KINETICS OF FOLATE METABOLISM

叶酸代谢动力学

• 批准号: 3874202
• 负责人: P F MORRISON
• 金额: --
• 依托单位: NATIONAL CENTER FOR RESEARCH RESOURCES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3874202
• 关键词: 1 carbon transferase; chemical kinetics; dihydrofolate reductase; enzyme model; folate; methotrexate; neoplasm /cancer chemotherapy; neoplastic cell; nutrition aspect of cancer; nutrition related tag; solute; thymidylate synthase; tissue /cell culture; trimetrexate; vitamin metabolism

Recent observations of folate pool dynamics in cells treated with trimetrexate or methotrexate have revealed different folate depletion responses in breast and colon cancer cell lines than in hepatoma lines. An explanation of this difference is being sought in terms of the biochemical kinetics of the folate cycle. Differences seem unlikely to arise from dissimilar Michaelis and inhibition constants, since known values do not vary greatly across the cell lines. On the other hand, maximum enzyme activities may vary across cell type and are suspected of accounting for different folate dynamics. At present, elevated activities of thymidylate synthase (TS), dihydrofolate reductase (DHFR), and glycinamide ribonucleotide transformylase (GT) are being examined for their ability to account for the different folate depletion rates observed in the various cell lines. Our folate cycle model (JBC 264 10552 1989) has been employed to show that ten-fold TS activity increases will deplete reduced folates down to experimental assay limits. The model has also shown that similar increases of DHFR activity will tend to offset any depletion caused by increased TS activity. With model calculations as a guide, colon and breast cell lines with order-of-magnitude TS increases are being investigated experimentally in the MB/NCI to verify the predicted depletion. In addition, DHFR, GT, and formyl-dihydrofolate synthetase activities are being monitored for interference effects suggested by the folate cycle model.

叶酸池动态变化的最新观察 甲氨蝶呤或甲氨蝶呤显示出不同的叶酸消耗 乳腺癌和结肠癌细胞株的反应比肝癌细胞系的反应要好。一个 这种差异的解释是从生物化学的角度进行的 叶酸循环的动力学。分歧似乎不太可能产生于 不同的米氏常数和抑制常数，因为已知值不 不同的细胞系之间差异很大。另一方面，最大的酶 不同细胞类型的活动可能不同，并被怀疑是 不同的叶酸动态。目前，胸腺嘧啶核苷活性升高 合成酶(TS)、二氢叶酸还原酶(DHFR)和甘氨酰胺 正在检测核糖核苷酸转换酶(GT)的能力 解释了不同的叶酸消耗率在不同的 细胞系。我们的叶酸循环模型(JBC264 10552 1989)已被采用 为了证明TS活性增加十倍将消耗减少的叶酸 降到实验的化验极限。该模型还表明，类似的 DHFR活性的增加将倾向于抵消以下原因造成的任何消耗 增加了TS活动。以模型计算为指导，冒号和 TS呈数量级增长的乳腺细胞系 在MB/NCI中进行了实验研究，以验证预测 耗尽。此外，DHFR、GT和甲酰二氢叶酸合成酶 正在对活动进行监测，以确定是否存在 叶酸循环模型。