Cytidine 5'-triphosphate synthetase as a target for inhibition by the antitumor agent 3-deazauridine.
Cytidine 5'-triphosphate synthetase as a target for inhibition by the antitumor agent 3-deazauridine.
复制标题
胞苷 5-三磷酸合成酶作为抗肿瘤剂 3-脱氮尿苷抑制的靶标。
作者：
R. P. McPartland;M. C. Wang;A. Bloch;H. Weinfeld
来自小牛肝脏的高度纯化的胞苷三磷酸合成酶的活性被证明可被 3-脱氮尿苷三磷酸（肿瘤细胞中 3-脱氮尿苷 (deaza-UR) 的主要代谢物）抑制。该抑制与三磷酸尿苷具有竞争性，通过 Dixon 和 Lineweaver-Burk 图确定的平均 Ki 值为 5.3 × 10-6 m。脱氮尿苷和脱氮尿苷单磷酸均未显着抑制该酶。白血病L1210细胞提取物中三磷酸尿苷胺化为三磷酸胞苷也被脱氮尿苷三磷酸抑制。结合发现，deaza-UR 对白血病 L1210 细胞体外生长的抑制可被胞苷逆转，并在较小程度上被尿苷和 2'-脱氧胞苷逆转，但不能被胸苷或 2'-脱氧尿苷逆转，这一观察结果表明 deaza-UR 通过干扰胞苷三磷酸合成酶的活性来发挥其生长抑制活性。
The activity of a highly purified cytidine triphosphate synthetase from calf liver was shown to be inhibited by 3-deazauridine triphosphate, a major metabolite of 3-deazuridine (deaza-UR) in tumor cells. The inhibition is competitive with respect to uridine triphosphate, and the average Ki value, determined by Dixon and Lineweaver-Burk plots, is 5.3 × 10-6 m. Neither deaza-UR nor deazauridine monophosphate inhibited the enzyme to a significant extent. The amination of uridine triphosphate to cytidine triphosphate in extracts of leukemia L1210 cells was also inhibited by deazauridine triphosphate. Coupled with the finding that the inhibition of the in vitro growth of leukemia L1210 cells by deaza-UR is reversed by cytidine and to a lesser extent by uridine and 2′-deoxycytidine, but not by thymidine or 2′-deoxyuridine, this observation suggests that deaza-UR exerts its growth-inhibitory activity by interfering with the activity of the cytidine triphosphate synthetase.