Phosphatidate phosphatase

Phosphatidate phosphatase (PAP) (EC 3.1.3.4) is a key regulatory enzyme in lipid metabolism, catalyzing the conversion of phosphatidate to diacylglycerol. The two substrates of PAP are phosphatidate and H2O, and its two products are diacylglycerol and phosphate, as shown here. Phosphatidate phosphatase (PAP) (EC 3.1.3.4) is a key regulatory enzyme in lipid metabolism, catalyzing the conversion of phosphatidate to diacylglycerol. The two substrates of PAP are phosphatidate and H2O, and its two products are diacylglycerol and phosphate, as shown here. The reverse reaction is catalyzed by the enzyme diacylglycerol kinase (DGK or DAGK), which replaces the hydroxyl group on diacylgylcerol with a phosphate from ATP, generating ADP in the process. While ATP is used by DGK in mammalian cells, yeast cells tend to use CTP as the high-energy phosphate donor instead. Mechanistically speaking, this has no effect on the overall reaction. In yeast, the forward direction is Mg 2 + {displaystyle {ce {Mg^2+}}} -dependent, while the reverse direction is Ca 2 + {displaystyle {ce {Ca^2+}}} -dependent. PAP1, a cytosolic phosphatidate phosphatase found in the lung, is also Mg 2 + {displaystyle {ce {Mg^2+}}} -dependent, but PAP2, a six-transmembrane-domain integral protein found in the plasma membrane, is not. PAP regulates lipid metabolism in several ways. In short, PAP is a key player in controlling the overall flux of triacylglycerols to phospholipids and vice versa, also exerting control through the generation and degradation of lipid-signaling molecules related to phosphatidate. When PAP is active, diacylglycerols formed by PAP can go on to form any of several products, including phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine, and triacylglycerol. Phospholipids can be formed from diacylglycerol through reaction with activated alcohols, and triacylglycerols can be formed from DAG through reaction with fatty acyl CoA molecules. When PAP is inactive, DGK drives the reaction in reverse, allowing phosphatidate to accumulate as it brings down DAG levels. Phosphatidate can then be converted into an activated form, CDP-DAG, through the liberation of a pyrophosphate from a CTP molecule, or into cardiolipin. CDP-DAG is a principal precursor used by the body in phospholipid synthesis. Furthermore, because both phosphatidate and DAG function as secondary messengers, PAP is able to exert extensive and intricate control of lipid metabolism far beyond its local effect on phopshatidate and DAG concentrations and the resulting effect on the direction of lipid flux as outlined above. PAP is upregulated by CDP-diacylglycerol, phosphatidylinositol (formed from reaction of CDP-DAG with inositol), and cardiolipin. PAP is downregulated by sphingosine and dihydrosphingosine. This makes sense in the context of the discussion above. Namely, a build up of products that are formed from phosphatidate serves to upregulate PAP, the enzyme that consumes phosphatidate, thereby acting as a signal that phosphatidate is in abundance and causing its consumption. At the same time, a build up of products that are formed from DAG serves to downregulate PAP, the enzyme that forms DAG, thereby acting as a signal that DAG is in abundance and its production should be slowed. PAP belongs to the family of enzymes known as hydrolases, and more specifically to the hydrolases that act on phosphoric monoester bonds. This enzyme participates in 4 metabolic pathways: glycerolipid, glycerophospholipid, ether lipid, and sphingolipid metabolism. The systematic name of this enzyme class is diacylglycerol-3-phosphate phosphohydrolase. Other names in common use include: There are several different genes that code for phosphatidate phosphatases. They fall into one of two types (type I and type II), depending on their cellular localization and substrate specificity. Type I phosphatidate phosphatases are soluble enzymes that can associate to membranes. They are found mainly in the cytosol and the nucleus. Encoded for by a group of genes named Lipin, they are substrate specific only to phosphatidate. There are speculated to be involved in the de novo synthesis of glycerolipids.