NITRIC OXIDE INHIBITION OF TARGET ENZYMES

在过去的几年里，一氧化氮（NO）已经成为一种重要的 在几个关键的生理过程中的介质。 一般来说，当 合成用于血管稳态、神经元通信，以及 免疫系统功能的NO水平受到严格控制。 在 此外，持续或升高的NO合成可能是有害的， 可能是内毒素休克的重要病因，炎症相关 组织损伤、神经病理学和N-亚硝胺诱导的 致癌作用 此外，NO可引起人类细胞中的突变， 细菌通过与DNA的脱氨基反应。 诱导型一氧化氮合酶 暗示为持续的NO形成的来源。 受体 介导的NO形成的组成型酶响应于 兴奋性氨基酸谷氨酸现在已经令人兴奋，但已经打开了 关于这种反应性物质的毒性的一些重要问题 分子。 该项目的总体长期目标是一个彻底的 在生物条件下NO的反应性的表征。 对这种反应性的理解是疾病状态不可或缺的 这是由高水平和持续的NO合成引起的。 具体 本项目的目标如下：本反应的目标，（2） 测定中性粒细胞NOS活性;（3）过氧化物酶和髓过氧化物酶活性 催化反应与NO和亚硝化反应，（4）研究非- 针对NO靶细胞防御系统，（5）为其他 项目包括：小鼠巨噬细胞NO合酶（NOS）的cDNA， 协同肝脏表达实验，N-烷基-L-精氨酸 作为NOS抑制剂的衍生物，以及抗 诱导型NOS。

Over the last several years nitric oxide (NO) has emerged as an important mediator in several key physiological processes. In general, when synthesized for blood vessel homeostasis, neuronal communication, and immune system function the levels of NO are tightly controlled. In addition, sustained or elevated synthesis of NO can be deleterious and may be important in the etiology of endotoxic shock, inflammation-related tissue damage, neuronal pathology and N-nitrosamine-induced carcinogenesis. Furthermore, NO can cause mutations in human cells and bacteria via deamination reactions with DNA. The inducible NOS has been implicated as the source of the sustained NO formation. Receptor mediated NO formation by the constitutive enzyme in response to the excitatory amino acid glutamate has now been exciting but has opened the door to some important questions regarding the toxicity of this reactive molecule. The overall long-term goal for this project is a thorough characterization of the reactivity of NO under biological conditions. An understanding of this reactivity is integral to the disease states brought about by high and sustained levels of NO synthesis. The specific aims of this project are as follows: The aims of this reactions, (2) characterize the neutrophil NOS, (3) study peroxidase and myeloperoxidase catalyzed reactions with NO and nitrosation reactions, (4) study non- target cell defense systems against NO, (5) provide key reagents to other projects including: cDNA for the murine macrophage NO synthase (NOS) for the collaborative liver expression experiments, N-alkyl-L-arginine derivatives as inhibitors for the NOS, and polyclonal antibodies against the inducible NOS.