Group III secretory phospholipase A2 (PLA2G3)

Group III secretory phospholipase A2 (PLA2G3) is an extracellular calcium-dependent enzyme structurally similar to bee venom phospholipase A2, with a unique central sPLA2 domain flanked by distinctive N- and C-terminal regions. PLA2G3 hydrolyzes the ester bond at the sn-2 position of extracellular phospholipids without strong substrate specificity, preferentially releasing polyunsaturated fatty acids (PUFAs), including arachidonic acid, linoleic acid, and docosahexaenoic acid. This leads to the generation of lysophospholipids and eicosanoids, mediators of inflammation and cellular signaling. PLA2G3 is secreted by mast cells, fibroblasts, and epididymal epithelial cells, playing key roles in promoting mast cell maturation, regulating allergic and anaphylactic responses, remodeling sperm membranes (essential for fertility), and driving proinflammatory and protumorigenic pathways, especially in the colon. Overexpression or hyperactivity of PLA2G3 is associated with chronic inflammatory diseases such as dermatitis and atherosclerosis, as well as increased risk for colon cancer and colitis. Conversely, genetic knockout in mice confers resistance to experimentally induced colitis and colon cancer. Because of its wide-ranging roles in lipid mediator generation and inflammation, PLA2G3 is considered a promising, though complex, therapeutic target for inflammatory diseases and certain cancers.

Other names

Group 3 secretory phospholipase A2PLA2G3sPLA2-IIIGIII sPLA2GIII-SPLA2SPLA2IIIPhosphatidylcholine 2-acylhydrolase 3

Inhibitors of PLA2G3 act by blocking its extracellular hydrolysis of phospholipids, thereby reducing the formation of pro-inflammatory and tumorigenic lipid mediators such as lysophospholipids and eicosanoids.