Current Enzyme Inhibition - Volume 8, Issue 2, 2012

Dihydrofolate reductase (DHFR) enzyme catalyzes the reduction of dihydrofolate to tetrahydrofolate using NADPH as a cofactor to restore the reduced folate pools for reactions requiring one carbon transfer. Folates are required for de novo synthesis of purines and thymidylate, as well as glycine, methionine and serine. For this reason, DHFR has been an important target for chemotherapy for many diseases including canc Read More

Chemoresistance is one of the major reasons for the failure of anticancer chemotherapy in treating advanced stage cancer. The mechanism of chemoresistance to fluoropyrimidines and antifolates has been extensively investigated in the past 40 years. It has been well established that thymidylate synthase (TYMS, TS) and dihydrofolate reductase (DHFR) are two major targets for fluoropyrimidines and antifolates, respec Read More

The ubiquitous enzyme dihydrofolate reductase (DHFR) is responsible for the reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate in an NADPH-dependent manner. The enzymes DHFR and thymidylate synthase (TS), which converts deoxyuridine monophosphate (dUMP) to deoxythymidine monophosphate (dTMP), are coupled in the folate pathway as the product of TS (dihydrofolate) is the substrate for DHF Read More

This brief review will cover recent advances and applications of molecular dynamics simulations of dihydrofolate reductase over the course of the past few years. The application of the technique to the study of kinetic isotope effects, binding free energy of drugs, impact of ligand binding on protein conformation and study of coupled motions in hydrogen tunneling reactions will be discussed.

Human malaria parasites, in particular the most dangerous species, Plasmodium falciparum, are responsible for more than a million deaths per year, mainly of young African children, as well as causing enormous social and economic problems in endemic countries. In the absence of efficacious vaccines, the main weapon against malaria infections is intervention with drugs. Within the antimalarial drugs currently deplo Read More

Cyclic AMP is an ubiquitous molecule that serves as an important second messenger for multiple signaling pathways. At least nine membrane-bound mammalian isoforms of adenylyl cyclase have been identified, and each isoform has a distinct pattern of tissue distribution as well as interaction with regulatory proteins within local cytosolic environment. Adenylyl cyclase is coupled to G-protein receptors and serves to c Read More