title: Differential inhibition of host and viral thymidylate synthetases by folylpolyglutamates.
abstract: The ability of folate analogues to inhibit host and viral thymidylate synthetases was measured using the corresponding Escherichia coli and T2-phage-induced enzymes. In the absence of Mg2+, 6 x 10(-7) M pteroylhexaglutamate inhibited the T2-phage-induced synthetase by 50%, but at least 100-fold greater levels of this compound were necessary to inhibit the E. coli synthetase by this amount. At 2.5 x 10(-6) M pteroylhexaglutamate, at least 80% inhibition of the T2-phage synthetase could be obtained with little or no inhibition of the E. coli enzyme. The pteroylmonoglutamate was about 2 orders of magnitude less inhibitory towards the T2-phage enzyme than the pteroyltri- to -heptaglutamates. However, upon addition of Mg2+ to the assay mixture, the inhibition produced by pteroylhexaglutamate was essentially reversed, with the E. coli synthetase now increasingly inhibited by this compound and the T2-synthetase only minimally impaired. Methotrexate and N10-formyl-2-amino-4-hydroxyquinazoline, although inhibitory to both enzymes in the presence or absence of Mg2+, did not show this differential selectivity. These results suggest that certain folate analogues may be useful in distinguishing between a host and an infecting organism's thymidylate synthetase and could thus provide an additional means of screening for potential chemotherapeutic agents.
mesh_terms: D003090:Coliphages / Q000201:enzymology*; D004926:Escherichia coli / Q000201:enzymology*; D005492:Folic Acid / Q000031:analogs & derivatives*; D007700:Kinetics; D008274:Magnesium / Q000494:pharmacology; D008727:Methotrexate / Q000494:pharmacology; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D011624:Pteroylpolyglutamic Acids / Q000494:pharmacology*; D013045:Species Specificity; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors*
chemical_list: D011624:Pteroylpolyglutamic Acids; D005492:Folic Acid; D008780:Methyltransferases; D013940:Thymidylate Synthase; D008274:Magnesium; D008727:Methotrexate