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.
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.
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