Structures, Mechanisms and Biogenesis of Amine Oxidases

含铜的胺氧化酶在自然界中分布广泛，参与生物伯胺的代谢。胺氧化酶在哺乳动物的心血管、胃肠和神经系统中可能具有多种功能。胺氧化酶也是结缔组织结构蛋白(弹性蛋白和胶原)的交联物。似乎许多具有抗真菌、抗原虫或抗癌活性的化合物可能以胺氧化酶为靶标。例如，用于治疗艾滋病患者的卡氏肺孢子虫肺炎(PCP)的主要药物扑热息痛属于抑制胺氧化酶的一类化合物。一个主要的目标是确定多种胺氧化酶的三维结构，包括人肾二胺氧化酶，它已经过表达并纯化到均一。其他主要目的是确定底物专一性和胺氧化酶选择性抑制的分子基础，并阐明胺氧化和辅因子(TPQ)生物发生的机制。此外，还将研究一种相关酶--半乳糖氧化酶的结构和生物发生。使用了定点突变、光谱、动力学测量和结晶学。结合结构和机理数据将使人们能够详细了解这些待开发的重要酶的结构和功能。

Copper-containing amine oxidases are widely distributed in nature and are involved in the metabolism of biogenic primary amines. Amine oxidases may have a variety of functions in the cardiovascular, gastrointestinal, and nervous systems of mammals. Amine oxidases are also responsible for the cross-linking of connective tissue structural proteins (elastin and collagen). It appears that numerous compounds with antifungal, antiprotozoal, or anticancer activities may target amine oxidases. For example pentamidine, a leading drug for the treatment of Pneumocystis carinii pneumonia (PCP) in AIDS patients belongs to class of compounds that inhibit amine oxidases. A major goal are to determine the 3-D structures of multiple amine oxidases, including human kidney diamine oxidase, which has been over-expressed and purified to homogeneity. Other major goals are to define the molecular bases for substrate specificity and selective inhibition among amine oxidases, and to elucidate the mechanisms of amine oxidation and cofactor (TPQ) biogenesis. In addition, the structure and biogenesis of a related enzyme, galactose oxidase, will be examined. Site-directed mutagenesis, spectroscopy, kinetics measurements, and crystallography are employed. Combining structural and mechanistic data will permit a detailed understanding of the structure and function of these important enzymes to be developed.