Purine deoxynucleosides and adenosine dialdehyde decrease 5-amino-4-imidazolecarboxamide (Z-base)-dependent purine nucleotide synthesis in cultured T and B lymphoblasts.
Deoxyadenosine (dAdo) and deoxyguanosine (dGuo) decrease methionine synthesis from homocysteine in cultured lymphoblasts; because of the possible trapping of 5-methyltetrahydrofolate this could lead to decreased purine nucleotide synthesis. Since purine deoxynucleosides could also inhibit purine synthesis de novo at an early step not involving folate metabolism, we measured in azaserine-treated cells 5-amino-4-imidazolecarboxamide (Z-base)-dependent purine nucleotide synthesis using [14C]formate. In the T lymphoblasts, Z-base-dependent purine nucleotide synthesis was decreased 26% by 0.3 microM-dAdo, 21% by 1 microM-dGuo and 28% by 1 microM-adenosine dialdehyde, a potent S-adenosylhomocysteine hydrolase inhibitor; homocysteine fully reversed the inhibitions. The B lymphoblasts were considerably less sensitive to the deoxynucleoside-induced decrease in Z-base-dependent purine nucleotide synthesis, with 100 microM-dAdo required for significant inhibition and no inhibition by dGuo at this concentration; homocysteine partly reversed the inhibition by dAdo. The observed decrease in Z-base-dependent purine nucleotide synthesis could not be attributed either to dUMP depletion changing the folate pools or to decreased ATP availability because dUrd was without effect and during the experimental period the intracellular ATP concentration did not change significantly. Cells with 5,10-methylenetetrahydrofolate reductase deficiency were relatively resistant to inhibition of Z-base-dependent purine nucleotide synthesis by dAdo and adenosine dialdehyde. Our results suggest that deoxynucleosides decrease purine nucleotide synthesis by trapping 5-methyltetrahydrofolate.
D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2); D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000243:Adenosine Deaminase / Q000172:deficiency; D000620:Aminoimidazole Carboxamide / Q000494:pharmacology*; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism*; D002460:Cell Line; D005492:Folic Acid / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D010088:Oxidoreductases / Q000172:deficiency; D011684:Purine Nucleosides / Q000494:pharmacology*; D011685:Purine Nucleotides / Q000096:biosynthesis*; D011683:Purine-Nucleoside Phosphorylase / Q000172:deficiency; D011687:Purines / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism*
D007093:Imidazoles; D011684:Purine Nucleosides; D011685:Purine Nucleotides; D011687:Purines; C027579:periodate-oxidized adenosine; D000620:Aminoimidazole Carboxamide; D005492:Folic Acid; D010088:Oxidoreductases; D045103:5,10-Methylenetetrahydrofolate Reductase (FADH2); D042965:Methylenetetrahydrofolate Reductase (NADPH2); D011683:Purine-Nucleoside Phosphorylase; D000243:Adenosine Deaminase; D000241:Adenosine