NITRIC OXIDE SYNTHASE--ENZYMOLOGY AND METABOLIC ROLE

描述：一氧化氮合酶催化精氨酸的转化 对瓜氨酸和不。NO激活可溶性鸟苷酸环化酶，并且 从而增加细胞内cGMP含量。由于cGMP是一种血管松弛药， 没有一代人具有深刻的生理和病理生理功能 维持正常血压。休克引起的低血压 而其他情况可能归因于NO的过量生产。自.以来 一氧化氮是由三种不同亚型的一氧化氮合酶产生的 被激活后，申请人建议开发基于机制的、异构体- 一氧化氮合酶的特异性抑制剂。四个互动但独立的目标是 呈上了。目标1涉及更好地理解 精氨酸转化为羟基精氨酸。目标2将调查 三种一氧化氮合酶亚型中的精氨酸/瓜氨酸结合位点(S)。目标3 将设计和合成与血红素结合的精氨酸和瓜氨酸 衍生品。目标4将形成共价反应，不可代谢 抑制性精氨酸和瓜氨酸衍生物。总体上的理由是 开发异构体特异性抑制剂的目的是提供实验性的 以及可能缓解低血压并发症的治疗工具 它们伴随着细胞因子诱导和内毒素血症休克。

DESCRIPTION: Nitric oxide synthase catalyzes the conversion of arginine to citrulline and NO. NO activates soluble guanylyl cyclase, and thereby increases cellular cGMP content. Since cGMP is a vasorelaxant, NO generation has profound physiologic and pathophysiologic function in maintaining normal blood pressure. The hypotension resulting from shock and other conditions may be attributed to overproduction of NO. Since NO is generated by three isoforms of NOS which may be differentially activated, the applicant proposes to develop mechanism-based, isoform- specific inhibitors of NOS. Four interactive but independent aims are presented. Aim 1 concerns a better understanding of the chemistry of arginine conversion to OH-arginine. Aim 2 will investigate the arginine/citrulline binding site(s) in the three NOS isoforms. Aim 3 will be to design and synthesise heme-binding arginine and citrulline derivatives. Aim 4 will develop covalently reactive, non-metabolizable inhibitory arginine and citrulline derivatives. The overall rationale for developing isoform specific inhibitors is to provide experimental as well as therapeutic tools which may alleviate hypotensive complications which accompany cytokine-induced and endotoxemic shock.