The Role of Secondary Interactions Relevant to Biological Reductions of Small Molecules

与小分子生物还原相关的次级相互作用的作用

• 批准号: 10451600
• 负责人: Nathaniel Kolnik Szymczak
• 金额: $ 37.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10451600
• 关键词: Acids; Active Sites; Address; Amino Acids; Ammonia; Atmosphere; Binding; Biological; Biological Availability; Communities; Complex; Development; Electron Transport; Electrons; Environment; Enzymes; Hydrogen Bonding; Knowledge; Life; Molecular; Molecular Structure; Nitrogen; Nitrogenase; Nutrient; Process; Protons; Role; Series; System; Testing; Translating; analog; base; biological systems; catalyst; design; metallicity; public health relevance; rational design; small molecule; uptake

Abstract: The conversion of dinitrogen to ammonia is required for the global nitrogen cycle and is accomplished biologically by nitrogenase enzymes. Although highly inert, dinitrogen is “fixed” by nitrogenase enzymes, and made biologically available, allowing uptake to form key nutrients necessary to sustain life. The nitrogenase enzyme active site features a multi-metallic core contained within a complex network of amino acids, which are necessary to orchestrate a series of multi-proton, multi-electron transfers to small molecule substrates during the reduction process. Although crucial for dinitrogen reduction, the precise molecular role that these secondary interactions serve to promote reduction is not well known. More explicitly, the scientific community does not precisely know where and how substrates bind, how electrons are delivered, and products released. Thus, there is an inherent gap in our knowledge underlying key contributors to nitrogenase reactivity. To address this gap, this proposal targets the design and study of small molecular constructs that contain highly directed and variable secondary coordination sphere interactions. We will use a rational design approach to prepare synthetic analogues that feature modifiable appended functionality (hydrogen-bond donors, Lewis acids/bases) in the secondary coordination sphere environment to evaluate cooperative reactivity. We will use these molecular structures to test key mechanistic hypotheses regarding the molecular-level reduction of substrates using secondary-sphere cooperativity. We propose that the same type of interactions evaluated in our synthetic systems that promote nitrogenase-type activity can be, by extension, adapted to describe biological systems. The knowledge we acquire will provide key needed contributions to mechanistic studies of nitrogenase function and also synthetic nitrogenases. Substrate activation promoted by highly directed secondary sphere interactions is a broad theme among many biocatalytic cycles, and thus, we envision that the results of our studies will have broad utility to elucidate meaningful contributors to enzymatic reactivity.

抽象的： 二氮转化为氨是全球氮循环所必需的，并且是通过生物完成的 尽管高度惰性，二氮仍被固氮酶“固定”并制成。 具有生物活性，可以吸收形成维持生命所需的关键营养物质。 活性位点具有包含在复杂的氨基酸网络中的多金属核心，这是必需的 在还原过程中协调一系列多质子、多电子转移到小分子底物 尽管对于二氮还原至关重要，但这些次级相互作用的精确分子作用。 促进减少的作用尚不为人所知，更明确的是，科学界并不确切知道。 底物在何处以及如何结合、电子如何传递以及产物如何释放因此，存在固有的。 我们对固氮酶反应性关键因素的了解存在差距，为了解决这一差距，本提案提出。 目标是设计和研究包含高度定向和可变次级的小分子结构 我们将使用合理的设计方法来制备合成类似物 二级结构中具有可修改的附加功能（氢键供体、路易斯酸/碱） 我们将使用这些分子结构来评估协同反应性。 使用二次球测试有关底物分子水平还原的关键机制假设 我们建议在我们的合成系统中评估相同类型的相互作用，以促进合作。 通过扩展，固氮酶类型的活性可以适用于描述生物系统。 获取将为固氮酶功能的机制研究以及合成提供关键所需的贡献 高度定向的次级球体相互作用促进底物活化是一个广泛的主题。 在许多生物催化循环中，因此，我们预计我们的研究结果将具有广泛的用途 阐明酶反应活性的有意义的贡献者。