NOVEL GENES OF THE MEVALONATE PATHWAY

甲羟戊酸途径的新基因

• 批准号: 6517789
• 负责人: SKAIDRITE K KRISANS
• 金额: $ 34.96万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6517789
• 关键词: HMG coA reductases; complementary DNA; endoplasmic reticulum; isomerase; isoprenoid; laboratory rabbit; laboratory rat; mevalonate; peroxisome; protein localization; steroid biosynthesis

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.

描述：基于流行病学研究，建议用于 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 Geraniol，Limonene和其他二级植物代谢的类产品， 其中许多发挥了广泛的抗肿瘤活性和胆固醇 抑制行动。假定异丙因的作用机理 由甲戊酸途径的酶介导。 研究人员最近分离了针对新型异戊酯（IPP）异构酶2的全长cDNA编码。该异构酶是一种新基因的产物，IS 位于细胞质室，而IPP异构酶1最近是 由我们的小组显示为过氧化物酶体。此外，调查人员 其他人已经证明HMG-COA还原酶也位于两个 不同的细胞内室，ER和过氧化物酶体以及PI具有 最近开发了仅表达过氧化物酶体的哺乳动物细胞系 HMG-COA还原酶蛋白。 在此提案中，PI解决了以下假设 异构酶和还原酶的双重定位（速率限制 异丙二烯途径中的酶）导致功能分离。一组 酶负责固醇生物合成；另一组，位于 空间分开的隔室，导致非螺旋醇的生物合成 产品。 为了检验该假设，提出了以下特定目标： 1）确定新型IPP异构酶的调节和功能2，2） 隔离编码过氧化物酶体HMG-COA还原酶的cDNA，3） 确定过氧化物酶体HMG-COA还原酶的调节和功能。