BIOINORGANIC CHEMISTRY

Joan B. Broderick Assistant Professor (b. 1965). B.S., 1987, Washington State University; Ph.D., 1992, Northwestern University; American Cancer Society Postdoctoral Fellow, 1992-1993, MIT; Assistant Professor, Amherst College, 1993-1998. Bioinorganic chemistry; mechanisms of biological radical generation and quenching; role of biological iron-sulfur clusters; oxygen activation by non-heme iron centers. 517-355-9715, Ext. 180 broderij@cem.msu.edu

One of the most fascinating roles for metals in biology is in the generation of biologically essential radicals. Metal centers as diverse as binuclear Fe, mononuclear Cu, and Co in adenosylcobalamin have been found to play central roles in the generation of catalytically essential radicals. Of particular interest is how biological systems generate and use radicals in a controlled way, avoiding deleterious radical chain reactions. We are examining a new paradigm for radical generation in biological systems, represented by enzymes that utilize Fe-S clusters and S-adenosylmethionine to initiate radical chemistry. These enzymes are involved in functions as diverse as ribonucleotide reduction, biotin synthesis, and glucose metabolism. We have recently focused on the pyruvate formate-lyase activating enzyme with the ultimate goal of determining the mechanism of this unusual radical generating system. Our studies are expanding to include other Fe-S enzymes that catalyze radical chemistry.

Continuing investigations of radical-generating enzymes will utilize techniques ranging from molecular biology to protein biochemistry to synthesis of small molecule models. In addition, a mainstay of the project is the use of a variety of spectroscopic techniques, both static and transient, to characterize the metalloenzymes and their reactions. Much of the spectroscopic studies are done here at MSU, using the superb magnetic resonance and LASER facilities, while others are done in collaboration with outside experts.

Another area of interest is the in vivo synthesis of iron-sulfur clusters. Although such clusters can spontaneously self-assemble in vitro, the conditions under which they do so are far removed from those found in vivo. Early evidence points to the involvement of specific metalloenzymes in the biosynthesis of iron-sulfur clusters. We are in the process of cloning the genes for these enzymes in order to pursue detailed spectroscopic and mechanistic studies of this interesting in vivo synthetic reaction.

The binding and activation of dioxygen is another critical function performed by iron metalloproteins. Due to the central role of such reactions, a detailed chemical understanding of their mechanisms has become an important theme of bioinorganic chemistry. We are particularly interested in the reversible binding and activation of dioxygen by non-heme iron centers. In collaboration with Dr. Will Broderick of MSU, we are working to develop a better understanding of the interaction of oxygen with non-heme iron centers in biology through the design, synthesis, and characterization of small-molecule models for non-heme sites in proteins. We utilize a variety of techniques, including X-ray crystallography, Raman, EPR, EXAFS, and magnetic susceptibility, as well as qualitative and quantitative characterization of reactions with dioxygen and organic substrates, to elucidate the roles of steric and electronic properties on reactivity of non-heme iron centers.

Representative Publications

Pyruvate Formate-Lyase Activating Enzyme: Strictly Anaerobic Isolation Yields Active Enzyme Containing a [3Fe-4S]⁺ Cluster, J. B. Broderick, T. F. Henshaw, J. Cheek, K. Wojtuszewski, S. R. Smith, M. R. Trojan, R. M. McGhan, A. Kopf, M. Kibbey, and W. E. Broderick, Biochem. Biophys, Res, Commun., 269, 451 (2000).

Coenzymes and Cofactors, J. B. Broderick, in Encyclopedia of Life Sciences, Nature Publishing Group: London, www.els.net (2000).

Catechol Dioxygenases, J. B. Broderick, Essays Biochem., 34,1 (1999).

Pyruvate Formate-Lyase Activating Enzyme is an Iron-Sulfur Protein, J. B. Broderick, R. A. Duderstadt, D. C. Fernandez, K. Wojtuszewski, T. F. Henshaw, and M. K. Johnson, J. Am. Chem. Soc., 31, 7396 (1997).

Coenzyme B₁₂-dependent Ribonucleotide Reductase: Evidence for the Participation of Five Cysteine Residues in Ribonucleotide Reduction, S. Booker, S. Licht, J. Broderick, and J. Stubbe, Biochemistry, 33, 12676 (1994).