THE INHIBITION OF PROTEIN PRENYLTRANSFERASES BY OXYGENATED METABOLITES OF LIMONENE AND PERILLYL ALCOHOL
THE INHIBITION OF PROTEIN PRENYLTRANSFERASES BY OXYGENATED METABOLITES OF LIMONENE AND PERILLYL ALCOHOL
复制标题
DOI：
10.1016/0304-3835(95)03747-k
复制
发表时间：
1995-05-08
期刊：
影响因子：
9.7
通讯作者：
GOULD, MN
中科院分区：
文献类型：
--
作者：
GELB, MH;TAMANOI, F;GOULD, MN
单萜类化合物柠檬烯和紫苏醇是治疗晚期大鼠乳腺癌的有效药物。柠檬烯目前正在癌症患者中进行临床试验。这些单萜及其含氧代谢产物先前已显示抑制培养细胞中的蛋白质异戊二烯化，因为ras蛋白的法尼基化对于其引起致癌转化的能力是至关重要的，抑制蛋白质异戊二烯化可能是柠檬烯和紫苏醇的抗肿瘤作用的基础。在这项研究中，我们测试的能力，柠檬烯及其含氧类似物抑制蛋白质异戊二烯化酶在体外。柠檬烯和紫苏醇及其主要体内代谢产物紫苏酸是哺乳动物和酵母蛋白法尼基转移酶（PFT）和蛋白香叶基香叶基转移酶（PGGT）的弱抑制剂。相反，柠檬烯和紫苏醇的次要代谢产物紫苏酸甲酯是两种酶的有效抑制剂。紫苏酸甲酯是酵母PFT相对于焦磷酸法呢酯的竞争性抑制剂。这些研究表明，如果抑制蛋白质异戊二烯化是柠檬烯和紫苏醇抗癌活性的机制，则这些单萜可能是通过代谢修饰转化为药理活性物质的前药。
The monoterpenes limonene and perillyl alcohol are effective therapeutic agents against advanced rat mammary cancer. Limonene is currently undergoing clinical testing in cancer patients. These monoterpenes and their oxygenated metabolites have been previously shown to inhibit protein prenylation in cultured cells, Since farnesylation of ras protein is critical for its ability to cause oncogenic transformation, inhibition of protein prenylation may be the basis of the anti-tumor effects of limonene and perillyl alcohol. In this study we test the ability of limonene and its oxygenated analogs to inhibit protein prenylation enzymes in vitro. Limonene and perillyl alcohol and their major in vivo metabolite, perillic acid, are weak inhibitors of both mammalian and yeast protein farnesyl transferase (PFT) and protein geranylgeranyl transferase (PGGT). In contrast, a minor metabolite of both limonene and perillyl alcohol, perillic acid methyl ester, is a potent inhibitor of both enzymes, Perillic acid methyl ester is a competitive inhibitor of yeast PFT with respect to farnesyl pyrophosphate. These studies suggest that if the inhibition of protein prenylation is a mechanism for limonene's and perillyl alcohol's anti-cancer activities, these monoterpenes may be prodrugs that are converted into pharmacologically-active substances by metabolic modification.