Metal Tetrapyrrole Biosynthesis: Inserting the Correct Metal

有了这个奖项，化学部的生命过程化学项目将资助佛蒙特大学的马修·利塔克博士研究金属四氯的生物合成。金属四吡咯是在整个生物系统中具有重要功能的小分子。例如，四吡咯铁（血红素）是红细胞运输氧气所必需的。人体需要四吡咯钴（维生素B12）来回收叶酸；叶酸是产生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。四吡啶镍（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质的最后一步。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尚不清楚。利塔克博士的研究项目试图回答这个基本问题。它还为可用于下一代能源应用的非天然金属四吡咯的生产提供了一个起点。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利塔克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联方案侧重于开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。本研究项目旨在提高对金属四吡咯生物合成的分子水平认识。金属四吡咯是通过长，多步骤的途径生物合成的，其中包括负责金属插入的螯合酶。令人惊讶的是，螯合酶选择正确的金属并将这种金属插入生长中的四吡咯配体的方法尚不清楚。文献中出现了三种相互竞争的假设：由金属亲和力驱动的金属特异性，由四吡咯畸变驱动的金属特异性，以及由产物抑制引起的金属特异性。利塔克博士和他的团队将使用新的光谱数据来区分这些提出的机制。例如，利用光谱学来测量不同螯合酶的金属亲和力，利用紫外/可见吸收和拉曼光谱来测量不同酶引起的四吡咯畸变，利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。该奖项反映了美国国家科学基金会的法定使命，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。

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.