Quesney-Huneeus V, Wiley M H, Siperstein M D
Proc Natl Acad Sci U S A. 1979 Oct;76(10):5056-60. doi: 10.1073/pnas.76.10.5056.
The relationship between 3-hydroxy-3-methylglutaryl (HMG) CoA reductase activity [mevalonate:NADP(+) oxidoreductase (CoA-acylating), EC 1.1.1.34] and DNA synthesis was studied in synchronized cultures of BHK-21 cells. During a 24-hr period of cell replication, two phases of accelerated thymidine incorporation into DNA corresponding to two S phases of the cell cycle occurred. A marked increase in activity of HMG CoA reductase was consistently observed at or just prior to each of these peaks of DNA synthesis. Moreover, when HMG CoA reductase activity was suppressed by the competitive inhibitor compactin, the normal S-phase burst of DNA synthesis was specifically and totally prevented. Finally, the compactin-induced inhibition of DNA synthesis could be completely reversed within minutes by the addition of mevalonate, the product of the HMG CoA reductase reaction. By contrast, addition of cholesterol-rich lipoproteins had no effect upon DNA synthesis in compactin-treated cells. These data demonstrate that HMG CoA reductase activity, and therefore the production of mevalonate, plays an essential role in the synthesis of DNA specifically during the S phase of the cell cycle. Moreover, the results indicate that this function of mevalonate in regulating DNA replication is independent of its conversion to cholesterol.
在BHK - 21细胞同步培养物中研究了3 - 羟基 - 3 - 甲基戊二酰（HMG）辅酶A还原酶活性[甲羟戊酸：NADP(+)氧化还原酶（辅酶A酰化），EC 1.1.1.34]与DNA合成之间的关系。在细胞复制的24小时期间，对应于细胞周期的两个S期，出现了两个加速胸苷掺入DNA的阶段。在这些DNA合成峰值出现时或之前，始终观察到HMG辅酶A还原酶活性显著增加。此外，当用竞争性抑制剂美伐他汀抑制HMG辅酶A还原酶活性时，DNA合成的正常S期爆发被特异性且完全阻止。最后，通过添加甲羟戊酸（HMG辅酶A还原酶反应的产物），美伐他汀诱导的DNA合成抑制在数分钟内可完全逆转。相比之下，添加富含胆固醇的脂蛋白对美伐他汀处理的细胞中的DNA合成没有影响。这些数据表明，HMG辅酶A还原酶活性以及因此甲羟戊酸的产生，在细胞周期的S期期间对DNA合成起着至关重要的作用。此外，结果表明甲羟戊酸在调节DNA复制中的这种功能与其转化为胆固醇无关。
