Phospholipase D1 (PLD1)

Phospholipase D1 (PLD1) is a phosphatidylcholine-specific phospholipase D enzyme encoded by the human PLD1 gene that hydrolyzes phosphatidylcholine to produce phosphatidic acid (PA) and choline, thereby regulating diverse signaling pathways and membrane dynamics. Canonical PLD enzymes contain two conserved HKD catalytic motifs, and human PLD1 shares this architecture along with regulatory PX and PH domains; PLD1 and the related PLD2 are highly similar in structure. PLD1 activity generates PA, a lipid second messenger that modulates processes including membrane trafficking, exocytosis, cytoskeletal reorganization, receptor-mediated endocytosis, migration, and metabolic signaling, positioning PLD1 as a therapeutic target in oncology and other diseases. PLD1 exists as splice variants (PLD1a, PLD1b) and interacts with multiple signaling proteins (e.g., CDC42, RHOA, RALA, PKC pathway components), with small-molecule inhibitors such as VU-0359595 providing isoform-selective pharmacology. Evidence links PLD1/PA signaling to cancer, Alzheimer’s disease, thrombosis, and type 2 diabetes, underscoring both its therapeutic promise and the need to manage on-target risks related to PA-dependent cellular functions.

Other names

Phosphatidylcholine-hydrolyzing phospholipase D1Choline phosphatidohydrolase 1PLD 1PLD1a (splice isoform)PLD1b (splice isoform)

Competitive or allosteric inhibition of PLD1 catalytic activity to reduce phosphatidic acid production (e.g., VU-0359595) Indirect inhibition via modulation of upstream activators such as PKC or ARF proteins impacting PLD1 activity (contextual/indirect)