Phospholipase D type 1

Phospholipase D1 (PLD1) catalyzes the hydrolysis of the phosphodiester bond of the glycerophospholipid phosphatidylcholine (PC) to form choline and phosphatidic acid (PA). PLD1 and the structurally related enzyme phospholipase D2 (PLD2) constitute the mammalian class of PC-specific PLDs. All of these enzymes share a common core domain formed by a duplicated catalytic motif, termed a PLD or HKD domain. The PLD domains are flanked by PLD-specific sequence motifs containing residues that are also critical for catalysis, possibly having roles in substrate recognition. PLD1 activity is under tight and complex regulation by both intra- and extracellular signals. Most ideas about the function of PLD1 consider its primary lipid product, PA, to be biologically active. The use of primary alcohols to attenuate PLD-catalyzed generation of PA by promoting the production of phosphatidyl alcohols (which are presumed to be biologically inactive) implicates PLD1 as a regulator of a diverse range of cellular processes that include cytoskeletal rearrangement; intracellular membrane vesicle transport, particularly involving the endoplasmic reticulum and Golgi apparatus; endocytosis and exocytosis; phagocytosis; normal and aberrant control of cell growth and survival; and stimulation of the oxidative respiratory burst in neutrophils. Some of these effects may involve presumptively PA-responsive target proteins that include the raf protein kinase, the mammalian target of rapamycin (mTOR), and certain isoforms of phosphatidylinositol-4-phosphate 5-kinase. PA can also be converted to the bioactive lipids diacylglycerol and lysoPA, which may be indirectly responsible for some aspects of PLD1 function. The application of more sophisticated strategies, including overexpression experiments, biochemical reconstitutions, and the use of mutant alleles of PLD1 with altered catalytic or regulatory properties that may interfere with endogenous PLD activities, support and, in some cases extend, these ideas about PLD1 function.