Recent studies indicate that the metabolism of diacylglycerol pyrophosphate (DGPP) is involved in a novel lipid signaling pathway. DGPP was first identified as the product of the phosphatidate (PA) kinase reaction in the plant Catharanthus roseus. DGPP has since been found in a variety of plants and in the yeast Saccharomyces cerevisiae. The amounts of DGPP in plants and in wild-type yeast are barely detectable and reminiscent of other lipid signaling molecules. Recent studies have shown that DGPP accumulates in plant tissues upon G protein activation through the stimulation of PA kinase activity and metabolic labeling studies have shown that DGPP is rapidly metabolized to PA, and then to diacylglycerol (DG). It has been suggested that the function of DGPP is to attenuate the signaling functions of PA, that DGPP is the precursor of the PA which serves as a signaling molecule, or that DGPP itself functions as a signaling molecule. DGPPase catalyzes the dephosphorylation of DGPP to yield PA and then catalyzes the dephosphorylation of PA to yield DG. The enzyme has been identified in a wide range of organisms including S. cerevisiae. The investigators hypothesize that the regulation of DGPPase regulates the cellular levels of DGPP, PA and DG. During the past grant period, the investigators purified and characterized two DGPPases from S. cerevisiae and isolated two genes (DPP1 and DPP2) encoding for the enzyme. The cloned genes will be characterized, and the investigators will examine the regulation of the DGPPases in response to inositol, growth mutants, and of elevated levels of DGPPase in strains that overexpress the enzymes. Enzymological and kinetic characterization of the purified DGPPases will be expanded. The regulation of the DGPPase activities by lipids and water-soluble intermediates of lipid metabolism will be examined. The investigators will also examine the DGPPase enzymes for covalent modification by phosphorylation. The proposed studies are expected to provide insight into the molecular and biochemical regulation of DGPPase and into the role DGPP plays in phospholipid metabolism and lipid signaling in S. cerevisiae. The results of these studies should be relevant to higher eukaryotic organisms.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM028140-19
Application #
6342777
Study Section
Physiological Chemistry Study Section (PC)
Program Officer
Chin, Jean
Project Start
1980-07-01
Project End
2001-12-31
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
19
Fiscal Year
2001
Total Cost
$255,106
Indirect Cost
Name
Rutgers University
Department
Nutrition
Type
Schools of Earth Sciences/Natur
DUNS #
038633251
City
New Brunswick
State
NJ
Country
United States
Zip Code
08901
Carman, George M; Han, Gil-Soo (2018) Phosphatidate phosphatase regulates membrane phospholipid synthesis via phosphatidylserine synthase. Adv Biol Regul 67:49-58
Park, Yeonhee; Han, Gil-Soo; Carman, George M (2017) A conserved tryptophan within the WRDPLVDID domain of yeast Pah1 phosphatidate phosphatase is required for its in vivo function in lipid metabolism. J Biol Chem 292:19580-19589
Hassaninasab, Azam; Han, Gil-Soo; Carman, George M (2017) Tips on the analysis of phosphatidic acid by the fluorometric coupled enzyme assay. Anal Biochem 526:69-70
Dey, Prabuddha; Su, Wen-Min; Han, Gil-Soo et al. (2017) Phosphorylation of lipid metabolic enzymes by yeast protein kinase C requires phosphatidylserine and diacylglycerol. J Lipid Res 58:742-751
Han, Gil-Soo; Carman, George M (2017) Yeast PAH1-encoded phosphatidate phosphatase controls the expression of CHO1-encoded phosphatidylserine synthase for membrane phospholipid synthesis. J Biol Chem 292:13230-13242
Qiu, Yixuan; Hassaninasab, Azam; Han, Gil-Soo et al. (2016) Phosphorylation of Dgk1 Diacylglycerol Kinase by Casein Kinase II Regulates Phosphatidic Acid Production in Saccharomyces cerevisiae. J Biol Chem 291:26455-26467
Park, Ki-Sook; Dubon, Maria Jose; Gumbiner, Barry M (2015) N-cadherin mediates the migration of MCF-10A cells undergoing bone morphogenetic protein 4-mediated epithelial mesenchymal transition. Tumour Biol 36:3549-56
Barneda, David; Planas-Iglesias, Joan; Gaspar, Maria L et al. (2015) The brown adipocyte protein CIDEA promotes lipid droplet fusion via a phosphatidic acid-binding amphipathic helix. Elife 4:e07485
Hsieh, Lu-Sheng; Su, Wen-Min; Han, Gil-Soo et al. (2015) Phosphorylation regulates the ubiquitin-independent degradation of yeast Pah1 phosphatidate phosphatase by the 20S proteasome. J Biol Chem 290:11467-78
Park, Yeonhee; Han, Gil-Soo; Mileykovskaya, Eugenia et al. (2015) Altered Lipid Synthesis by Lack of Yeast Pah1 Phosphatidate Phosphatase Reduces Chronological Life Span. J Biol Chem 290:25382-94

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