Phosphatidate (PA) phosphatase catalyzes the dephosphorylation of (PA) to yield diacylglycerol (DAG) and Pi. The DAG generated in the reaction is used for the synthesis of triacylglycerol, and for the synthesis of phospholipids via the Kennedy pathway. By the nature of its reaction, PA phosphatase also controls the cellular content of PA, which is the precursor of phospholipids synthesized via the CDP-DAG pathway. PA is also a signaling molecule that triggers phospholipid synthesis gene expression, membrane expansion, vesicular trafficking, secretion, and endocytosis. Biochemical and genetic studies to establish the roles of PA phosphatase in lipid metabolism became possible by our discoveries of the PA phosphatase-encoding genes from yeast (e.g., PAH1) and human (e.g., LPIN1). The importance PA phosphatase in lipid metabolism is exemplified by its mutant phenotypes. In yeast, pah1 mutants exhibit defects in the transcriptional regulation of phospholipid synthesis genes, the anomalous expansion of the nuclear/ER membrane, and a 90 % reduction in TAG content in stationary phase cells. Studies with mice and humans have shown that genetic defects In lipin 1 and lipin 2 are manifested in several metabolic diseases that include lipodystrophy, obesity, peripheral neuropathy, myoglobinuria, and inflammation. We also discovered a novel CTP-dependent DGK1-encoded DAG kinase in yeast that counterbalances the activity of PA phosphatase to control the cellular contents of PA and DAG. In the MERIT Award Extension period, we will continue studies to identify novel mechanisms that govern the expression and regulation of yeast PAH1-encoded PA phosphatase and DGK1-encoded DAG kinase, and examine their roles In lipid metabolism and cell physiology. Pah1p is subject to proteasome-mediated degradation, and the mechanisms governing this regulation will be pursued. How App1p PA phosphatase contributes to endocytosis (e.g., through membrane fission/fusion events as mediated by the control of PA/DAG levels) will be examined. We will pursue studies on the enzymological and kinetic characterization of human lipin 2 and 3 PA phosphatases, and examine their regulation and physiological roles.

Public Health Relevance

Phosphatidate phosphatase and diacylglycerol kinase control the balance of phosphatidate and diacylglycerol that are intermediates in lipid metabolism. Genetics defects in phosphatidate/diacylglycerol balance are manifested in metabolic disorders that include lipodystrophy, obesity, peripheral neuropathy, myoglobinuria, and Inflammation.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Method to Extend Research in Time (MERIT) Award (R37)
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Special Emphasis Panel (NSS)
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Nie, Zhongzhen
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Rutgers University
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Carman, George M (2018) Discoveries of the phosphatidate phosphatase genes in yeast published in the Journal of Biological Chemistry. J Biol Chem :
Carman, George M; Han, Gil-Soo (2018) Phosphatidate phosphatase regulates membrane phospholipid synthesis via phosphatidylserine synthase. Adv Biol Regul 67:49-58
Hayes, Matthew; Choudhary, Vineet; Ojha, Namrata et al. (2017) Fat storage-inducing transmembrane (FIT or FITM) proteins are related to lipid phosphatase/phosphotransferase enzymes. Microb Cell 5:88-103
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
Carman, George; Taylor, Alexandra (2017) Masochistic Enzymology: Dennis Vance's Work on Phosphatidylcholine. J Biol Chem 292:4753-4754
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
Temprano, Ana; Sembongi, Hiroshi; Han, Gil-Soo et al. (2016) Redundant roles of the phosphatidate phosphatase family in triacylglycerol synthesis in human adipocytes. Diabetologia 59:1985-94
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

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