Phospholipases A2

Phospholipases A2 (PLA2s) constitute a superfamily of enzymes that hydrolyze regiospecifically the sn-2 ester bond of the phospholipids, producing lysophospholipids and free fatty acids. The PLA2s are amphiphilic in nature, evolved to work at the water/lipid interface, acting on phospholipid assemblies rather than on isolated single phospholipids. The superfamily of PLA2s comprises at least six big families of isoenzymes, namely secreted PLA2 (sPLA2), cytosolic PLA2 (cPLA2), Ca2+ independent PLA2 (iPLA2), lipoprotein-associated PLA2 (LpPLA2), lysosomal PLA2 (LPLA2), and adipose tissue-specific PLA2 (AdPLA2), all reviewed here, with their structure, location, mechanism of action, substrate specificity, interfacial kinetics, and tissue distribution presented in detail. Ca2+ is a key cofactor required in catalysis performed by sPLA2s and in the activation and function of other PLA2 groups, also detailed in this work. The PLA2s play important physiologic and pathologic roles, being involved in sepsis, inflammation and different cancers, glaucoma, obesity, and Alzheimer’s disease, which require their inhibition. We also reviewed the main classes of inhibitors for different PLA2 groups, presenting the evolution and state of the art of inhibitor design for each PLA2 families, their potency, selectivity, and toxicity as key factors limiting their clinical translation into clinical use.