2008 Faculty Researchers

Lesa Beamer, PhD

Structural studies of key enzymes from human pathogens

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Office Location

105A Schlundt Annex

Phone #:

Office: (573) 882-6072
Fax: (573) 884-4812

Summary

Enzymes in the -D-phosphohexomutase superfamily play critical roles in carbohydrate metabolism and other biosynthetic pathways. The importance of these proteins is demonstrated by their distribution in nature: at least one family member is found in all organisms from bacteria to humans. Detailed studies of enzymes in this family are of interest in fields such as metabolic engineering and also as targets for inhibitor design. To this end, we have obtained clones of ~ 15 members of the - D-phosphohexomutase superfamily from human pathogens, including Y. pestis, S. aureus, P. aeruginsoa, and V. cholera. These proteins will be expressed, purified and targeted for crystallization efforts.

We will use X-ray crystallography to define the structural determinants of substrate specificity for the -D-phosphohexomutases via studies of proteins in different sub-groups of the family. There are four major sub-groups within this enzyme family that utilize glucose, mannose, glucosamine, or acetylglucosamine-based phosphohexoses as substrates. In particular, we hope to characterize enzyme-substrate complexes of phosphoglucomutase for the first time. In addition, we will determine the structure of an uncharacterized member ofthe superfamily, phosphoglucosamine mutase, in complex with its substrates. In combination with previously determined structures of other proteins in the superfamily, we will conduct sequence-structure analyses of the four sub¬groups of this enzyme superfamily, in order to define key residues in the active site that can be used to predict likely functional roles. These efforts are a first step toward the design of specific inhibitors for this enzyme family that may aid in treatment of infections by these important human pathogens.