Phospholipid metabolism

Phospholipid Structure - The Body's Bricks

• Amphipathic Nature: Possesses both a water-loving (hydrophilic) head and a water-fearing (hydrophobic) tail.
• Core Components:
  • Hydrophilic Head: A negatively charged phosphate group linked to an alcohol (e.g., choline, serine, ethanolamine).
  • Hydrophobic Tail: Two long-chain fatty acids esterified to a glycerol-3-phosphate backbone.
• Function: This dual nature drives the formation of the lipid bilayer, the fundamental structure of all cell membranes.

⭐ Phosphatidylcholine (Lecithin) is the most abundant phospholipid in eukaryotic cell membranes and the primary constituent of lung surfactant, crucial for reducing surface tension in alveoli.

Phospholipid Synthesis - Building the Bilayer

• Primary Goal: Synthesize phospholipids from a glycerol backbone (Glycerol-3-P) and fatty acids for membrane structure.
• Key Precursor: Diacylglycerol (DAG) is formed by adding 2 fatty acyl-CoAs to Glycerol-3-P.
• Activation Step (CTP-dependent): Two main strategies for adding the polar head group:
  • Strategy 1 (e.g., PI, PG): Activate DAG with CTP → CDP-DAG, then add head group (Inositol, Glycerol).
  • Strategy 2 (e.g., PC, PE): Activate head group with CTP → CDP-Choline/Ethanolamine, then add to DAG.

⭐ Lung Surfactant: Dipalmitoylphosphatidylcholine (DPPC) is the major component. Deficiency in premature infants leads to Neonatal Respiratory Distress Syndrome (NRDS) due to alveolar collapse.

Phospholipid Degradation - Signal & Recycle

• Cellular membranes are constantly remodeled. Phospholipids are degraded by phospholipases to recycle components or generate signaling molecules.
• Key Enzymes & Products:
  • Phospholipase A₂ (PLA₂): Cleaves the fatty acid at position 2. Critically, this releases arachidonic acid, the precursor for prostaglandins and leukotrienes.
  • Phospholipase C (PLC): Cleaves the head group, generating diacylglycerol (DAG) and inositol trisphosphate (IP₃), key second messengers in signal transduction.

⭐ High-Yield: Corticosteroids exert their anti-inflammatory effects by inhibiting Phospholipase A₂, thereby blocking the production of all downstream eicosanoids (prostaglandins, thromboxanes, leukotrienes).

Clinical Correlations - Membrane Maladies

• Neonatal Respiratory Distress Syndrome (NRDS):

  • Deficiency of dipalmitoylphosphatidylcholine (DPPC), the major component of lung surfactant.
  • Leads to ↑ alveolar surface tension & atelectasis (collapse).
  • Assess fetal lung maturity via Lecithin/Sphingomyelin (L/S) ratio; ratio >2 indicates maturity.

• Paroxysmal Nocturnal Hemoglobinuria (PNH):

  • Acquired PIGA gene mutation → defective GPI anchor for surface proteins (e.g., CD55, CD59).
  • Results in complement-mediated intravascular hemolysis.

• Barth Syndrome (X-linked):

  • TAZ gene mutation → defective cardiolipin synthesis.
  • Causes mitochondrial dysfunction, cardiomyopathy, neutropenia.

⭐ PNH is characterized by the triad of hemolytic anemia, pancytopenia, and thrombosis. It is an acquired hematopoietic stem cell disorder.

• Pulmonary surfactant, primarily dipalmitoylphosphatidylcholine (lecithin), prevents alveolar collapse; its deficiency causes Neonatal RDS.
• The Lecithin/Sphingomyelin (L/S) ratio in amniotic fluid, ideally >2, predicts fetal lung maturity.
• Phosphatidylinositol is crucial for second messenger systems like IP3 and DAG.
• Sphingomyelin is a key component of the myelin sheath; its accumulation characterizes Niemann-Pick disease.
• Cardiolipin is unique to the inner mitochondrial membrane; it's an antigenic target in syphilis (VDRL/RPR tests).
• Phospholipid synthesis primarily occurs in the smooth ER.