Of the three major isoforms, alpha, mu, and pi, pi is the predominant form in cancer cells. Comparison of the active sites and transition state analogs of the three isozymes revealed a potential strategy for achieving isozyme selectivity. Application of this strategy has resulted in a pi-selective NO donor. Folate cofactors are essential for life.
Mammals derive folates from their diets.
In contrast, most microorganisms must synthesize folate de novo . Therefore, HPPK is an ideal target for the development of novel antimicrobial agents, which are urgently needed to fight the worldwide crisis of antibiotic resistance. HPPK contains 158 amino acid residues and is thermostable, which makes it an excellent model system for the study of the pyrophosphoryl transfer mechanism, of which little is known. Our analysis of these structures has provided essential information on the reaction mechanism of pyrophosphoryl transfer and critical knowledge for the design of novel antimicrobial molecules. We have been collaborating on this research with Honggao Yan, Ph.D., Michigan State University and Christopher J. Michejda, Ph.D., Structural Biophysics Laboratory, National Cancer Institute.