Metal Tetrapyrrole Biosynthesis: Inserting the Correct Metal

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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.