Structure function studies on the glutamate racemase enzyme from Bacillus anthracis

AEI 23

Shahila Mehboob, shahila@uic.edu and Michael E. Johnson. Center for Pharmaceutical Biotechnology, University of Illinois at Chicago, 900 S. Ashland Ave, MC 870, Room 1052, Chicago, IL 60607
Our overall goal is to develop new therapeutic agents specifically targeted to anthrax. We have identified glutamate racemase as an enzyme that is essential for bacterial survival. Glutamate racemase converts L-Glu to D-Glu and this D-Glu is a key precursor to the formation of the peptidoglycan layer. There are two isoforms of this enzyme, RacE1 and RacE2, in B. anthracis. Two cysteines in the active site are responsible for the deprotonation and reprotonation of glutamate. Interestingly, although these two isoforms share a high sequence similarity, their kinetic and structural properties are different. Design of inhibitors for glutamate racemase expected to covalently link to the two active site cysteines, revealed that inhibitors binding to a Cys at the mouth of the active site also resulted in enzyme inhibition. These studies led to the identification of molecules that can crosslink cysteine and tyrosine residues.