到同质性 并对其动力学性质进行了表征。人体鱼鳞片的晶体 适用于x射线衍射研究的材料将在 为了解析脱辅酶的三维结构， NAD+络合酶和酰辅酶A络合酶。立地 定向诱变和合理的抑制剂设计研究将 发起以确认或进一步发展我们对 酶机制。对Schad的刻画将提供 关于类似蛋白质的作用方法的信息，如 AS长链(LCHAD)和过氧化物型L-3-羟基酰辅酶A 脱氢酶。这些研究将有助于解释突变 这导致了SCHAD和LCHAD的缺陷，并提供了更大的 了解与此相关的疾病状态 不足之处。

Short chain L-3-hydroxyacyl CoA dehydrogenase (SCHAD) is a mitochondrial enzyme involved in the metabolism of fatty acids. It catalyzes the oxidation of the hydroxyl group of L-3-hydroxyacyl CoA to a keto group, concomitant with the reduction of NAD+ to NADH. Deficiencies in this enzyme result in various disease states, including hypertrophic cardiomyopathy, skeletal myopathy, hypoketotic hypoglycemia, and liver dysfunction. The proposed research utilizes a multi-faceted approach to understanding the structure-function relationships present in human SCHAD. SCHAD will be purified to homogeneity from an appropriate expression system and its kinetic properties characterized. Crystals of human SCHAD suitable for x-ray diffraction studies will then be prepared in order to resolve the three-dimensional structure of the apoenzyme, the NAD+-complexed enzyme, and the acyl-CoA-complexed enzyme. Site directed mutagenesis and rational inhibitor design studies will be initiated to confirm or further develop our understanding of the enzyme mechanism. Characterization of SCHAD would provide information about the method of action of analogous proteins, such as long chain (LCHAD) and peroxisomal L-3-hydroxyacyl CoA dehydrogenases. These studies would help explain the mutations which result in SCHAD and LCHAD deficiencies, and provide a greater understanding of the disease states associated with these deficiencies.