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Research

My overall research interests involve the fields of enzymology and protein chemistry. Proteins are very interesting molecules that serve a variety of functions in living organisms. My current research involves studies in three areas as briefly described below:

humancrCarbonyl Reductase – Carbonyl reductase (CR), E.C. 1.1.1.184, catalyzes the NADPH-dependent reduction of a wide range of carbonyls. CR has been connected to several important processes including but not limited to quinone detoxification, neuroprotection, prostaglandin metabolism, and, of clinical interest, anthracycline metabolism. CR reduction of anthracyclines significantly impacts their use in the treatment of cancer as it has been linked to both drug resistance and cardiotoxicity mechanisms. Therefore, inhibition of CR in conjunction with anthracycline therapy offers the potential both to increase the effectiveness of the drugs and to decrease the risk of the associated cardiotoxicity. The major emphasis of this work is to better understand how CR recognizes the molecules to which it binds, be they substrates or inhibitors. Equipped this information, drugs may be designed to control CR with the intention of reducing the risk of cardiotoxicity during anthracycline cancer treatment. Also, as the role of CR is other pathways is better understood such drugs may be used to treat other diseases as well. Pictured ar right: Structure of human carbonyl reductase. Fromhttp://www.rcsb.org/pdb/explore/explore.do?structureId=1WMA

horseliverAlcohol Dehydrogenase – Alcohol dehydrogenase (ADH), E.C. 1.1.1.1, catalyzes the reversible oxidation of ethanol, using NAD as a cofactor. This reaction is a rate-limiting step in alcohol metabolism. ADH may be an important determinant in the development of alcoholism and fetal alcohol syndrome and is therefore widely studied. In addition, it often studied to gain insight into how enzymes catalyze reactions. My research project with ADH focuses on evaluating the contribution of electrostatic interactions in coenzyme binding. In past studies, a lysine at position 228 (K228) has been implicated in controlling, at least in part, coenzyme (NAD+ and NADH) binding. In particular, the positive charge at this position is hypothesized to interact with the negatively charged coenzymes. In order to evaluate the role of charge at position 228, we mutated the lysine at this position to alanine, glutamine, and glutamate, each of which changes the charge at this position. In a past study this lysine was also mutated to arginine, which conserves the positive charge at 228. Currently, all of these mutants are being analyzed for effects on coenzyme binding using steady state and transient kinetics, equilibrium binding studies, and computational chemistry. Pictured at left: Structure of horse liver alcohol dehydrogenase. From http://www.rcsb.org/pdb/explore.do?structureId=1HLD

 

phosphoPhosphotriesterase – Phosphotiesterase (PTE), E.C. 3.1.8.1, catalyzes the hydrolysis of synthetic organophosphate triesters and phosphorofluoridates. Compounds in this family include several pesticides and nerve agents. This enzyme has potential use in nerve agent and pesticide decontamination. Work in my lab involves using protein chemistry and genetic engineering techniques to modify this enzyme to enhance its utility in organophosphate compound degradation. Pictured at right: Structure of bacterial phosphotriesterase. From http://www.rcsb.org/pdb/explore/explore.do?structureId=1P6C