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BIOORGANIC CHEMISTRY
My research can be summarized as the design, synthesis, and study of new organic molecules, primarily directed toward biological applications. The majority of work in my group involves the design and synthesis of artificial receptors for biological compounds and ions. Current specific targets for receptor design include glucose, sialic acid, neurotransmitters, nucleic acids, and metal ions. The design aspects of this work involve extensive use of computer modeling and novel use of the computer program CAVEAT. CAVEAT is used to discover structures that allow precise positioning of functional groups for efficient multivalent interaction with the target compound. Compounds designed using our computer-based methods are synthesized and studied as receptors for the targeted biological compounds and ions in solution. Incorporation of fluorescent signaling moieties into these receptors provides fluorescence-based sensors of potential use in medical and environmental diagnostic applications. We have recently completed the synthesis of a fluorescent receptor/sensor for glucose, which is of interest for potential application as a glucose sensor for persons with diabetes. We are now extending this project to the development of simple biomimetic catalysts, using CAVEAT to discover backbone structures for precise relative positioning of catalytic groups..
We are also continuing to pursue an older project in my group directed at the chemistry and enzymology of Coenzyme A (CoA). My group has developed a versatile method for the synthesis of analogs of CoA using a combination of enzymatic and nonenzymatic reactions. This method is being used to prepare CoA analogs that mimic the transition states and intermediates in enzyme-catalyzed reactions. These analogs are used to probe mechanistic and structural questions in CoA utilizing enzymes. As about 4% of all enzymes use CoA or a thioester of CoA as a substrate, this work can be applied to a large number of enzymes, including enzymes of pharmaceutical importance. One such target is the protein palmitoyltransferase, which catalyzes transfer of the palmitoyl group from palmitoyl-CoA to a cysteine thiol group of a peptide or protein. Analogs of palmitoyl-CoA are being prepared to inhibit this reaction. These analogs will be useful in studying for example the palmitoylation of the ras protein, implicated in about 30% of all cancers.
All of the research in my group is based largely on synthesis and students in my group spend most of their time doing synthetic chemistry. Individual projects may also involve computational modeling and measurements of binding constants by NMR, calorimetry, fluorescence, etc. The CoA project involves a variety of biochemical techniques including enzyme isolation and assays of enzyme activity..
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