Relative substrate activities of structurally related pteridine, quinazoline, and pyrimidine analogs for mouse liver folylpolyglutamate synthetase.
Several structurally related series of folate analogs were studied as substrates for mouse liver folylpolyglutamate synthetase (FPGS). A comparison of the kinetics of the interaction of this enzyme with folate analogs that contained the quinazoline ring in place of the pteridine ring with those of the analogous pteridines demonstrated that the quinazoline derivatives were more efficient substrates for and tighter binding inhibitors of this enzyme. A series of 2,4-diaminopyrimidine dihydrofolate reductase inhibitors were found to be substrates for FPGS; these are the first known compounds without a fused ring system analogous to the pteridine ring of the folate molecule that are substrates for FPGS. Several 5,8-dideazafolate derivatives that lack the 2-amino group had activity as substrates for FPGS equivalent to that of the corresponding 5,8-dideazafolates. When a homologous series of 5,8-dideazafolic acid analogs with hydrocarbon substituents on the 10-nitrogen were studied, these substituents were found to diminish the efficiency of utilization of these analogs as substrates for FPGS; this effect increased with increasing chain length of the hydrocarbon. It was concluded that neither the 2-amino group nor an intact pyrazine ring of folates and folate analogs are essential for the binding of folates to the active site of mouse liver FPGS but that the pyrazine ring probably serves to position other regions of the folate molecule that interact with amino acid residues in the active site. It was also inferred from these observations that the volume within the active site of FPGS above/below the pyrazine ring or near the 10-position of folate derivatives are regions of limited bulk tolerance; binding of folate analogs with substituents at these positions probably distorts the active site.
Moran
R G
RG
Department of Biochemistry, University of Southern California, Los Angeles 90033.
Colman
P D
PD
Jones
T R
TR
D000588:Amines; D000818:Animals; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D051379:Mice; D010453:Peptide Synthases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011621:Pteridines / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism; D011799:Quinazolines / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D000588:Amines; D011621:Pteridines; D011743:Pyrimidines; D011799:Quinazolines; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase