With this award, the Chemistry of Life Processes Program in the Chemistry Division is funding Professor Yisong Guo from Carnegie Mellon University to study three enzyme-catalyzed reactions that are required to make novel highly bioactive compounds in microorganisms. The three enzymes employ the same basic structure around the iron atom, yet carry out three quite different reactions; the reasons for this difference in structure-function relationship is a fundamental question in biological chemistry. For example, iron in the same basic environment can result in the formation of carbon-oxygen bonds on the one hand or carbon sulfur bonds on the other. The research applies cutting edge methodology to reveal just how these reactions take place on an atom-by-atom basis. The research results may provide useful guidelines in designing new molecular catalysts and biocatalysts to perform these important and challenging chemical transformations. Research supported by this award also provides a training ground for students in physical chemistry, bioinorganic chemistry, biochemistry, enzymology, and catalysis. The knowledge generated through this project is integrated into educational activities where graduate, undergraduate, and high school students play an active role in discovering how reactions are catalyzed by iron-dependent enzymes.
Non-heme mononuclear iron (NHM-Fe) dependent enzymes catalyze exceedingly diverse enzymatic reactions, ranging from "classical" hydroxylation, to desaturation, epoxidation, halogenation, epimerization, aromatic ring expansion, ring contraction, and ring opening. The structures of the iron centers catalyzing these diverse reactions are surprisingly simple. The first coordination sphere of the iron only contains histidine (His) and/or aspartic/glutamic acid (Asp/Glu) residues. The goal of this project is to provide a molecular level understanding of the similarity and difference of these structural motifs in controlling oxygen activation and the subsequent chemical transformations, as well as on the catalytic roles of redox active protein residues near the iron centers. To achieve this goal, detailed mechanistic studies are conducted on three NHM-Fe enzymes that contain 2-His-1-Asp or 3-His iron binding motifs. A combined biochemical, kinetic and spectroscopic approach is used. This research is expected to provide crucial insights into the catalytic versatility of NHM-Fe enzymes. The project includes a comprehensive educational program at the graduate and undergraduate levels and outreach to K-12 students around the concepts that relate to reaction rates and catalysis.
