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Dr. Raushel
http://www.chem.tamu.edu/rgroup/raushel/ Our research is focused on elucidating the relationship between protein structure and enzyme activity. Enzymes of current interest include the amidotransferase family of proteins. These enzymes utilize the hydrolysis of glutamine as a source of the nucleophile ammonia. Our primary interest is carbamoyl phosphate synthetase. This enzyme initiates the synthesis of carbamoyl phosphate from glutamine, ATP and bicarbonate in a reaction mechanism that involves four separate chemical events and three reaction intermediates. The x-ray structure has been solved and it has unveiled the relative location of three separate active sites connected to one another by a molecular tunnel nearly 100 Angstrom long. Graduate students will be involved in the design and synthesis of site-specific inhibitors and in the development of new kinetic methods for determining allosteric communication between the three active sites. This project will be expanded to examine the structural and mechanistic details of CPS from other sources where the protein architecture is even more complicated and we will search for other enzymes with complex molecular tunnels. We have recently initiated a structural and mechanistic assessment of the reactions catalyzed by two enzymes involved in the biosynthesis of coenzyme B12, cbiA and cbiP. These two enzymes are responsible for the amidation of six separate carboxylate groups attached to the corrin ring system. The other major project is directed at the amidohydrolase superfamily of enzymes. This family of enzymes catalyzes the hydrolysis of phosphate and carboxylate esters and amides. We are interested in the evolution of the binuclear and mononuclear metal centers from a given set of protein ligands found within the context of an alpha/beta barrel core and the diversity for the activation of the hydrolytic water molecule. We are developing novel methods for the construction of new proteins with new catalytic activities or substrate specificities. One of these projects involves the design and preparation of novel enzymes for the hydrolysis of chemical warfare agents and the alterations in the substrate and stereochemical specificity. Our most recent project is directed at the elucidation of substrate and reaction specificity for proteins of unknown function in the amidohydrolase superfamily. We use a combination of high throughput synthesis of substrate libraries and computational docking of a virtual substrate library. |
