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: 8885996
• 负责人: Nathaniel Kolnik Szymczak
• 金额: $ 28.72万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8885996
• 关键词: Accounting; Acids; Active Sites; Address; Air; Alkanes; Amino Acids; Ammonia; Binding; Biological; Carbon Dioxide; Carbon monoxide dehydrogenase; Chemistry; Communities; Complex; Computer Simulation; Coupling; Development; Electron Transport; Electrons; Environment; Enzymes; Ethylenes; Goals; Heteronuclear NMR; Hydrazine; Hydrogen Bonding; In Situ; Individual; Knowledge; Life; Ligands; Metals; Modification; Molecular; Nature; Nitrogen; Nitrogenase; Nutrient; Oxidases; Pathway interactions; Play; Process; Property; Protons; Reaction; Research; Research Design; Respiration; Role; Series; Site; Spectrum Analysis; Structure; Substrate Interaction; System; Testing; Transition Elements; Translating; Variant; X ray diffraction analysis; X-Ray Diffraction; analog; base; biological systems; catalyst; cytochrome c oxidase; enzyme structure; expectation; metal complex; metalloenzyme; planetary Atmosphere; public health relevance; scaffold; small molecule; synthetic construct; uptake

 DESCRIPTION (provided by applicant): 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 during the reduction process. Although crucial for dinitrogen reduction, the precise molecular role that these secondary interactions take to promote reduction is not well known. More explicitly, the scientific community does not precisely know where and how substrates bind, and how electrons are delivered to N2. 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 maintain a constant environment within the primary coordination sphere, and modify appended functionality (hydrogen-bond donors/acceptors, Lewis acids/bases) in the secondary coordination sphere environment to evaluate cooperative reactivity. We will use these intermediate 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.

 描述（由适用提供）：全球氮循环需要二氮转化为氨，并通过氮酶从生物学上完成。尽管高度惰性，但二氮是由氮酶“固定”的，并使生物学上可用，从而使摄取可以形成维持生命所需的关键营养素。氮酶活性位点具有一个多金属核心，该核心包含在复杂的氨基酸网络中，这对于在还原过程中编排一系列多物种，多电子转移是必不可少的。尽管对于减少二氮的至关重要，但这些二次相互作用促进还原的精确分子作用并不众所周知。更明确的是科学 社区不确定底物的限制以及如何将电子传递到N2。这，我们的知识中存在一个继承差距，氮反应性的关键因素。为了解决这一差距，该建议针对的是包含高度定向且可变的二级配位球体相互作用的小分子构建体的设计和研究。我们将在初级协调领域保持恒定的环境，并在次级协调球环境中修改附加功能（氢键供体/受体，刘易斯酸/碱基）以评估坐标反应性。我们将使用这些中间结构来检验有关使用次级球形协调的底物分子降低的关键机理假设。我们建议，在我们的合成系统中评估的相同类型的相互作用可以通过扩展为描述生物系统的促进氮酶类型活性。我们获得的知识将为氮酶功能和合成氮酶的机械研究提供重要的贡献。高度定向的次级球相互作用促进的底物激活是许多生物催化循环中的广泛主题，因此，我们想象我们的研究结果将具有广泛的实用性，以阐明有意义的酶促反应性。