Phosphatidic acid phosphatase (PAP) catalyzes the dephosphorylation of phosphatidic acid (PA) to yield diacylglycerol (DAG) and Pi. The DAG generated in the reaction is used for the synthesis of triacylglycerol (TAG), and for the synthesis of phosphatidylethanolamine and phosphatidylcholine via the Kennedy pathway. By the nature of its reaction, PAP 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 PAP in lipid metabolism became possible by our discoveries of the PAP-encoding genes from the yeast Saccharomyces cerevisiae (e.g., PAH1) and mammals (e.g., LPIN1). The importance PAP 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. In the next grant period, we will focus on the regulated expression of the yeast PAH1-encoded PAP enzyme during growth and its role in lipid metabolism (specific aim 1). In addition, we will expand our studies on PAP to include the enzymology and biochemical regulation of the human LPIN1-, LPIN2-, and LPIN3-encoded PAP isoforms (specific aim 2). We also discovered a novel CTP-dependent DGK1-encoded DAG kinase in yeast that counterbalanced the activity of PAP to control the cellular contents of PA and DAG. The dgk1 mutation suppresses phenotypes caused by the pah1 mutation, whereas the overexpression of DAG kinase blunts phenotypes caused by the overexpression of PAP. In yeast, TAG hydrolysis (e.g., lipolysis) to DAG and fatty acids is a prerequisite for membrane phospholipid synthesis and resumption of growth from the stationary phase. We will examine the role and regulation of the DGK1-encoded DAG kinase enzyme in this metabolism (specific aim 3).

Public Health Relevance

The activities of phosphatidic acid phosphatase and diacylglycerol kinase control the cellular balance of phosphatidic acid and diacylglycerol, which are lipid precursors used for the synthesis of membrane phospholipids and triacylglycerol. Phosphatidic acid is also a signaling molecule that triggers phospholipid synthesis gene expression, membrane expansion, secretion, and endocytosis. Genetic defects of phosphatidic acid phosphatase in yeast, mice, and humans 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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Biochemistry and Biophysics of Membranes Study Section (BBM)
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Chin, Jean
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Rutgers University
Schools of Earth Sciences/Natur
New Brunswick
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Carman, George M; Han, Gil-Soo (2018) Phosphatidate phosphatase regulates membrane phospholipid synthesis via phosphatidylserine synthase. Adv Biol Regul 67:49-58
Carman, George M (2018) Discoveries of the phosphatidate phosphatase genes in yeast published in the Journal of Biological Chemistry. J Biol Chem :
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
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
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

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