Phospholipase D (PLD) (PLD)

Phospholipase D (PLD) is a critical signaling enzyme that catalyzes the hydrolysis of phosphatidylcholine to generate phosphatidic acid (PA) and choline. PA serves as a potent second messenger, influencing diverse cellular processes such as mitogenesis, membrane trafficking, and cytoskeletal remodeling (UniProt P47580, O14802). A defining characteristic of mammalian PLD isoforms, PLD1 and PLD2, is their absolute requirement for phosphatidylinositol 4,5-bisphosphate (PIP2) as a cofactor for catalytic activity; PIP2 binds to specific domains to facilitate membrane localization and activation (PubMed: 21114284). Dysregulation of the PLD/PA signaling axis is strongly associated with cancer progression, where it promotes tumor growth, survival, and metastasis, as well as inflammatory and neurodegenerative conditions (PubMed: 24367510). Therapeutic strategies focus on small-molecule inhibitors that either block the catalytic site or interfere with regulatory interactions, such as the PIP2-binding domain. However, because PLD is involved in fundamental processes like endocytosis and exocytosis, safety concerns regarding systemic inhibition include potential disruptions to immune cell function and intracellular transport (PubMed: 15659715).

Other names

Phosphatidylcholine cholinephosphohydrolasePLD1PLD2Choline phosphatase

Inhibition of the enzymatic conversion of phosphatidylcholine to phosphatidic acid and choline; interference with PIP2-mediated activation of the enzyme.