Eicosanoid Synthesis

1. 1

   Membrane phospholipid -> arachidonic acid + lysophospholipid

   Phospholipase A2 3.1.1.4 ST-0315 Irreversible/directional rate-limiting Ca2+
   In Phospholipid

   Out Arachidonic acid Lysophospholipid
   › Notes

   Rate-limiting release of the 20:4 omega-6 precursor. Corticosteroids suppress this step.

2. 2

   Arachidonic acid + 2 O2 -> PGG2 -> PGH2

   Cyclooxygenase (COX-1 / COX-2; PTGS1/2) 1.14.99.1 ST-0316 Irreversible rate-limiting O2 heme
   In Arachidonic acid O2

   Out PGG2
   › Notes

   Bifunctional cyclooxygenase + peroxidase. Irreversibly acetylated by aspirin; reversibly inhibited by other NSAIDs; COX-2 selectively inhibited by coxibs.

3. 3

   PGH2 -> PGE2 / PGD2 / PGF2alpha / PGI2 / TXA2

   Tissue-specific synthases (PGE synthase; prostacyclin synthase; thromboxane synthase) ST-0317 Irreversible/directional
   In PGH2

   Out PGE2 / PGD2 / PGF2alpha / PGI2 / TXA2
   › Notes

   Endothelium favours PGI2 (vasodilator, antiaggregatory); platelets favour TXA2 (vasoconstrictor, proaggregatory) - the basis of low-dose aspirin cardioprotection.

4. 4

   Arachidonic acid + O2 -> 5-HPETE -> LTA4

   5-Lipoxygenase (ALOX5) + FLAP 1.13.11.34 ST-0318 Irreversible/directional O2 Fe
   In Arachidonic acid O2

   Out 5-HPETE
   › Notes

   Branch point of the leukotriene arm; zileuton inhibits 5-LOX.

5. 5

   LTA4 -> LTB4, or LTA4 + glutathione -> LTC4 -> LTD4 -> LTE4

   LTA4 hydrolase; LTC4 synthase + gamma-glutamyl transpeptidase 3.3.2.6 / 4.4.1.20 ST-0319 Irreversible/directional Glutathione
   In LTA4

   Out LTB4, or LTA4 Glutathione (GSH)
   › Notes

   LTB4 is a neutrophil chemoattractant; the cysteinyl leukotrienes are the slow-reacting substance of anaphylaxis and are blocked at the receptor by montelukast/zafirlukast.

Showing all 5 steps.