New chemical tools for studying cellular iron homeostasis and iron-dependent enzymes




Fikes, Audrey Gayle

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Metal ions, including Fe(II/III), can be classified based on their location within a cell: they can serve as cofactors in proteins where they are tightly bound or they can exist as members of the labile iron pool. The interaction between these pools of iron as well as the different roles that iron plays are an important area of study due to the implications of Fe in disease. The goal of this research was to develop new tools that would enable us to elucidate the roles that labile iron and iron-dependent proteins play in disease development and progression. Thus, the focus of my research can be broadly classified into two separate areas of focus, caged Fe complexes and probes for Fe dependent enzymes. We first demonstrated the feasibility of moving beyond traditional photocaged metal complexes by employing a disulfide-containing Fe complex, FeL1Cl. In our proof-study-work, reactivity of the Fe to produce ROS is caged by the ligand but upon cleavage of the disulfide bond by a reducing agent, the reactivity of the Fe is uncaged. Further improvements have been made toward making water stable disulfide complexes for cellular applications by employing a more flexible ligand scaffold, which is seen with the ligand L [superscript CN]. We have also explored using CpFeArenes as possible photocaged Fe complexes. Initial cells studies indicate that these compounds are relatively non-toxic and can be taken up by the cell to increase total cellular Fe. Our work with Fe-dependent proteins has focused on both heme and non-heme Fe proteins. For heme proteins, we have investigated the possibility of using hydrazine-based probes for activity-based protein profiling. For non-heme proteins, we have designed, synthesized and tested fluorescent probes for Fe(II) 2-oxoglutarate dependent enzymes.



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