CAREER: Geometric and Electronic Contributions to Bio-inspired Reactivities of Heme-superoxide Intermediates

职业：几何和电子对血红素超氧化物中间体的仿生反应活性的贡献

• 批准号: 2422277
• 负责人: Gayan Wijeratne
• 金额: $ 71万
• 依托单位: University of Alabama Tuscaloosa
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2024
• 资助国家: 美国
• 起止时间: 2024-04-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=2422277&HistoricalAwards=false
• 关键词: CAREER; Geometric; Electronic; Contributions; Bio

With support from the Chemistry of Life Processes Program in the Division of Chemistry and the Established Program to Stimulate Competitive Research (EPSCoR) Dr. Gayan B. Wijeratne at the University of Alabama at Birmingham will investigate the chemistry of small molecules with heme iron centers such as the ones that activate oxygen in human biology. These model systems can be extremely versatile, yet straightforward probes for comprehending the complicated mechanistic details that govern oxygen mediated reactivities in biology. Dr. Wijeratne and his team will utilize these powerful tools in shedding light on yet unknown knowledge that can lead to pathways for efficient syntheses of complex molecules, and the discovery of catalysts that can enhance the efficiency of catalysts of oxygen reduction benefiting alternative energy applications. This work will involve bio-inspired design and synthesis of fresh model systems that combine organic and inorganic synthetic toolkits, and analyses of reactivities that draw parallels to biological functionalities. As well, a broad variety of cryogenic spectroscopic tools will be employed, offering a uniquely specialized skillset to contributing high-school, undergraduate, graduate, and postdoctoral researchers. Outreach and educational aspects of this project will involve the orientation of Birmingham City high school students toward Regional Science Fair via a newly designed Science Club program. Proposed efforts will strive to bridge the gap of scientific literacy of youngsters in the City of Birmingham, which is one of the most income-segregated school districts in the country. Heme-containing dioxygenases play pivotal roles in human physiology, disease progression, and aging, consequently attracting substantial research interests within the past decade. However, exact mechanistic details concerning these are only faintly understood. Heme superoxide adducts are presumed to be active oxidants in heme dioxygenases, however, details pertaining to their definitive involvement in the actual enzymatic mechanism remain elusive. Synthetic model systems have long-served as powerful tools in addressing such mechanistic ambiguities, but synthetic heme superoxide adducts are often found to be sluggish oxidants. This anomaly calls for revaluation of explicit modeling of synthetic systems with direct relevance to their biological mode of action. Comprehension of mechanistic details of such model systems can also be of direct benefit for the design of superior synthetic methodologies targeting important complex organic molecules and homogeneous dioxygen reduction catalysts to be used in alternative energy applications. Proposed research will address this gap in knowledge by generating a library of synthetic heme superoxide model systems with divergent structural properties, and thorough investigation into how such structural modulations would influence their reactivity signatures. This work will vertically advance the fundamental understanding of reactivity-governing geometric, electronic, and non-covalent structural properties of mid-valent heme-oxygen intermediates, introducing a new era of heme-oxygen model chemistry. Outreach activities of this project will directly benefit the majority of underrepresented high schoolers in the Birmingham, Alabama area through cutting-edge research opportunities and high-quality one-on-one mentoring opportunities geared toward strengthening their preparatory phase for Regional Science Fair.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

在化学系生命过程化学项目和刺激竞争研究既定项目 (EPSCoR) 的支持下，阿拉巴马大学伯明翰分校的 Gayan B. Wijeratne 博士将研究具有血红素铁中心的小分子的化学，例如作为在人体生物学中激活氧气的物质。这些模型系统非常通用，但可以作为简单的探针，用于理解控制生物学中氧介导的反应性的复杂机制细节。 Wijeratne 博士和他的团队将利用这些强大的工具揭示未知的知识，这些知识可以找到有效合成复杂分子的途径，并发现可以提高氧还原催化剂效率的催化剂，从而有利于替代能源应用。这项工作将涉及结合有机和无机合成工具包的新模型系统的仿生设计和合成，以及与生物功能相似的反应性分析。此外，还将采用各种低温光谱工具，为高中生、本科生、研究生和博士后研究人员提供独特的专业技能。该项目的外展和教育方面将涉及通过新设计的科学俱乐部计划引导伯明翰市高中生参加区域科学博览会。拟议的努力将努力缩小伯明翰市青少年科学素养的差距，该市是该国收入隔离最严重的学区之一。 含血红素的双加氧酶在人类生理学、疾病进展和衰老中发挥着关键作用，因此在过去十年中吸引了大量的研究兴趣。然而，人们对这些的确切机制细节知之甚少。血红素超氧化物加合物被认为是血红素双加氧酶中的活性氧化剂，然而，有关它们最终参与实际酶促机制的细节仍然难以捉摸。合成模型系统长期以来一直是解决此类机械模糊性的强大工具，但合成血红素超氧化物加合物通常被发现是迟缓的氧化剂。这种异常现象要求重新评估与其生物作用模式直接相关的合成系统的显式建模。了解此类模型系统的机械细节也可以直接有益于设计针对重要复杂有机分子和用于替代能源应用的均相分子氧还原催化剂的高级合成方法。拟议的研究将通过生成具有不同结构特性的合成血红素超氧化物模型系统库来解决这一知识空白，并深入研究这种结构调制将如何影响其反应性特征。这项工作将垂直推进对中价血红素-氧中间体反应性控制的几何、电子和非共价结构特性的基本理解，引入血红素-氧模型化学的新时代。该项目的外展活动将通过尖端研究机会和高质量的一对一指导机会，直接造​​福阿拉巴马州伯明翰地区大多数代表性不足的高中生，以加强他们为区域科学博览会的准备阶段。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。