CAREER: Understanding O2 activation by Manganese/Iron Oxygenases and their Models

About This Grant

With the support of the Chemistry of Life Processes Program in the Chemistry Division, Dr. Jonathan Rittle from the University of California, Berkeley investigates molecular complexes and enzymes that mediate challenging oxygen-dependent reactions. Biological systems harness atmospheric oxygen for central metabolism, the augmentation of potential pharmaceuticals, and the activation of strong chemical bonds. The importance of these systems has been recognized by generations of chemists, yet, the intimate molecular mechanisms by which they operate remain unclarified. The proposed experimental procedures will take advantage of a two-pronged approach that investigates both natural enzymes and synthetic mimics with tools that allow for in depth monitoring of chemical changes occurring upon oxygen exposure. This pursuit allows graduate students and postdoctoral fellows to acquire specialized training in chemical synthesis, enzymology, X-ray crystallography, and a battery of spectroscopic methods. This project is also integrated into an outreach program to empower community college students with the tools and strategies needed to expand their career prospects and network. This research project seeks to investigate a class of oxygen-dependent decarboxylases that operate with an unusual bimetallic active site. Enzymatic studies on distantly related enzymes suggest that these decarboxylase enzymes may operate with active sites containing iron, manganese, or mixtures thereof. Since these decarboxylases are essential for the biosynthesis of highly bioactive peptides and are numerous in microbial genomes, the Rittle group will investigate their mechanism of action via a combination of enzymology, spectroscopy and structural studies. As the critical oxygen-activated states of these, and many other oxygenases have proven difficult to trap and characterize, they also seek to prepare novel synthetic complexes that allow modeling of spectroscopic, structural and/or functional features. Through these efforts, PI Rittle and his group have recently designed a system that allows observation of oxygen binding by a dimetallic active site and subsequent observation of an O-O bond cleavage event within single crystals. 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.