Phosphatidate phosphohydrolase

Lipid phosphate phosphohydrolases (LPPs), formerly called type 2 phosphatidate phosphohydrolases (PAP-2), catalyse the dephosphorylation of bioactive phospholipids (phosphatidic acid, ceramide-1-phosphate) and lysophospholipids (lysophosphatidic acid, sphingosine-1-phosphate). The substrate selectivity of individual LPPs is broad in contrast to the related sphingosine-1-phosphate phosphatase. LPPs are characterized by a lack of requirement for Mg2+ and insensitivity to N-ethylmaleimide. Three subtypes (LPP-1, LPP-2, LPP-3) have been identified in mammals. These enzymes have six putative transmembrane domains and three highly conserved domains that are characteristic of a phosphatase superfamily. Whether LPPs cleave extracellular mediators or rather have an influence on intracellular lipid phosphate concentrations is still a matter of debate. 

Pittner, R.A., Fears, R. and Brindley, D.N. (1985). Effects of glucocorticoids and insulin on activities of phosphatidate phosphohydrolase, tyrosine aminotransferase and glycerol kinase in isolated rat hepatocytes in relation to the control of triacyglycerol synthesis and gluconeogenesis. Biochem. J. 225 455—462. 

The activity of PLD on phosphatidylcholine generates phosphatidic acid, and this may be further metabolised by the enzyme phosphatidate phospho-hydrolase to form DAG (Fig. 6.19). Furthermore, the activity of DAG kinase can convert the DAG (generated either from phosphatidic acid or from the activity of PLC) back into phosphatidic acid. Both phosphatidic acid and DAG have functions as second messengers thus the activities of PLD, phosphatidate phosphohydrolase and DAG kinase all play important roles in the generation of these intracellular signalling molecules. 

The enzyme phosphatidate phosphohydrolase can be inhibited by propranolol, although this inhibitor is not completely specific. Thus, propranolol treatment of neutrophils results in the increased formation of phosphati-dic acid and the decreased formation of DAG. There is increasing evidence... 

Billah, M. M., Eckel, S., Mullmann, T. J., Egan, R. W., Siegel, M. I. (1989). Phosphatidylcholine hydrolysis by phospholipase D determines phosphatidate and diglyceride levels in chemotactic peptide-stimulated human neutrophils. Involvement of phosphatidate phosphohydrolase in signal transduction. J. Biol. Chem. 264, 17069-77. 

Mullmann, T.J., Siegel, M.L, Egan, R.W. and Billah, M.M., 1991, Sphingosine inhibits phosphatidate phosphohydrolase in human neutrophils by a protein kinase C-independent mechanism, J. Biol. Chem. 266 2013-2016. 

MA Balboa, J Balsinde, EA Dennis. Involvement of phosphatidate phosphohydrolase in arachidonic acid mobilization in human amnionic WISH cells. J Biol Chem 273 7684-7690, 1998. 

The PLD isozymes hydrolyze phosphatidylcholine (PC) to produce PA, which is considered to be an important lipid signaling molecule. PA can be dephosphorylated to DAG by the action of phosphatidate phosphohydrolase (PAP). Thus, both PLD and PAP can modulate the levels of both PA and PLD-derived DAG in the heart. Different agents such as norepinephrine (NE), endothelin-1 and angiotensin 11 (ANG II) have been shown to increase the formation of PA in the cardiomyocytes (Sadoshima and Izumo, 1993 Ye et al.,... 

Asemu G., Dent M.R., Singal T., Dhalla N.S., Tappia P.S. Differential changes in phospholipase D and phosphatidate phosphohydrolase activities in ischemia-reperfusion of rat heart. Arch. Biochem. Biophys. 436 (2005) 136-144. 

Williams S.A., Tappia P.S., Yu C.H., Bibeau M., Panagia V. Impairment of the sarcolemmal phosphohpase D-phosphatidate phosphohydrolase pathway in diabetic cardiomyopathy. J. Mol. Cell. Cardiol. 30 (1998) 109-118. 

Yu C.H., Panagia V., Tappia P.S., Liu S.Y., Takeda N., Dhalla N.S. Alterations of sarco-lemmal phospholipase D and phosphatidate phosphohydrolase in congestive heart failure. Biochim. Biophys. Acta 1584 (2002) 65-72. 

Cha, J.Y., Mameda, Y Yamamoto, K., Oogami, K. and Yanagita, T. (1998) Association Between Hepatic Triacylglycerol Accumulation Induced by Administering Orotic Acid and Enhanced Phosphatidate Phosphohydrolase Activity in Rats, Biosci. Biotechnol. Biochem. 62,508-513. 

