The phospholipase A2 superfamily as a central hub of bioactive lipids and beyond

In essence, "phospholipase A2" (PLA2) means a group of enzymes that release fatty acids and lysophospholipids by hydrolyzing the sn-2 position of glycerophospholipids. To date, more than 50 enzymes possessing PLA2 or related lipid-metabolizing activities have been identified in mammals, and these are subdivided into several families in terms of their structures, catalytic mechanisms, tissue/cellular localizations, and evolutionary relationships. From a general viewpoint, the PLA2 superfamily has mainly been implicated in signal transduction, driving the production of a wide variety of bioactive lipid mediators. However, a growing body of evidence indicates that PLA2s also contribute to phospholipid remodeling or recycling for membrane homeostasis, fatty acid β-oxidation for energy production, and barrier lipid formation on the body surface. Accordingly, PLA2 enzymes are considered one of the key regulators of a broad range of lipid metabolism, and perturbation of specific PLA2-driven lipid pathways often disrupts tissue and cellular homeostasis and may be associated with a variety of diseases. This review covers current understanding of the physiological functions of the PLA2 superfamily, focusing particularly on the two major intracellular PLA2 families (Ca2+-dependent cytosolic PLA2s and Ca2+-independent patatin-like PLA2s) as well as other PLA2 families, based on studies using gene-manipulated mice and human diseases in combination with comprehensive lipidomics.