Design Principles for Metalloprotein Chemistry

Metalloproteins catalyze some of Nature’s most amazing and difficult chemical transformations. One such transformation, of interest to our laboratory, is the use of a high valent Fe-based oxidant to facilitate the functionalization of a traditionally inert C–H bond. Since this chemistry is vital to a variety of biochemical pathways, metalloproteins are recognized for their potential to build natural products with medical, environmental, and industrial relevance, and to degrade environmental contaminants. However, the practical applicability of metalloproteins, in many cases, is limited by a gap in knowledge regarding structure–function relationships. Within our broad interests of elucidating the structure and mechanism of understudied metalloproteins, I will highlight our work on the Rieske Oxygenases. I will showcase our progress toward identifying the architectural motifs that Rieske oxygenases employ to dictate site-selectivity, substrate specificity, and reaction outcome in different enzyme systems. Furthermore, I will detail our mechanistic work on a divergent Rieske oxygenase that catalyzes two iterative monooxygenation reactions. Collectively, this work adds to our fundamental understanding of Rieske oxygenase chemistry, provides predictive power for thinking about how other members of the 70,000-membered enzyme class can be custom-tuned to catalyze alternative reactions, and will facilitate rational engineering of these catalysts.