NITRIC OXIDE SYNTHASE--ENZYMOLOGY AND METABOLIC ROLE

一氧化氮合酶——酶学和代谢作用

• 批准号: 2900291
• 负责人: OWEN W GRIFFITH
• 金额: $ 21.37万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-06-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2900291
• 关键词: Mammalia; aminoacid metabolism; arginine; chemical synthesis; citrulline; enzyme inhibitors; enzyme mechanism; hydroxylation; hypotension; isozymes; nitric oxide; nitric oxide synthase

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.

产品说明： 一氧化氮合酶催化精氨酸的转化 NO激活可溶性鸟苷酸环化酶， 从而增加细胞cGMP含量。 由于cGMP是一种血管舒张剂， NO的产生在机体内具有重要的生理和病理生理功能， 维持正常的血压。 休克引起的低血压 等情况可能是由于NO生产过剩造成的。由于 NO是由三种NOS亚型产生的，它们可能是不同的。 激活后，申请人建议开发基于机制的同种型， NOS的特异性抑制剂。 四个相互作用但独立的目标是 提出了 目标1涉及更好地理解 精氨酸转化为OH-精氨酸。 目标2将调查 在这三种NOS同工型中的精氨酸/瓜氨酸结合位点。 目标3 设计并合成血红素结合精氨酸和瓜氨酸 衍生物. 目标4将开发共价反应，非代谢 抑制性精氨酸和瓜氨酸衍生物。 总体理由 开发亚型特异性抑制剂的目的是提供实验性的， 以及可以减轻水肿并发症的治疗工具 其伴随有马槟榔碱诱导的和内毒素血症性休克。