Phospholipase A2 and arachidonic acid metabolism enzymes (PLA2/AA pathway)

The Phospholipase A2 (PLA2) and arachidonic acid (AA) inflammatory pathway is a central enzymatic cascade responsible for the production of bioactive lipid mediators known as eicosanoids. The pathway is initiated when PLA2 enzymes hydrolyze membrane phospholipids to release free arachidonic acid, which serves as the primary substrate for downstream metabolic branches [1]. These branches include the cyclooxygenase (COX-1 and COX-2) pathway, which generates prostaglandins and thromboxanes, and the lipoxygenase (e.g., 5-LOX) pathway, which produces leukotrienes [2, 3]. These mediators are critical orchestrators of the inflammatory response, regulating processes such as vasodilation, pain signaling, and immune cell recruitment [4, 5]. Dysregulation of this pathway is a hallmark of various chronic inflammatory diseases, including rheumatoid arthritis, asthma, and cardiovascular disorders [5]. Consequently, enzymes within this cascade are major therapeutic targets for widely used drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit COX enzymes, and leukotriene modifiers used in respiratory medicine [4, 6].

Other names

Arachidonic acid cascadeEicosanoid biosynthetic pathwayPLA2-COX-LOX pathwayArachidonate metabolism

Drugs targeting this pathway act by inhibiting specific enzymes to prevent the synthesis of pro-inflammatory mediators. This includes the irreversible or competitive inhibition of COX-1 and COX-2 to block prostaglandin production, the inhibition of 5-LOX to prevent leukotriene synthesis, and the indirect inhibition of PLA2 via the induction of annexins by corticosteroids [4, 6].