NOVEL GENES OF THE MEVALONATE PATHWAY

描述：根据流行病学研究， 降低癌症和心血管疾病的风险强调了 水果、蔬菜和谷物。这些食物是主要的饮食来源 香叶醇、柠檬烯和其它植物次生代谢的类异戊二烯产物， 其中许多发挥广泛的抗肿瘤活性， 镇压行动。提出了类异戊二烯的作用机理 由甲羟戊酸途径的酶介导。 研究人员最近分离了一种新的异戊基二磷酸（IPP）异构酶2的全长cDNA。这种异构酶是一种新基因的产物， 定位于细胞质区室，而IPP异构酶1最近 我们的研究小组发现它定位于过氧化物酶体。此外，调查人员 和其他人已经证明HMG-CoA还原酶也定位于两个 不同的细胞内区室，ER和过氧化物酶体，和PI具有 最近开发了一种只表达过氧化物酶体的哺乳动物细胞系 HMG-CoA还原酶蛋白。 在本提案中，PI解决了以下假设： 异构酶和还原酶的双重定位（限速 异戊烯类化合物途径中的酶）导致功能分离。一组 酶负责甾醇的生物合成;另一组，位于 空间上分离的隔室，导致非甾醇的生物合成 产品. 为了检验这一假设，提出了以下具体目标： 1）确定新型IPP异构酶2的调节和功能，2） 分离编码过氧化物酶体HMG-CoA还原酶的cDNA，和3） 确定过氧化物酶体HMG-CoA还原酶的调节和功能。

DESCRIPTION: Based on epidemiological studies, dietary patterns recommended for lowering the risks of cancer and cardiovascular disease emphasize the value of fruits, vegetables and cereals. These foods are the primary dietary source of geraniol, limonene and other isoprenoid products of secondary plant metabolism, many of which exert broad antitumorigenic activities and cholesterol suppressive actions. The mechanism of action of the isoprenoids is postulated to be mediated by enzymes of the mevalonate pathway. The investigators have recently isolated a full length cDNA coding for a novel isopentyl diphosphate (IPP) isomerase 2. This isomerase is a product of a novel gene and is localized to the cytoplasmic compartment, whereas IPP isomerase 1 was recently shown by our group to be localized to the peroxisomes. In addition, the investigators and others have demonstrated that HMG-CoA reductase is also localized in two distinct intracellular compartments, ER and peroxisomes, and the PIs have recently developed a mammalian cell line that expresses only the peroxisomal HMG-CoA reductase protein. In this proposal the PIs address the hypothesis that the dual localization of the isomerase and the reductase (the rate limiting enzyme) in the isopreniod pathway leads to separation of functions. One set of enzymes is responsible for sterol biosynthesis; the other set, located in a spatially separate compartment, leads to biosynthesis of the non-sterol products. To test this hypothesis the following specific aims are proposed: 1)to determine the regulation and function of the novel IPP isomerase 2, 2)to isolate the cDNA which encodes the peroxisomal HMG-CoA reductase, and 3)to determine the regulation and function of the peroxisomal HMG-CoA reductase.