Antifolates induce primary inhibition of the de novo purine pathway prior to 5-aminoimidazole-4-carboxamide ribotide transformylase in leukemia cells.
Polyglutamated dihydrofolate, accumulated as a result of potent inhibition of dihydrofolate reductase (DHFR), has been postulated to directly inhibit the purine pathway at 5-aminoimidazole-4-carboxamide ribotide (AICAR) transformylase (reaction 9) in leukemia cells exposed to methotrexate (MTX). We have observed that 25 microM MTX or piritrexim, a "non-classical" antifolate, induce several-fold accumulations of AICAR and N-succino-AICAR to a combined cellular concentration of 89 microM in mouse L1210 leukemia cells after 2 h. By contrast, complete inhibition of reaction 4 by 25 microM azaserine results in accumulation of N-formyl-glycinamide ribotide (FGAR) polyphosphates to a combined cellular concentration of greater than 10 mM. MTX prevented azaserine-induced accumulation of FGAR polyphosphates. Hence, these antifolates induce primary inhibition of the de novo purine pathway at, or prior to, glycinamide ribotide transformylase (reaction 3).
Lyons
S D
SD
Department of Biochemistry, University of Sydney, NSW, Australia.
Christopherson
R I
RI
D000217:Acyltransferases / Q000037:antagonists & inhibitors*; D000818:Animals; D001377:Azaserine / Q000494:pharmacology; D005493:Folic Acid Antagonists / Q000494:pharmacology*; D019877:Hydroxymethyl and Formyl Transferases; D007939:Leukemia L1210 / Q000378:metabolism*; D008727:Methotrexate / Q000494:pharmacology; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D011685:Purine Nucleotides / Q000378:metabolism; D011687:Purines / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D005493:Folic Acid Antagonists; D011685:Purine Nucleotides; D011687:Purines; D011743:Pyrimidines; D001377:Azaserine; D019877:Hydroxymethyl and Formyl Transferases; D051027:Phosphoribosylaminoimidazolecarboxamide Formyltransferase; D000217:Acyltransferases; C024530:piritrexim; D008727:Methotrexate