Models for nitrate reductases and related enzymes

描述(申请人提供)：由单核钼酶(MME)催化的氧化还原反应会严重影响人类健康。辅因子生物合成缺陷不仅通过亚硫酸盐氧化酶(SO)和黄嘌呤氧化酶(XO)缺陷导致婴儿死亡，而且XO也与缺血后再灌注期间的组织损伤有关。此外，天然细菌群对氧阴离子的转化也会导致诸如非霍奇金淋巴瘤(硝酸盐还原酶，NR)和砷中毒(砷酸还原酶，亚砷酸盐氧化酶)等病理情况。在更全球的范围内，单核钼酶参与了碳、氮、硫和砷的生物地球化学循环的关键反应。本研究计划的重点是利用模拟系统了解控制钼中心活性的因素，以探索硝酸还原酶和相关酶的结构功能关系。在过去三年中，我们在美国国立卫生研究院区域赠款的支持下取得了重大进展(11篇出版物)，包括开发了合成新型钼配合物的方法，包括氧原子转移反应的稳定中间体，开发了详细的动力学分析方案，以及新一代二硫杂环戊烯配体。有了这些工具，我们提出了以下研究目标：设计和合成新的具有构象应变的二硫杂环钼配合物；了解二氧钼(VI)中心的OAT反应性细节；了解单氧钼(VI)中心和脱氧钼(IV)中心的OAT反应性。拟议的研究结果将对金属酶(包括MME)领域及其对人类健康的影响做出重大贡献。

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.