CRYSTAL STRUCTURE OF L-3-HYDROXACYL COA DEHYDROGENASE

短链L-3-羟酰辅酶A脱氢酶（SCHAD）是一种具有生物活性的辅酶A脱氢酶。 参与脂肪酸代谢的线粒体酶。它 催化L-3-羟酰基的羟基氧化， CoA至酮基，同时NAD+减少至 NADH。这种酶的缺陷导致各种疾病状态， 包括肥厚型心肌病，骨骼肌病， 低酮性低血糖和肝功能障碍拟议 研究利用多方面的方法来了解 存在于人SCHAD中的结构-功能关系。SCHAD将 从合适的表达系统中纯化至均一 并表征了其动力学性质。人SCHAD晶体 然后将制备适合于X射线衍射研究的 为了解析脱辅基酶的三维结构， NAD+复合酶和酰基辅酶A复合酶。网站 定向诱变和合理的抑制剂设计研究将是 发起，以确认或进一步发展我们对 酶机制SCHAD的表征将提供 关于类似蛋白质的作用方法的信息，例如 作为长链（LCHAD）和过氧化物酶体L-3-羟酰辅酶A - 是的这些研究有助于解释 这会导致SCHAD和LCHAD缺陷，并提供更大的 了解与这些疾病相关的疾病状态 缺陷

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.