Phospholipase D

Phospholipase D (PLD) (EC 3.1.4.4; also known as lipophosphodiesterase II, lecithinase D, choline phosphatase; systematic name: phosphatidylcholine phosphatidohydrolase) is an anesthetic-sensitive and mechanosensitive enzyme of the phospholipase protein superfamily that catalyzes the hydrolysis of membrane phospholipids.

The canonical reaction is:

${\displaystyle {\text{phosphatidylcholine}}+{\text{H}}_{2}{\text{O}}\rightarrow {\text{choline}}+{\text{phosphatidic acid}}}$

Phospholipases occur widely across bacteria, yeast, plants, animals, and viruses. PLD's principal substrate is phosphatidylcholine, which it hydrolyzes to produce the membrane lipid phosphatidic acid (PA) and soluble choline in a cholesterol-dependent process termed substrate presentation.

Plants encode numerous PLD isoenzymes, with molecular weights ranging from approximately 90 to 125 kDa. In mammals, six PLD isoenzymes (PLD1–PLD6) are expressed. PLD1 and PLD2 are the best characterized, responsible for classical phosphatidylcholine hydrolysis and PA signaling. Other isoforms, such as PLD3 and PLD4, function as endolysosomal nucleases rather than phospholipases, reflecting diversification of the PLD superfamily.

Phospholipase D activity plays essential roles in membrane trafficking, cytoskeletal reorganization, receptor-mediated endocytosis, exocytosis, cell migration, and broader signal transduction pathways.In addition to their well-established catalytic functions, PLD enzymes are increasingly recognized as key regulators of membrane dynamics and cellular signaling beyond lipid hydrolysis. PLD-generated phosphatidic acid not only acts as a signaling lipid itself but also serves as a precursor for the biosynthesis of other lipid second messengers, including diacylglycerol (DAG) and lysophosphatidic acid (LPA). Phosphatidic acid can directly recruit and regulate a variety of downstream effector proteins, thereby integrating PLD activity into complex cellular processes such as mTOR signaling, membrane curvature sensing, and vesicular trafficking. In addition to these functions, PLD enzymes contribute to setting the threshold for sensitivity to anesthesia and mechanical force.

Dysregulation of PLD has been implicated in several pathophysiological conditions, including Parkinson's disease, Alzheimer's disease, cancer, diabetes mellitus, and autoimmune diseases.