Crucial steps in the biosynthesis of clinically important antibiotics (penicillin, fosfomycin, and chlorobiocin) and pesticides (phosphinothricin, a component of the herbicides Basta and Liberty) involve the reaction of dioxygen with nonheme iron enzymes, including the mononuclear enzymes isopenicillin N synthase and hydroxyethylphosphonate dioxygenase and the diiron enzyme myo-inositol oxygenase. The catalytic cycles of these enzymes are thought to involve a highly reactive Fe(III)-superoxo intermediate that acts as an oxidant, though such a species has proven difficult to isolate and characterize. The preparation and characterization of synthetic compounds that mimic the structure (both geometric and electronic) of putative enzymatic intermediates can provide significant insight into complex biological systems. Herein is proposed a new methodology for the preparation and thorough characterization of novel mononuclear iron-superoxo compounds. Initial studies will focus on trapping the putative Fe(III)-superoxo species through the reaction of dioxygen with [TpFeIIX] (Tp = hydrotris(pyrazolyl)borate, X = a-keto acids, RC(O)CO2-, or alkoxides, RO-). The steric and electronic properties of both the Tp supporting ligand and of the cosubstrate X are readily tuned to prolong the lifetime of the Fe(III)-superoxo species. The relevant intermediate will be characterized by a variety of spectroscopic (electronic absorption, resonance Raman, Mossbauer, and X-ray absorption spectroscopies) and computational (density functional theory and time-dependent density functional theory) techniques in order to generate a complete, experimentally-validated electronic structure description. Subsequent reactivity studies will quantify the oxidizing power of the Fe(III)-superoxo species toward the bound cosubstrate X and toward external organic substrates. In addition, only two synthetic diiron-superoxo species have been reported, and the electronic structures of both compounds are poorly understood. Therefore, the diiron-superoxo compound formed upon reaction of [Fe2(u-OH)2(6-Me3- TPA)2](OTf)2 with dioxygen (Shan, X. and Que, L. Proc. Nat. Acad. Sci. 2005, 102, 5340) will be thoroughly characterized. The previously reported electronic absorption and resonance Raman spectroscopic studies will be complemented by Mossbauer, and X-ray absorption spectroscopies, as well as the computational techniques described above. Finally, the experimentally-validated electronic structure descriptions obtained for the mononuclear and dinuclear model compounds described above will be used to critically evaluate the proposed catalytic cycles that invoke Fe(III)-superoxo intermediates.

Public Health Relevance

It is of critical importance to understand the fundamental chemical reactions that are necessary for the production of widely used antibiotics (penicillin, fosfomycin, and chlorobiocin) and pesticides (phosphinothricin, a component of the herbicides Basta and Liberty). The biosynthesis of each of these compounds relies on the interaction of oxygen with iron-containing enzymes in complex biological systems, and the relevant chemical details are poorly understood. In this work, we propose to prepare and thoroughly characterize synthetic complexes that model the structures and reactivities of these enzymes in order to gain insight into the biosynthesis of these clinically- and environmentally-significant compounds.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F04A-B (20))
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Marino, Pamela
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University of Minnesota Twin Cities
Schools of Arts and Sciences
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