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Phosphatidate phosphatase,a key regulator of lipid homeostasis
Authors:Florencia Pascual  George M Carman
Institution:Department of Food Science and Rutgers Center for Lipid Research, Rutgers University, New Brunswick, NJ 08901, USA
Abstract:Yeast Pah1p phosphatidate phosphatase (PAP) catalyzes the penultimate step in the synthesis of triacylglycerol. PAP plays a crucial role in lipid homeostasis by controlling the relative proportions of its substrate phosphatidate and its product diacylglycerol. The cellular amounts of these lipid intermediates influence the synthesis of triacylglycerol and the pathways by which membrane phospholipids are synthesized. Physiological functions affected by PAP activity include phospholipid synthesis gene expression, nuclear/endoplasmic reticulum membrane growth, lipid droplet formation, and vacuole homeostasis and fusion. Yeast lacking Pah1p PAP activity are acutely sensitive to fatty acid-induced toxicity and exhibit respiratory deficiency. PAP is distinguished in its cellular location, catalytic mechanism, and physiological functions from Dpp1p and Lpp1p lipid phosphate phosphatases that utilize a variety of substrates that include phosphatidate. Phosphorylation/dephosphorylation is a major mechanism by which Pah1p PAP activity is regulated. Pah1p is phosphorylated by cytosolic-associated Pho85p–Pho80p, Cdc28p-cyclin B, and protein kinase A and is dephosphorylated by the endoplasmic reticulum-associated Nem1p–Spo7p phosphatase. The dephosphorylation of Pah1p stimulates PAP activity and facilitates the association with the membrane/phosphatidate allowing for its reaction and triacylglycerol synthesis. This article is part of a Special Issue entitled Phospholipids and Phospholipid Metabolism.
Keywords:TAG  triacylglycerol  DAG  diacylglycerol  PA  phosphatidate  PAP  PA phosphatase  PC  phosphatidylcholine  PE  phosphatidylethanolamine  PI  phosphatidylinositol  PS  phosphatidylserine  CDP-DAG  CDP-diacylglycerol  CL  cardiolipin  DGPP  diacylglycerol pyrophosphate  ER  endoplasmic reticulum  NEM  N-ethylmaleimide  UASINO  inositol-responsive upstream activating sequence
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