NOVEL GENES OF THE MEVALONATE PATHWAY

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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.