ABSTRACT
Interestingly, the position of the double bond in 3-Deazaneplanocin (DZNep) and Cyclopentenyl Cytosine (CPE-C) was different from that found in two closely related FDA approved drugs: Abacavir, an inhibitor of HIV RT approved in 1998 for the treatment of AIDS, and Entecavir, also an inhibitor of reverse transcription approved in 2005 for the treatment of chronic hepatitis B infection. A known inhibitor of the de novo pathway, such as the bisubstrate inhibitor N-phosphonoacetyl-l-aspartate, targets the enzyme aspartate transcarbamoylase, but despite its ability to reduce uridine synthesis, it is not very effective because plasma uridine levels are usually quite high. CTP synthetase has a glutamine amidotransferase domain that hydrolyzes glutamine and a synthetase domain that catalyzes the ATP-dependent phosphorylation of UTP and the subsequent reaction with the ammonia liberated from glutamine. An increase in the activity of CTP synthetase in tumors is associated with transformation and progression.
