NOVEL GENES OF THE MEVALONATE PATHWAY

描述：根据流行病学研究，推荐的饮食模式 降低癌症和心血管疾病的风险强调 水果、蔬菜和谷类食品。这些食物是营养物质的主要饮食来源 香叶醇、柠檬烯和其他植物次生代谢的异戊二烯类产物， 其中许多具有广泛的抗肿瘤活性和胆固醇 压抑行为。推测了异戊二烯类化合物的作用机理 由甲氧戊酸途径的酶介导。 研究人员最近分离到了编码一种新的异戊二磷酸(IPP)异构酶2的全长cDNA.这种异构酶是一个新基因的产物， 定位于细胞质，而IPP异构酶1是最近发现的 由我们的小组显示定位于过氧酶体。此外，调查人员 另一些人证明了HMG-CoA还原酶也定位于两个 不同的细胞内隔室，内质网和过氧化物体，PI有 最近开发出一种只表达过氧化物体的哺乳动物细胞系 HMG-CoA还原酶蛋白。 在这项提案中，PI解决了这样的假设 异构酶和还原酶的双重定位(限速 异戊二烯途径中的酶)导致功能分离。一套 酶负责甾醇的生物合成；另一组位于 空间分离的隔室，导致非甾醇的生物合成 产品。 为了验证这一假设，提出了以下具体目标： 1)确定新的IPP异构酶2，2)的调节和功能 分离编码过氧化物体HMG-CoA还原酶的cDNA3)至 确定过氧化体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.