In vitro metabolism of 5,8-dideazafolates and 5,8-dideazaisofolates by mammalian folylpoly-gamma-glutamate synthetase.
The in vitro metabolism of a variety of 5,8-dideazafolate and 5,8-dideazaisofolate analogues by pig liver folylpolyglutamate synthetase and the specificity of the enzyme for some polyglutamate derivatives of these analogues have been investigated. All 4-oxo-quinazoline analogues were metabolized to long chain polyglutamate derivatives, primarily the pentaglutamate, whereas 4-amino-quinazolines were metabolized to a lesser extent, with the accumulation of di- and triglutamate derivatives. This pattern of metabolism was consistent with the large drop in Vmax/Km and Vmax values for folylpolyglutamate synthetase observed with diglutamate derivatives of 4-aminofolate analogues. The extent of metabolism of the various analogues did not correlate with the relative substrate effectiveness of their parent monoglutamate derivatives. The 5-chloro and 5-methyl substitutions of quinazolines enhanced the addition of glutamate residues to 4-amino derivatives but markedly impaired the metabolism of 4-oxo derivatives.
Coll
R J
RJ
Department of Nutritional Sciences, University of California, Berkeley 94720.
Cesar
D
D
Hynes
J B
JB
Shane
B
B
D000630:Aminopterin / Q000031:analogs & derivatives / Q000378:metabolism; D000818:Animals; D005493:Folic Acid Antagonists / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D010453:Peptide Synthases / Q000378:metabolism*; D011624:Pteroylpolyglutamic Acids / Q000378:metabolism; D011799:Quinazolines / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D005493:Folic Acid Antagonists; D011624:Pteroylpolyglutamic Acids; D011799:Quinazolines; C035530:5,8-dideazaisofolic acid; C025928:CB 3705; D010453:Peptide Synthases; C023103:folylpolyglutamate synthetase; D000630:Aminopterin