Thus, it is likely that rate of TG-synthesis is controlled by coordinate regulation of the activities of mitochondrial P-oxidation and phosphatidate phosphohydrolase. The instant hypotriglyceridemic effect observed in rats given 3-thia fatty acids can be explained by a sudden increase in mitochondrial fatty acid oxidation and a decrease in phosphatidate phosphohydrolase. This alteration is accompanied by a reduction in the... 

Pittner RA, Fears R, Brindley DN (1985) Effects of cAMP, Glucocorticoids and Insulin on the Activities of Phosphatidate Phosphohydrolase, Tyrosine Aminotransferase and Glycerol Kinase in Isolated Rat Hepatocytes in Relation to the Control of Triglycerol Synthesis and Gluconeogenesis. Biochem J 225 455... 

Phosphatidate phosphohydrolase has already been briefly discussed in relation to glycerophospholipid synthesis (Section 11.2.1). The enzyme was first discovered in plants (Kates, 1955) and, subsequently, identified in animal tissues. It has been purified from a large number of mammalian tissues including liver, kidney, intestinal mucosa, adipose tissue, erythrocyte membranes and avian salt glands (cf. O Doherty, 1978). The intracellular distribution of mammalian phosphatidate phosphohydrolase is complicated. It has been found in several particulate fractions-mitochondrial, lysosomal and microsomal (cf. Sedgwick and Hubscher, 1967). Most workers... 

Plant phosphatidate phosphohydrolase was mainly microsomal in castor bean seeds (Moore etal, 1973) but mainly soluble in leaves (Heinz, 1977). There may also be activity in chloroplast fractions (cf. Douce and Joyard, 1980). 

At present, little is known about the phosphatidate phosphohydrolase step in the biosynthetic pathway to triacylglycerols. The enzyme was specifically measured by Moore et al, (1973) in subcellular fractions of castor bean endosperm and found to be located mainly in the endoplasmic reticulum, with some activity in the soluble fraction. In leaves, the highest specific activity was found in an undefined particulate fraction, whereas the m or part of the activity was soluble (Heinz, 1977). Other evidence for a specific phosphatidate phosphohydrolase activity in chloroplast membranes was indirect (Joyard and Douce, 1977). Care must always be taken to ensure that the activity is not due to a nonspecific phosphatase in view of the report by Blank and Snyder (1970) that wheat germ contains an acid phosphatase capable of dephosphorylating phosphatidic acid. The enzyme described by Moore et al. 

PA is a minor component of the ER membrane that accounts for less than 1% of total ER membrane lipids (Allan, 1996). Formed PA is rapidly consumed by the activity of phosphatidate phosphohydrolase (PAP). In order to measure the formation of PA, the dynamics of PA formation and consumption has to be controlled. This is achieved by exploiting a unique transphosphatidylation reaction that is catalyzed by PLD enzymes. In this reaction, the aliphatic chain of a primary alcohol is transferred to the phosphatidyl moiety of the phosphatidic acid product. In the presence of low concentrations of primary alcohols, PLD enzymes generate phospha-tidylalcohols, which are not recognized by PAP and are not efficiently consumed (Morris et ah, 1997). Therefore the measurement of transphosphatidylation activity of PLD provides a convenient assay that avoids the otherwise highly dynamic nature of the lipid remodeling cascade induced by Sari to support COPII mediated ER export. 

Heidarian E, Jafari-Dehkordi E, Seidkhani-Nahal A (2011) Effect of garlic on Hvct phosphatidate phosphohydrolase and plasma lipid levels in hyperlipidemic rats. Food Chem Toxicol 49(5) 1110-1114. doi 10.1016/j.fct.2011.02.001... 

The loss of labelled phosphatidate from the microsomal Fraction E (Table 1) is harder to understand. Some of it is converted to CDP-diacylglycerol for resynthesis of phosphatidyl-inositol but some could be converted to diacylglycerol by phosphatidate phosphohydrolase. Fraction E contains plasma membrane fragments as well as endoplasmic reticulum and so the phosphatidate changes could reflect synthetic reactions (endoplasmic reticulum) or hydrolysis to diacylglycerol (plasma membrane, Cotman et al., 1971). 

Siess, E.A. and Hofstetter M.M. (1996) Identification and phosphatidate phosphohydrolase purified from rat liver membranes on SDS-polyacrylamide gel electrophoresis, FEBS Letters 381, 169-173... 

Martin, A, Gomez-Munoz, A, Waggoner, DW, Stone, JC and Brindley, DN (1993) Decreased activities of phosphatidate phosphohydrolase and phospholipase D in ras and t5irosine kinase (fps) transformed fihrohlasts. J Biol Chem, 268, 23924-23932. 

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