Julie A. Kovacs

Professor of Chemistry
(Bioinorganic and Inorganic, Ph.D., Harvard University, 1986)

(206) 543-0713
kovacs@chem.washington.edu
Research group website

Research Description.

Approximately one third of all enzymes contain transition-metal ions as their key active component.  Metal ions promote a number of critical biological processes ranging from the biosynthesis of neurotransmitters, DNA, and hormones, to the transport of electrons and dioxygen, and the conversion of electrochemical to chemical energy.  The molecular–level details regarding metalloenzyme function emerge from several complementary lines of study, at the interface of chemistry, biology, and physics.  By modeling the metal ion’s local environment (i.e., its primary coordination sphere), and making systematic changes to this environment, one can determine, at the molecular-level, if there is a correlation between structure, physical properties, and function.  Since numerous disease states have been associated with malfunctioning, biomedically-essential metalloenzymes, an understanding of the fundamental properties that control their function is vital to human health.

Research in the Kovacs group is aimed at determining how thiolate ligands influence function in non-heme iron enzymes.  The general approach involves the design and synthesis of organic N- and S-containing molecules (“ligands”) possessing an architecture likely to promote reactivity once coordinated to a transition-metal ion.  Molecules are designed to mimic the local protein environment of a targeted enzyme’s metal ion.  We then wrap the ligand around a transition-metal ion, and examine the structure, properties, and reactivity of the resulting complex.  By systematically altering the structure of our organic ligand, we can then look for correlations between structure, electronic (color), magnetic (spin-state) and reactivity properties.  Reactivity is monitored using low temperature electronic absorption spectroscopy and EPR, and then compared on the basis of kinetic and thermodynamic parameters. 

The Kovacs group was the first to show that alkyl thiolate ligands stabilize low-spin Fe(III), make low-spin Co(III) reactive (a trans-labilizing effect), and tune redox potentials so as to favor superoxide reduction.  Our group reported the first example of a thiolate-ligated Fe(III)-peroxide, and were the first to report metrical parameters for a mononuclear Fe(III)-OOH in any ligand environment.  Iron-peroxides are key intermediates formed during cytochrome P450-promoted oxidation reactions, and superoxide reductase (SOR)-promoted superoxide reduction.  Kovacs’ group recently reported a rare example of a functional bioinorganic model that, like SOR, reduces superoxide to afford hydrogen peroxide.  Superoxide is a toxic radical implicated in cancer, Alzheimer’s and Parkinson’s disease.  Each step of this reaction, including proton addition, and electron addition, can be monitored in our biomimetic system, at the molecular-level.  The first step in this reaction was found to be highly proton-dependent.  Kinetics studies are underway in order to elucidate the mechanism.