Differential inhibition of homotrimeric dUTPases by the 3'-azido derivative of dideoxy-UTP.
The inhibitory effects of 3'-azido-2',3'-dideoxyuridine-5'-triphosphate in complex with the Mg2+ ion (azido-ddUTP.Mg) on the dUTPases of the human, E. coli, and equine infectious anemia virus have been compared. Azido-ddUTP is analogous to drugs used in the treatment of HIV. Here it is shown to inhibit the bacterial dUTPase in a competitive manner (Ki = 9.3 microM), but to exhibit only marginal or no binding to the human and viral dUTPases, respectively. This is the first demonstration of an inhibitor with a strong preference for binding to a bacterial dUTPase over the human enzyme. The specific binding to the E. coli dUTPase is surprising in view of the close to identical substrate pockets among the three dUTPases tested. The results are discussed with reference to the possibility of designing active site directed inhibitors that bind to the homotrimeric dUTPase of a pathogen but not to the human form.
Palmén
Lorena Gonzalez
LG
Chemistry and Biomedical Sciences, School of Pure and Applied Natural Sciences, Kalmar University, Kalmar, Sweden.
Kvassman
Jan-Olov
JO
D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D011755:Pyrophosphatases / Q000037:antagonists & inhibitors*; D014544:Uridine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D011755:Pyrophosphatases; C020020:dUTP pyrophosphatase; D014544:Uridine Triphosphate