Brown M S, Goldstein J L
J Lipid Res. 1980 Jul;21(5):505-17.
The availability of compactin (ML-236B), a potent competitive inhibitor of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, has permitted the demonstration of a hitherto unsuspected aspect of mevalonate metabolism and isoprenoid synthesis in cultured mammalian cells. 3-Hydroxy-3-methylglutaryl Coenzyme A reductase, the enzyme that synthesizes mevalonate, appears to be regulated through a multivalent feedback mechanism. Full suppression of the reductase requires the presence of at least two regulators: 1) cholesterol, which is normally derived exogenously from plasma low density lipoprotein (LDL), and 2) a nonsterol product, which is normally synthesized endogenously from mevalonate. Evidence indicates that both of these regulators of the reductase may be essential for the growth of mammalian cells in culture. The multivalent feedback regulation of 3-hydroxy-3-methylglutaryl Coenzyme A reductase, together with secondary regulatory changes in other enzymes of the sterol synthetic pathway, coordinates the branched pathway of mevalonate metabolism so as to assure a constant supply of cholesterol and nonsterol products. These new findings have important implications for the understanding of isoprenoid metabolism and its relation to cell growth.
美伐他汀（ML - 236B）是一种有效的3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶竞争性抑制剂，它的存在使得在培养的哺乳动物细胞中得以证明甲羟戊酸代谢和类异戊二烯合成中一个迄今未被怀疑的方面。合成甲羟戊酸的3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶似乎是通过多价反馈机制进行调节的。完全抑制该还原酶需要至少两种调节因子的存在：1）胆固醇，其通常从血浆低密度脂蛋白（LDL）外源获得；2）一种非甾醇产物，其通常由甲羟戊酸内源合成。有证据表明，还原酶的这两种调节因子对于培养的哺乳动物细胞生长可能都是必不可少的。3 - 羟基 - 3 - 甲基戊二酰辅酶A还原酶的多价反馈调节，连同甾醇合成途径中其他酶的二级调节变化，协调了甲羟戊酸代谢的分支途径，以确保胆固醇和非甾醇产物的持续供应。这些新发现对于理解类异戊二烯代谢及其与细胞生长的关系具有重要意义。
