Early classifications of matter distinguished inorganic compounds as “involving neither organic life nor the products of organic life.” As more sophisticated chemical methods were developed, it became clear that this dichotomy was lacking. Many first-row transition metals are absolutely essential components of catalytic and regulatory pathways of living systems, but the same essential element can be poisonous in higher quantities.

We focus on the chemistry of molecules that control the intracellular balancing act. In addition, we are studying the way structure influences metal-catalyzed air oxidation of organic substrates. We have found that subtle distortions of the geometry can be used to control the reactivity of the terminal metal-oxo center. In all of the above problems, we eventually arrive at a fundamental question: How does the stereochemistry of the coordination center control the chemical reactivity and biological function of the metal center?

As we probe transition metal binding proteins, we often find new inorganic chemistry. We invent or employ a variety of methods in the fields of coordination chemistry and biochemistry to resolve the mechanisms of interest. Common tools include small-molecule crystallography, fluorescence spectroscopy, multinuclear NMR, and EPR spectroscopy. In most cases, we synthesize organic ligands and coordination compounds that allow us to probe the reactivity, spectroscopy, or intracellular chemistry of the target metal ion. In other cases, we clone, express, and purify the target protein in order to probe its structure and function.

In one area we are focusing on chemistry, structure, and function of the metalloregulatory proteins. These small proteins act as metal receptors that regulate gene expression. We have proposed that another class of metalloproteins acts as chaperones for metal ions within the cell. Such proteins may have reasonable thermodynamic binding constants for specific metal ions, but can undergo rapid ligand exchange reactions in which the metal ion is passed to the proper biological partner. Characterization of these proteins will reveal fundamental molecular aspects of heavy-metal homeostasis and may provide insight into fatal metal-based disorders, such as Menkes’ syndrome and Wilson’s disease.

As we probe the structures and the substitution mechanisms of the metal centers in these proteins, we are learning how many well-established inorganic principles apply in the highly compartmentalized chemistry of the cell. These new rules in turn are used to design inorganic medicines for the control of human disease.

Professor O’Halloran is the director of the Chemistry of Life Processes Institute.

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