The enzyme phosphatidate phosphatase (PAP, EC 3.1.3.4) is a key regulatory enzyme in lipid metabolism, catalyzing the conversion of phosphatidate to diacylglycerol:
a 1,2-diacylglycerol 3-phosphate + H2O a 1,2-diacyl-sn-glycerol + phosphate
The reverse conversion is catalyzed by the enzyme diacylglycerol kinase, which replaces the hydroxyl group on diacylgylcerol with a phosphate from ATP, generating ADP in the process.
In yeast, the forward direction is Mg2+-dependent, while the reverse process is Ca2+-dependent. PAP1, a cytosolic phosphatidate phosphatase found in the lung, is also Mg^2+-dependent, but PAP2, a six-transmembrane-domain integral protein found in the plasma membrane, is not.
Role in the regulation of lipid flux
Phosphatidate phosphatase regulates lipid metabolism in several ways. In short, it 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 the phosphatase is active, diacylglycerols formed by it 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 diacylglycerols through reaction with fatty acyl CoA molecules. When phosphatidate phosphatase is inactive, diacylglycerol kinase catalyzes the reverse conversion, allowing phosphatidate to accumulate as it brings down diacylglycerol levels. Phosphatidate can then be converted into an activated form, CDP-diacylglycerol by liberation of a pyrophosphate from a CTP molecule, or into cardiolipin. This is a principal precursor used by the body in phospholipid synthesis. Furthermore, because both phosphatidate and diacylglycerol function as secondary messengers, phosphatidate phosphatase is able to exert extensive and intricate control of lipid metabolism far beyond its local effect on phopshatidate and diacylglycerol concentrations and the resulting effect on the direction of lipid flux as outlined above.
Enzyme regulation
Phosphatidate phosphatase is up-regulated by CDP-diacylglycerol, phosphatidylinositol (formed from reaction of CDP-diacylglycerol with inositol), and cardiolipin. It is down-regulated 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 up-regulate the phosphatase, 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 down regulate the enzyme that forms diacylglycerol, thereby acting as a signal that this is in abundance and its production should be slowed.
Classification
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.
Nomenclature
The systematic name is diacylglycerol-3-phosphate phosphohydrolase. Other names in common use include: phosphatidic acid phosphatase (PAP), 3-sn-phosphatidate phosphohydrolase, acid phosphatidyl phosphatase, phosphatidic acid phosphohydrolase, phosphatidate phosphohydrolase, and lipid phosphate phosphohydrolase (LPP).
Types
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
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.
Each of the 3 Lipin proteins found in mammals—Lipin1, Lipin2, and Lipin3—has unique tissue expression motifs and distinct physiological functions.
Regulation
Regulation of mammalian Lipin PAP enzymes occurs at the transcriptional level. For example, Lipin1 is induced by glucocorticoids during adipocyte differentiation as well as in cells that are experiencing ER proliferation. Lipin2, on the other hand, is repressed during adipocyte differentiation.