The Influence of Primary Coordination Sphere in Aromatic C-C Ring Scission: Mechanistic Studies of 3-His Coordinated Non-heme Iron Enzymes

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With the support of the Chemistry of Life Processes (CLP) Program in the Chemistry Division, Dr. Rupal Gupta from the College of Staten Island, City University of New York will investigate the biological degradation of aromatic organic molecules by iron enzymes. The focal point of chemical reactions responsible for the decomposition of these compounds is an iron center that is tethered to the protein via a scaffold ubiquitously found in most iron enzymes. However, several novel iron-binding scaffolds have been recently identified. The influence of these atypical binding sites on enzymatic reactivity, efficiency and selectivity is not clear. The proposed studies will evaluate the role of metal binding scaffolds toward enzymatic function in a systematic manner. Findings from these studies will inform the design of artificial catalysts and offer insights into the challenging chemical reactions performed by Nature. This project will also contribute to the rigorous training of undergraduates and high school students, who will be introduced to concepts of biochemistry, enzymology and spectroscopy through outreach programs and will be offered opportunities to conduct curriculum-based research. Non-heme iron enzymes that catalyze a myriad of chemical reactions typically bear a metal-binding motif composed of two histidine and one carboxylate residues (2-His-1-carboxylate). Recently, several atypical metal binding motifs such as 3-His, 3-His-1-carboxylate and 4-His, have been identified. Such variations in the primary coordination sphere that clearly alter the ligand field at the metal center are expected to influence the catalysis carried out by the iron center. The overall goal of this project is to gain a systematic understanding of the influence of the primary coordination sphere on the reactivity and catalysis of non-heme iron enzymes performing C-C ring scission. By utilizing a combination of biochemical and spectroscopic methodologies, reaction mechanisms of 3-His aromatic ring cleaving enzymes will be investigated with a focus on identifying the influence of the primary coordination sphere on reaction kinetics and, electronic and magnetic properties of the reaction intermediates. These studies will help evaluate the properties of atypical metal binding motifs and their impact on the reactivity and substrate selectivity.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.