Professor of Chemistry, College of Literature, Science, and the Arts
Professor of Biological Chemistry, Medical School
Department of Chemistry
University of Michigan
930 N. University Ave.
Ann Arbor MI 48109-1055 USA
Office: (734) 763-6096
Fax: (734 615-3790
Our laboratory focuses on two areas of chemical biology. In one area, we seek to understand the remarkable catalytic prowess of enzymes, in particular those that use free radicals in catalysis. In the other area we are exploring the potential for developing novel biological catalysts and therapeutic agents offered by the de-novo design and synthesis of novel proteins incorporating highly fluorinated amino acids. Our research is inherently inter-disciplinary in nature and draws on a synergistic combination of bio-organic, bio-inorganic and bio-physical chemistry.
Our laboratory is interested in enzymology and protein design. Our research is inherently inter-disciplinary in nature and draws on a synergistic combination of bio-organic, bio-inorganic and bio-physical chemistry. We are fortunate to enjoy various productive collaborations with other research groups at Michigan.
We are currently studying three enzymes that catalyze unusual and chemically difficult reactions that involve metal cofactors and/or reactive free radical intermediates. Benzylsuccinate synthase is a free radical-containing enzyme that catalyzes the first step in the metabolism of toluene – anaerobic bacteria that contain this enzyme can live on toluene as their sole carbon source! Glutamate mutase catalyzes an unusual carbon skeleton rearrangement involved in glutamate fermentation; it uses coenzyme B12, a cobalt-containing organo-metallic complex, to generate reactive free radicals that initiate the reaction mechanism. Lastly, we have begun to study aldehyde decarbonylase, an iron-dependent enzyme that catalyzes the conversion of long-chain aldehydes to alkanes and carbon monoxide, which is involved in hydrocarbon biosynthesis in plants and algae.
Increasingly, our attention is focused on enzymes involved in hydrocarbon metabolism as these may prove useful for the synthesis of new biofuels and bioremediation of hydrocarbon-contaminated soils. Our primary goal is to understand how these enzymes generate and control chemically reactive intermediates to catalyze their reactions; we then aim to apply what we learn to engineer new pathways for hydrocarbon metabolism.
Our interest in protein design led us to explore the properties of novel ‘Teflon-like’ proteins that incorporate highly fluorinated amino acids within their hydrophobic cores. We have designed a series of model proteins that contain the fluorinated amino acid hexafluoroleucine to examine how fluorination can be used to modulate the physical and biological properties of proteins. We found that fluorinated proteins exhibit remarkable stability that allows them to resist unfolding by heat and organic solvents and degradation by proteases. We are applying these design principles to the development of fluorinated antimicrobial peptides, short peptides that kill bacteria by selectively disrupting their membranes. We are also developing methods to follow the fate of peptides in vivo using fluorine NMR as a probe.