Mechanisms and inhibition of enzymes involved in pyrimidine and purine biosynthesis

Understanding how enzymes catalyze reactions and the precise interactions that occur between enzymes and the molecules they interact with provides us with the knowledge to guide drug development. The enzyme cytidine 5'-triphosphate (CTP) synthetase makes CTP. CTP is utilized for many functions including the manufacture of genetic material and cell membranes. Guanosine 5'-triphosphate (GTP) regulates CTP synthetase activity by activating the enzyme under some conditions and inhibiting under other conditions. I am studying this regulation by determining how molecules that mimic the structure of GTP interact with the enzyme. By examining how well these molecules either activate or inhibit the enzyme, I will identify the precise interactions required for regulation of enzyme activity. This work is being conducted with bacterial and hamster CTP synthetases. The latter enzyme is an excellent model for human CTP synthetase. Understanding catalysis by CTP synthetase may reveal means of blocking GTP-dependent activation and inhibiting the enzyme. Since normally proliferating cells are not as dependent on CTP synthetase as malignant cells, inhibition of CTP synthetase may serve as a mode of chemotherapy. In addition, inhibitors of CTP synthetase may also serve to augment current chemotherapy protocols, and act as antiviral (including anti-HIV) and antiprotozoal agents.