Structures, Mechanisms and Biogenesis of Amine Oxidases

含铜胺氧化酶广泛分布于自然界，参与生物伯胺的代谢。 胺氧化酶在哺乳动物的心血管、胃肠道和神经系统中可能具有多种功能。胺氧化酶也负责结缔组织结构蛋白（弹性蛋白和胶原蛋白）的交联。 似乎许多具有抗真菌、抗原生动物或抗癌活性的化合物可以靶向胺氧化酶。 例如，用于治疗AIDS患者的卡氏肺孢子虫肺炎（PCP）的主要药物喷他脒属于抑制胺氧化酶的化合物类别。 一个主要目标是确定多种胺氧化酶的3-D结构，包括人肾二胺氧化酶，其已被过度表达和纯化至均一。 其他主要目标是确定底物特异性和胺氧化酶之间的选择性抑制的分子基础，并阐明胺氧化和辅因子（TPQ）生物合成的机制。 此外，一个相关的酶，半乳糖氧化酶的结构和生物发生，将被检查。 采用定点诱变、光谱学、动力学测量和晶体学。 结合结构和机械数据将允许详细了解这些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.