Models for nitrate reductases and related enzymes

硝酸还原酶和相关酶的模型

• 批准号: 6848982
• 负责人: PARTHA BASU
• 金额: $ 22.28万
• 依托单位: DUQUESNE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6848982
• 关键词: chemical kinetics; chemical synthesis; electron transport; enzyme activity; enzyme complex; enzyme mechanism; enzyme model; metalloenzyme; molybdenum; nitrate reductases; oxidation reduction reaction; protein structure function; respiratory enzyme; spectrometry; xanthine oxidase

DESCRIPTION (provided by applicant): Redox reactions catalyzed by mononuclear molybdoenzymes (MMEs) can seriously impact human health. Not only do defects in the cofactor biosynthesis result in infant death, through sulfite oxidase (SO) and xanthine oxidase (XO) deficiencies, but XO has also been linked to tissue damage during reperfusion following ischemic conditions. In addition, the transformation of oxyanions by native bacterial flora can also lead to pathological conditions such as non-Hodgkin's lymphoma (nitrate reductase, NR) and arseniasis (arsenate reductase, arsenite oxidase). On a more global scale, mononuclear molybdoenzymes are involved in key reactions of biogeochemical cycles of carbon, nitrogen, sulfur and arsenic. The focus of this research program is to understand the factors that control the reactivity of the molybdenum center using analog systems to probe the structure function relationship in nitrate reductases and related enzymes. Our significant progress in the past three years with support from an NIH AREA grant (11 publications) includes developing procedures for the synthesis of novel molybdenum complexes including stable intermediates of oxygen atom transfer reactions, and the development of protocols for detailed kinetic analysis, and new generation of dithiolene ligands. With these tools in hand, we propose the following research goals: to design and synthesize new oxo-molybdenum complexes with conformationally strained dithiolene ligands; to understand details of OAT reactivity from dioxo-Mo(VI) center and to understand the OAT reactivity of the monooxo-Mo(VI) center and desoxo-Mo(IV) center. The results of the proposed research will make a significant contribution to the field of metalloenzymes (including MMEs) and their impact on human health.

描述（由申请人提供）：单核细胞内氧化还原酶（MME）催化的氧化还原反应会严重影响人体健康。辅因子生物合成的缺陷不仅通过亚硫酸氧化酶（SO）和黄嘌呤氧化酶（XO）缺陷导致婴儿死亡，而且XO还与缺血条件后再灌注期间的组织损伤有关。此外，天然细菌植物群对含氧阴离子的转化也可导致非霍奇金淋巴瘤（硝酸盐还原酶，NR）和亚砷酸盐（砷酸盐还原酶，亚砷酸盐氧化酶）等病理状态。在更全球的范围内，单核辅酶参与碳、氮、硫和砷的地球化学循环的关键反应。本研究计划的重点是了解控制钼中心的反应性的因素，使用模拟系统来探测硝酸还原酶和相关酶的结构功能关系。在过去三年中，我们在NIH AREA资助（11篇出版物）的支持下取得了重大进展，包括开发用于合成新型钼络合物的程序，包括氧原子转移反应的稳定中间体，以及开发详细动力学分析的方案，以及新一代二硫杂环戊烯配体。有了这些工具在手，我们提出了以下研究目标：设计和合成新的氧代钼配合物与构象紧张的二硫杂环戊烯配体，了解细节的OAT反应从二氧代钼（VI）中心和了解OAT反应的单氧代钼（VI）中心和脱氧钼（IV）中心。这项研究的结果将为金属酶（包括MMEs）及其对人类健康的影响领域做出重大贡献。