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Metal Tetrapyrrole Biosynthesis: Inserting the Correct Metal

金属四吡咯生物合成：插入正确的金属

基本信息

批准号：
2003627
负责人：
Matthew Liptak
金额：
$ 39.9万
依托单位：
University of Vermont & State Agricultural College
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-15 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2003627&HistoricalAwards=false
关键词：
Metal Tetrapyrrole Biosynthesis Inserting Correct

项目摘要

With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Dr. Matthew Liptak at the University of Vermont to investigate the biosynthesis of metal tetrapyrroles. Metal tetrapyrroles are small molecules that have essential functions throughout biological systems. For example, an iron tetrapyrrole (heme) is required for oxygen transport by red blood cells. A cobalt tetrapyrrole (vitamin B12) is required for recycling of folate in humans; folate is one of the B vitamins necessary for the production of DNA and other genetic material and for cell division. A nickel tetrapyrrole (cofactor F430) is required for methanogenesis by bacteria in the deep sea; methanogenesis is the last step in the degradation of biomass by these bacteria. As seen in these examples, a different specific metal is required for different biological processes, but the mechanism(s) by which biology selects the correct metal for each type of process is/are unknown. Dr. Liptak’s research program seeks to answer this fundamental question. It also provides a starting point for the production of non-natural metal tetrapyrroles that can be employed for next-generation, energy applications. This project is integrated with an outreach program that provides local high school students the opportunity to do research in the Liptak laboratory during the summer. A second integrated outreach program in collaboration with a local museum focuses on the development of interactive activities related to the broader impact of metal tetrapyrrole biosynthesis on nutrition and the environment.This research project aims to advance molecular-level understanding of metal tetrapyrrole biosynthesis. Metal tetrapyrroles are biosynthesized by long, multi-step pathways that include a chelatase enzyme responsible for metal insertion. Surprisingly, the means by which chelatases select the correct metal and insert this metal into the growing tetrapyrrole ligand is unknown. Three competing hypotheses have emerged in the literature: metal specificity driven by metal affinity, metal specificity driven by tetrapyrrole distortion, and metal specificity arising from product inhibition. Dr. Liptak and his team will use new spectroscopic data to distinguish among these proposed mechanisms. For example, optical spectroscopies are used to measure the metal affinities of different chelatases, UV/vis absorption and Raman spectroscopies are employed to measure tetrapyrrole distortions induced by different enzymes, and activity assays are utilized to determine whether the reactions are inhibited by the product. Ultimately, the project aims to reveal how life selectively inserts iron into heme, cobalt into B12, and nickel into F430.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.

有了这个奖项，化学系的生命过程化学项目资助佛蒙特大学的Matthew Liptak博士研究金属四吡咯的生物合成。金属四吡咯是在整个生物系统中具有基本功能的小分子。例如，四吡咯铁（血红素）是红细胞运输氧气所必需的。四吡咯钴（维生素B12）是人体叶酸循环所必需的;叶酸是生产DNA和其他遗传物质以及细胞分裂所必需的B族维生素之一。四吡咯镍（辅因子F430）是深海细菌产甲烷所必需的;产甲烷是这些细菌降解生物量的最后一步。从这些例子中可以看出，不同的生物过程需要不同的特定金属，但生物学为每种类型的过程选择正确金属的机制是未知的。Liptak博士的研究计划旨在回答这个基本问题。它还为生产可用于下一代能源应用的非天然金属四吡咯提供了起点。该项目与一个外展计划相结合，该计划为当地高中生提供了在夏季在Liptak实验室进行研究的机会。与当地博物馆合作的第二个综合外展计划侧重于发展与金属四吡咯生物合成对营养和环境的更广泛影响有关的互动活动。该研究项目旨在促进对金属四吡咯生物合成的分子水平的理解。金属四吡咯是通过包括负责金属插入的螯合酶的长的多步骤途径生物合成的。令人惊讶的是，螯合酶选择正确的金属并将该金属插入生长的四吡咯配体中的方法是未知的。在文献中出现了三种相互竞争的假说：金属亲和力驱动的金属特异性，四吡咯扭曲驱动的金属特异性，以及产物抑制引起的金属特异性。Liptak博士和他的团队将使用新的光谱数据来区分这些拟议的机制。例如，使用光学光谱来测量不同螯合酶的金属亲和力，使用UV/维斯吸收和拉曼光谱来测量由不同酶诱导的四吡咯畸变，并且使用活性测定来确定反应是否被产物抑制。最终，该项目旨在揭示生命如何选择性地将铁插入血红素，将钴插入B12，将镍插入F430。该奖项反映了NSF的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。