Structure, function, and regulation of group V phospholipase A(2).
The hydrolysis of membrane phospholipid by phospholipase A(2) (PLA(2)) is a key step in the production of inflammatory eicosanoids. Recent cell studies have shown that secretory group V PLA(2) (gVPLA(2)) is involved in agonist-induced eicosanoid biosynthesis in mouse P388D1 cell line, mast cells, and transfected HEK 293 cells. gVPLA(2) is homologous to other group II PLA(2) family members but has distinctive enzymatic properties, including its activity to effectively hydrolyze phosphatidylcholine (PC) vesicles and the outer plasma membrane of mammalian cells. Mutational studies showed that gVPLA(2) has a unique structure that allows effective binding to PC membranes and efficient catalysis of an active-site-bound PC substrate. Thanks to this unique structure and activity, exogenously added gVPLA(2) can induce the eicosanoid biosynthesis in unstimulated inflammatory cells, including human neutrophils and eosinophils, suggesting that it might be able to trigger inflammatory responses under certain physiological conditions. Extensive structure-function and cell studies showed that gVPLA(2) could act directly on the outer plasma membranes of neutrophils and eosinophils. The release of fatty acids and lysophospholipids from the cell surfaces induces the translocation and activation of cytosolic PLA(2) and 5-lipoxygenase, resulting in the leukotriene synthesis. In case of neutrophils, induction of leukotriene B(4) synthesis by gVPLA(2) leads to the phosphorylation of cytosolic PLA(2) by a leukotriene B(4) receptor and MAP kinase-mediated mechanism. Finally, heparan sulfate proteoglycans in neutrophils appear to play a role of internalizing and degrading the cell surface-bound gVPLA(2) to protect the cells from extensive lipolytic damage.
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Department of Chemistry (M/C 111), University of Illinois at Chicago, 60607-7061, USA. wcho@uic.edu
D000595:Amino Acid Sequence; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D017124:Conserved Sequence; D003600:Cytosol / Q000201:enzymology; D015777:Eicosanoids / Q000096:biosynthesis; D004804:Eosinophils / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D008563:Membrane Lipids / Q000378:metabolism; D008969:Molecular Sequence Data; D009504:Neutrophils / Q000187:drug effects / Q000378:metabolism*; D010741:Phospholipases A / Q000737:chemistry / Q000145:classification* / Q000378:metabolism / Q000494:pharmacology; D010743:Phospholipids / Q000378:metabolism
D015777:Eicosanoids; D008563:Membrane Lipids; D010743:Phospholipids; D001094:Arachidonate 5-Lipoxygenase; D010741:Phospholipases A