Metalloenzymes catalyze remarkably diverse and sometimes extremely difficult reactions in biological systems. The theme of our research is the use of biochemical, spectroscopic, and synthetic approaches to elucidate detailed chemical mechanisms for some of nature?s metal catalysts.
An area of particular interest is the mechanism by which certain metalloenzymes initiate radical catalysis. Metal centers as diverse as binuclear Fe, mono-nuclear Cu, and Co in adenosylcobalamin have been found to play central roles in the generation of catalytically essential radicals. Fe-S clusters have also recently been found to be involved in radical catalysis in a group of S-adenosylmethionine-dependent enzymes. These enzymes are ubiquitious and catalyze a variety of functions, including ribonucleotide reduction, biotin and lipoic acid synthesis, glucose metabolism, and repair of UV-induced DNA damage. The mechanism by which these enzymes initiate radical catalysis is not understood and is a major focus of our research. Our work over the past several years has demonstrated a novel interaction between S-adenosylmethionine (AdoMet) and the enzyme-bound iron-sulfur cluster, in which the AdoMet coordinates a unique iron site of the cluster. We believe this coordination positions AdoMet for reductive cleavage by the cluster, which results in generation of an intermediate 5?-deoxyadenosyl radical.
Another area of interest is the in vivo synthesis of Fe-S 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. Evidence points to the involvement of specific metalloenzymes in the biosynthesis of Fe-S clusters, although the mechanism of cluster biosynthesis and its relation to iron homeostasis is not well understood.
Other projects include the investigation of metalloenzymes that quench protein-centered radicals and others that dehalogenate chlorinated organic compounds.