Antifolates induce primary inhibition of the de novo purine pathway prior to 5-aminoimidazole-4-carboxamide ribotide transformylase in leukemia cells.

Abstract

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).

• Authors: S D Lyons, R I Christopherson
• Journal: Biochemistry international (Biochem Int) Vol. 24 Issue 1 Pg. 187-97 (May 1991) ISSN: 0158-5231 [Print] Australia
• PMID: 1768258 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Folic Acid Antagonists
• Purine Nucleotides
• Purines
• Pyrimidines
• Azaserine
• Hydroxymethyl and Formyl Transferases
• Phosphoribosylaminoimidazolecarboxamide Formyltransferase
• Acyltransferases
• piritrexim
• Methotrexate

Topics

• Acyltransferases (antagonists & inhibitors)
• Animals
• Azaserine (pharmacology)
• Folic Acid Antagonists (pharmacology)
• Hydroxymethyl and Formyl Transferases
• Leukemia L1210 (metabolism)
• Methotrexate (pharmacology)
• Phosphoribosylaminoimidazolecarboxamide Formyltransferase
• Purine Nucleotides (metabolism)
• Purines (metabolism)
• Pyrimidines (pharmacology)
• Tumor Cells, Cultured (drug effects, metabolism)