Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

dUDP-GlcNAc, the 2'-deoxyribosyl analogue of UDP-GlcNAc, has been identified in human lymphoid cells treated with the dihydrofolate reductase inhibitor, methotrexate. It was shown previously that elevation of dUTP accompanies the gross expansion in intracellular deoxyuridylate pools that results from the methotrexate-induced block in thymidylate synthetase activity (1). dUDP-GlcNAc presumably is formed from dUTP acting in place of UTP in the normal pathway for formation of UDP-GlcNAc. Neither dUTP nor dUDP-GlcNAc has been detected in untreated cells. Inhibition of thymidylate synthetase by treatment of cells with 5-fluorodeoxyuridine (5-FdUrd) also causes the appearance of dUDP-GlcNAc, and, in addition, 5-FdUDP-GlcNAc, synthesized from 5-FdUTP. The metabolic effects, if any, of these analogues are not known. Synthesis of the analogues may help to limit accumulation of dUTP and 5-FdUTP under circumstances in which the deoxyuridine triphosphatase mechanism is insufficient.
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PMID:2'-deoxyribosyl analogues of UDP-N-acetylglucosamine in cells treated with methotrexate or 5-fluorodeoxyuridine. 622 93

The biochemical effects of the antitumor agent N-(4-(N-(( 2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino) benzoyl)-L -glutamic acid (CB3717) were studied in WI-L2 cultured human lymphoblastoid cells. CB3717 was a potent inhibitor of human thymidylate synthetase; the inhibition was competitive with 5,10-methylenetetrahydrofolate (Ki = 4.9 X 10(-9) M). CB3717 also inhibited human dihydrofolate reductase, competitively with dihydrofolate (Ki = 2.3 X 10(-8) M). The growth-inhibitory effect of CB3717 could be prevented completely by 10 microM thymidine. Administration of thymidine could be delayed for up to 8 hr after CB3717 treatment without cytotoxicity but, if thymidine was delayed for 24 hr, severe toxicity resulted. Incubation for 16 hr in the presence of a growth-inhibitory concentration of CB3717 did not result in the appearance of dihydrofolate in WI-L2 cells. These results indicate that, in the presence of CB3717, thymidylate synthetase, rather than dihydrofolate reductase, became rate-limiting for the cycle of dihydrofolate oxidation and reduction. Treatment of cells for 16 hr at an IC50 concentration of CB3717 caused a decrease of 88% in cellular dTTP and a 2,300% increase in dUMP. The level of dUDP also increased, and traces of dUTP appeared in treated cells. No large changes were seen in ribonucleotide pools. A kinetic analysis was made, by computer simulation, of predicted consequences of metabolic effects of compounds that inhibit both dihydrofolate reductase and thymidylate synthetase. It was concluded that, even if the Ki of the inhibitor for thymidylate synthetase were 3 orders of magnitude higher (weaker) than the Ki for dihydrofolate reductase, thymidylate synthetase could still become rate-limiting.
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PMID:Biochemical effects of a quinazoline inhibitor of thymidylate synthetase, N-(4-(N-(( 2-amino-4-hydroxy-6-quinazolinyl)methyl)prop-2-ynylamino) benzoyl)-L-glutamic acid (CB3717), on human lymphoblastoid cells. 666 Dec 52