A new folate antimetabolite, 5,10-dideaza-5,6,7,8-tetrahydrofolate is a potent inhibitor of de novo purine synthesis.
A new folate antimetabolite, 5,10-dideaza-5,6,7,8-tetrahydrofolate is a potent inhibitor of de novo purine synthesis.
复制标题
DOI：
--
复制
发表时间：
1989-01
期刊：
影响因子：
--
通讯作者：
G. Beardsley;B. Moroson;E. C. Taylor;R. Moran
中科院分区：
文献类型：
--
作者：
G. Beardsley;B. Moroson;E. C. Taylor;R. Moran
5,10-二脱氮酸四氢叶酸 (DDATHF) 是一种新型抗代谢药，旨在作为二氢叶酸还原酶以外位点叶酸代谢的抑制剂。研究发现 DDATHF 在 10-30 nM 浓度范围内可抑制培养物中 L1210 和 CCRF-CEM 细胞的生长。 DDATHF 对 L1210 和 CCRF-CEM 细胞生长的抑制作用可被次黄嘌呤或氨基咪唑甲酰胺逆转。添加胸苷和次黄嘌呤可以防止 DDATHF 对生长的抑制，但单独添加胸苷则不能。 5-甲酰四氢叶酸以剂量依赖性方式逆转 DDATHF 的作用。 DDATHF 在体外对二氢叶酸还原酶或胸苷酸合酶没有明显的抑制活性，但被发现是叶酰聚谷氨酸合成酶的极好底物。 DDATHF 对脱氧尿苷或胸苷掺入 DNA 的影响很小或没有影响，这与经典二氢叶酸还原酶抑制剂甲氨蝶呤的影响形成鲜明对比。研究发现 DDATHF 消耗细胞 ATP 和 GTP 的浓度与抑制白血病细胞生长的浓度相同，表明 DDATHF 的作用位点位于从头嘌呤生物合成途径中。完整 L1210 细胞中甲酰甘酰胺核糖核苷酸的合成受到 DDATHF 的抑制，其浓度依赖性与生长抑制相同。这表明 DDATHF 抑制甘氨酰胺核糖核苷酸转化酶，这是嘌呤从头合成的第一个叶酸依赖性酶。 DDATHF 是一种有效的叶酸类似物，可通过直接或间接抑制甘氨酰胺核糖核苷酸转化酶来抑制嘌呤合成。
5,10-Dideazatetrahydrofolate (DDATHF) is a new antimetabolite designed as an inhibitor of folate metabolism at sites other than dihydrofolate reductase. DDATHF was found to inhibit the growth of L1210 and CCRF-CEM cells in culture at concentrations in the range of 10-30 nM. The inhibitory effect of DDATHF on the growth of L1210 and CCRF-CEM cells was reversed by either hypoxanthine or aminoimidazole carboxamide. Growth inhibition by DDATHF was prevented by addition of both thymidine and hypoxanthine, but not by thymidine alone. 5-Formyltetrahydrofolate reversed the effects of DDATHF in a dose-dependent manner. DDATHF had no appreciable inhibitory activity against either dihydrofolate reductase or thymidylate synthase in vitro, but was found to be an excellent substrate for folylpolyglutamate synthetase. DDATHF had little or no effect on incorporation of either deoxyuridine or thymidine into DNA, in distinct contrast to the effects of the classical dihydrofolate reductase inhibitor, methotrexate. DDATHF was found to deplete cellular ATP and GTP over the same concentrations as those inhibitory to leukemic cell growth, suggesting that the locus of DDATHF action was in the de novo purine biosynthesis pathway. The synthesis of formylglycinamide ribonucleotide in intact L1210 cells was inhibited by DDATHF with the same concentration dependence as inhibition of growth. This suggested that DDATHF inhibited glycinamide ribonucleotide transformylase, the first folate-dependent enzyme of de novo purine synthesis. DDATHF is a potent folate analog which suppresses purine synthesis through direct or indirect inhibition of glycinamide ribonucleotide transformylase.