phospholipase A2

**Function and mechanism** - PLA2 cleaves the fatty acid at the sn-2 position of glycerophospholipids (e.g., phosphatidylcholine) in the cell membrane. Products: free fatty acid (usually arachidonic acid) + lysophospholipid. - Arachidonic acid is the rate-limiting substrate for eicosanoid synthesis: - Cyclooxygenase (COX-1/COX-2) -> prostaglandins (PGE2, PGI2), thromboxane A2 - 5-Lipoxygenase -> leukotrienes (LTB4, LTC4, LTD4, LTE4) - Lysophospholipid can be converted to platelet-activating factor (PAF), a mediator of inflammation, bronchoconstriction, and platelet aggregation. - Calcium-dependent. Cytosolic PLA2 (cPLA2) is activated by increased intracellular Ca2+ and phosphorylation (e.g., MAP kinase) after receptor stimulation (e.g., by bradykinin, histamine, or cytokines).

**Pharmacology (high-yield)** - **Corticosteroids** induce lipocortin (annexin A1), which inhibits PLA2. This blocks both the COX and lipoxygenase pathways. This explains why steroids are broadly anti-inflammatory, unlike NSAIDs (COX only) or zileuton (5-lipoxygenase only). - NSAIDs/aspirin act downstream on COX. Montelukast and zafirlukast block CysLT1 receptors. Zileuton inhibits 5-lipoxygenase.

**Clinical associations** - **Acute pancreatitis:** Trypsin activates pancreatic PLA2 (and other proenzymes) and lipase. This causes fat necrosis, membrane damage, and autodigestion of the pancreas. Pancreatic PLA2 also degrades surfactant phospholipids, which contributes to ARDS in severe pancreatitis. - **Venoms:** PLA2 is a major component of bee venom (melittin works with it), many snake venoms (e.g., cobras, vipers, and coral snakes), and some spider venoms. It causes membrane lysis, hemolysis (lysophospholipids), myonecrosis, and neurotoxicity (presynaptic neurotoxins such as beta-bungarotoxin). - **Bacterial toxin analogy:** Clostridium perfringens alpha-toxin is a phospholipase C (lecithinase), not PLA2. It causes myonecrosis (gas gangrene) and double-zone hemolysis. Do not confuse the two. - **Phospholipase C** cleaves at the phosphate head group, producing DAG and IP3 (Gq pathway). PLA2 acts at the sn-2 acyl chain. - **Inflammation:** Secretory PLA2 (sPLA2) levels rise in sepsis, RA, and atherosclerosis. Lipoprotein-associated PLA2 (Lp-PLA2) is a marker of vascular inflammation and cardiovascular risk (a PLA2-family enzyme, also called PAF acetylhydrolase). - **Surfactant and lung:** PLA2 breaks down dipalmitoylphosphatidylcholine (DPPC, the main surfactant phospholipid), so excess activity can worsen lung injury. - **Antiphospholipid and others:** Chronic inflammation involves eicosanoid excess driven by PLA2.

**Classification** - Secreted (sPLA2): low molecular weight, requires mM Ca2+ (pancreatic, venom). - Cytosolic (cPLA2): Ca2+-dependent translocation to membranes, with specificity for arachidonic acid. Main source of eicosanoids. - Ca2+-independent (iPLA2): involved in membrane remodeling. - Lp-PLA2: circulates with LDL.

**Exam pearls** - Steroid -> lipocortin -> inhibits PLA2 -> decreases arachidonic acid -> decreases prostaglandins AND leukotrienes. - Membrane phospholipid -> (PLA2) -> arachidonic acid -> (COX) -> prostaglandins/thromboxane; -> (5-LOX) -> leukotrienes. - Pancreatitis: premature trypsinogen activation -> activates PLA2 -> autodigestion.