Phospholipid Metabolism

Phospholipid Basics - Structure & Function Fiesta

• Core: Amphipathic lipids; glycerol backbone, 2 fatty acid tails (hydrophobic), phosphate, and alcohol head group (hydrophilic).
  • Sphingomyelin: Sphingosine backbone instead of glycerol.
• Key alcohols defining phospholipid type: Choline (forms Lecithin/Phosphatidylcholine), Ethanolamine (forms Cephalin/Phosphatidylethanolamine), Serine, Inositol.
• Functions:
  • Primary structural component of cell membranes (bilayer formation).
  • Lung surfactant (majorly Dipalmitoylphosphatidylcholine - DPPC).
  • Signal transduction (e.g., Phosphatidylinositol 4,5-bisphosphate $PIP_2 ightarrow IP_3 + DAG$).
  • Reservoir for Arachidonic Acid (precursor to eicosanoids).

⭐ The Lecithin/Sphingomyelin (L/S) ratio in amniotic fluid is a critical indicator of fetal lung maturity; a ratio > 2:1 suggests maturity (lower risk of Neonatal Respiratory Distress Syndrome).

Glycerophospholipid Synthesis - Building Blocks Bonanza

• Foundation: Glycerol-3-Phosphate (G3P) (from glycolysis/glycerol kinase) & activated Fatty Acyl-CoAs.
• Key Intermediate: Phosphatidic Acid (PA) from sequential acylation of G3P ($G3P + 2 \text{ Acyl-CoA} \rightarrow PA$).
• PA branches for head group attachment:
  1. DAG Pathway: PA $\rightarrow$ Diacylglycerol (DAG) by dephosphorylation.
     • DAG + CDP-Choline $\rightarrow$ Phosphatidylcholine (PC, Lecithin).
     • DAG + CDP-Ethanolamine $\rightarrow$ Phosphatidylethanolamine (PE, Cephalin).
     • PE methylation (liver, SAM) $\rightarrow$ PC.
  2. CDP-DAG Pathway: PA + CTP $\rightarrow$ CDP-Diacylglycerol (activated form).
     • CDP-DAG + Inositol $\rightarrow$ Phosphatidylinositol (PI).
     • CDP-DAG + Serine $\rightarrow$ Phosphatidylserine (PS).
     • CDP-DAG + Glycerol-3-P $\rightarrow$ Phosphatidylglycerol (PG) (via PG-Phosphate).
     • PG + CDP-DAG $\rightarrow$ Cardiolipin (Diphosphatidylglycerol; Inner Mitochondrial Membrane).

⭐ Dipalmitoylphosphatidylcholine (DPPC), a type of PC, is the primary component of lung surfactant; deficiency causes Neonatal Respiratory Distress Syndrome (NRDS).

Sphingomyelin & Degradation - Sphingo & Snip Snip

• Sphingomyelin: Ceramide (sphingosine + fatty acid) + phosphocholine.
  • Key in myelin sheath & cell membranes.
  • Synthesis: Ceramide + Phosphatidylcholine $\xrightarrow{Sphingomyelin \ Synthase}$ Sphingomyelin + Diacylglycerol (DAG).
• Degradation (Sphingomyelinolysis):
  • Sphingomyelin $\xrightarrow{Sphingomyelinase}$ Ceramide + Phosphocholine.
  • 📌 Niemann-Pick (A/B): Sphingomyelinase deficiency. "No man picks his nose with his sphinger."

    ⭐ Accumulation of sphingomyelin in lysosomes (liver, spleen, CNS) causes hepatosplenomegaly & neurodegeneration in Niemann-Pick disease (Types A/B).

• Phospholipases ("Snip Snip"): Hydrolyze phospholipids at specific sites.
  • PLA1: Cleaves acyl group at C1.
  • PLA2: Cleaves acyl group at C2 (releases arachidonic acid).
  • PLC: Cleaves before phosphate (yields DAG + phospho-headgroup).
  • PLD: Cleaves after phosphate (yields phosphatidic acid + headgroup).

Clinical Significance - When Lipids Go Rogue

• Respiratory Distress Syndrome (RDS):
  • ↓ Dipalmitoylphosphatidylcholine (DPPC), a key lung surfactant.
  • Lecithin/Sphingomyelin (L/S) ratio < 2 in amniotic fluid signals fetal lung immaturity.

  ⭐ L/S ratio < 2 is a critical indicator of fetal lung immaturity and RDS risk.

• Sphingolipidoses: Lysosomal storage diseases from enzyme deficiencies.
  • Niemann-Pick Disease: Sphingomyelinase deficiency; ↑ Sphingomyelin. Features: hepatosplenomegaly, cherry-red spot.
  • Tay-Sachs Disease: β-Hexosaminidase A deficiency; ↑ GM2 ganglioside. Features: cherry-red spot, NO hepatosplenomegaly, neurodegeneration.
  • Gaucher Disease: Glucocerebrosidase deficiency; ↑ Glucocerebrosides. Most common; hepatosplenomegaly, bone crises, pancytopenia.
• Multiple Sclerosis (MS): Autoimmune demyelinating disease; ↓ phospholipids (esp. plasmalogens) & sphingolipids in myelin.

High‑Yield Points - ⚡ Biggest Takeaways

• Lecithin (Phosphatidylcholine): Key lung surfactant; deficiency causes RDS. DPPC is vital.
• Phosphatidylinositol: Source of second messengers IP3 & DAG.
• Cardiolipin: Inner mitochondrial membrane; antigenic in syphilis (Wassermann test).
• Sphingomyelin: Accumulates in Niemann-Pick disease (sphingomyelinase deficiency).
• Phospholipase A2: Releases arachidonic acid (eicosanoid precursor); inhibited by corticosteroids.
• Phospholipase C: Generates IP3 & DAG from PIP2 for signaling_pathways_activation_and_cellular_responses_regulation_by_hormones_and_neurotransmitters_leading_to_calcium_release_and_protein_kinase_c_activation