Several signal transduction processes in cells utilize lipidderived second messengers. These molecules are generated by the action of phospholipases on cellular lipids. Phospholipase A2 (PLA2) hydrolyzes the acyl group from the sn-2 position of glycerophospholipids. Two major types of PLA2 are found in cells: the cytosolic form (cPLA2) and the secretory form (sPLA2). cPLA2, an 85 kDa enzyme, preferentially hydrolyzes phospholipids containing arachidonate at the sn-2 position and provides free arachidonic acid for the synthesis of eicosanoids. cPLA2 is found in a variety of cells where it acts as a receptor-regulated enzyme that can mediate agonist-induced arachidonic acid release. It is activated by low levels of Ca2+. sPLA2, following its release from cells, plays an important role in inflammation and in antimicrobial defense. However, excessive activity of sPLA2 has been shown to result in tissue damage and is linked to organ failure associated with critical illness. PLA2 inhibitors are considered as desirable candidates for control and management of diseases related to eicosanoid production, such as allergy, inflammation, thrombosis, airway secretion, and cell proliferation.
Phospholipase C (PLC) is another important member of the family that controls the production of inositol-1,4,5- trisphosphate (IP3). IP3 is involved in cytosolic Ca2+ release and diacylglycerol (DAG) production, both of which activate protein kinase C. Phospholipase D (PLD) catalyzes the hydrolysis of phosphatidylcholine to form phosphatidic acid (PA) and released choline headgroup. The PA can itself act as a signal molecule by activating a PA-activated kinase, or can be hydrolyzed to form DAG by the action of PA phosphohydrolase.