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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
3R01DK058040-05S1
Application #
6917477
Study Section
Nutrition Study Section (NTN)
Program Officer
May, Michael K
Project Start
2000-09-15
Project End
2005-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
5
Fiscal Year
2004
Total Cost
$7,082
Indirect Cost
Name
San Diego State University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
073371346
City
San Diego
State
CA
Country
United States
Zip Code
92182
Kovacs, Werner J; Charles, Khanichi N; Walter, Katharina M et al. (2012) Peroxisome deficiency-induced ER stress and SREBP-2 pathway activation in the liver of newborn PEX2 knock-out mice. Biochim Biophys Acta 1821:895-907
Kovacs, Werner J; Tape, Khanichi N; Shackelford, Janis E et al. (2009) Peroxisome deficiency causes a complex phenotype because of hepatic SREBP/Insig dysregulation associated with endoplasmic reticulum stress. J Biol Chem 284:7232-45
Clizbe, Daun B; Owens, Michelle L; Masuda, Kimberly R et al. (2007) IDI2, a second isopentenyl diphosphate isomerase in mammals. J Biol Chem 282:6668-76
Kovacs, Werner J; Tape, Khanichi N; Shackelford, Janis E et al. (2007) Localization of the pre-squalene segment of the isoprenoid biosynthetic pathway in mammalian peroxisomes. Histochem Cell Biol 127:273-90
Kovacs, Werner J; Shackelford, Janis E; Tape, Khanichi N et al. (2004) Disturbed cholesterol homeostasis in a peroxisome-deficient PEX2 knockout mouse model. Mol Cell Biol 24:1-13
Breitling, Rainer (2004) Pathogenesis of peroxisomal deficiency disorders (Zellweger syndrome) may be mediated by misregulation of the GABAergic system via the diazepam binding inhibitor. BMC Pediatr 4:5
Breitling, Rainer; Laubner, Daniela; Clizbe, Daun et al. (2003) Isopentenyl-diphosphate isomerases in human and mouse: evolutionary analysis of a mammalian gene duplication. J Mol Evol 57:282-91
Kovacs, Werner J; Krisans, Skaidrite (2003) Cholesterol biosynthesis and regulation: role of peroxisomes. Adv Exp Med Biol 544:315-27
Lewin, Tal M; Van Horn, Cynthia G; Krisans, Skaidrite K et al. (2002) Rat liver acyl-CoA synthetase 4 is a peripheral-membrane protein located in two distinct subcellular organelles, peroxisomes, and mitochondrial-associated membrane. Arch Biochem Biophys 404:263-70
Breitling, Rainer; Sharif, Orzala; Hartman, Michelle L et al. (2002) Loss of compartmentalization causes misregulation of lysine biosynthesis in peroxisome-deficient yeast cells. Eukaryot Cell 1:978-86

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