Eicosinoids synthesis with systematic diagram

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Eicosanoid Synthesis - Complete Overview

What Are Eicosanoids?

Eicosanoids are bioactive lipid mediators derived from 20-carbon (eicosa = 20) polyunsaturated fatty acids (PUFAs). The primary precursor in humans is arachidonic acid (AA) - C20:4, Δ5,8,11,14 - an omega-6 fatty acid that cannot be synthesized de novo; it must be obtained from the diet directly or converted from linoleic acid (found in plant oils).

Step 1: Release of Arachidonic Acid from Membrane Phospholipids

Arachidonic acid is stored esterified at the sn-2 position of membrane phospholipids. It is released by two mechanisms:

Enzyme	Mechanism
Phospholipase A₂ (PLA₂)	Directly cleaves arachidonic acid from sn-2 of phosphoacylglycerols. Inhibited by glucocorticoids (via lipocortin/annexin induction)
Phospholipase C (PLC)	Cleaves phosphorylated inositol → yields DAG containing AA → further lipase action releases free AA

Triggers for activation: histamine, bradykinin, cytokines, thrombin, and mechanical stimuli all interact with plasma membrane receptors to activate PLA₂.

Fig. 31.15 Overview Diagram (Basic Medical Biochemistry, 6e):

Overview of eicosanoid metabolism showing arachidonic acid release from membrane phospholipids and its three metabolic pathways

Step 2: Three Major Metabolic Pathways

Once released into the cytosol, arachidonic acid is metabolized by three enzymatic pathways. The type of eicosanoid produced is tissue-specific, determined by which downstream "synthases" are expressed in a given cell type.

Fig. 31.16 Three-Pathway Branch Diagram (Basic Medical Biochemistry, 6e):

Branching diagram showing arachidonic acid splitting into cyclooxygenase, lipoxygenase, and cytochrome P450 pathways

Pathway 1: Cyclooxygenase (COX) Pathway

Key products: Prostaglandins, Prostacyclin (PGI₂), Thromboxanes (TX)

Fig. 31.18 Detailed COX Pathway (Basic Medical Biochemistry, 6e):

Detailed cyclooxygenase pathway showing biosynthesis of prostaglandins and thromboxane from arachidonic acid via PGG2 and PGH2 intermediates

Mechanism (step by step):

Arachidonic Acid
        ↓  COX (+ 2 O₂) — blocked by Aspirin/NSAIDs
     PGG₂  (unstable endoperoxide; hydroperoxy at C15)
        ↓  Peroxidase (GSH → GSSG)
     PGH₂  (stable endoperoxide; hydroxyl at C15)
        ↓ ← Tissue-specific synthases branch here
   ┌────┬──────────┬──────────────┬──────────────┐
PGD₂  PGE₂     PGI₂ (PGI synthase) TXA₂ (TXA synthase)
 ↓      ↓            ↓                   ↓
PGF₂α  PGF₂α   Prostacyclin         Thromboxane A₂
(via 9-keto    (endothelial cells)   (platelets)
 reductase)

COX isoforms:

Isoform	Expression	Role
COX-1	Constitutive (most tissues)	Housekeeping: gastric protection, platelet TXA₂, renal blood flow
COX-2	Inducible (by IL-1, TNF, LPS)	Inflammation, pain, fever; vascular PGI₂ (endothelium)

Key end products and their cell sources:

Product	Cell Source	Major Effect
TXA₂	Platelets	Vasoconstriction, platelet aggregation (stimulates thrombosis)
PGI₂ (Prostacyclin)	Vascular endothelium	Vasodilation, inhibits platelet aggregation
PGE₂	Widespread	Vasodilation, fever (via EP3), pain sensitization, bronchodilation
PGF₂α	Uterus, lung	Vasoconstriction, bronchoconstriction, uterine contraction
PGD₂	Mast cells, brain	Bronchoconstriction, physiological sleep (via DP1/adenosine)

Pathway 2: Lipoxygenase (LOX) Pathway

Key products: Leukotrienes, HETEs, Lipoxins

Arachidonic Acid
        ↓  5-LOX (+ O₂)
    5-HPETE (5-hydroperoxy-eicosatetraenoic acid)
        ↓
      LTA₄ (leukotriene A₄ - epoxide intermediate)
     ┌──────────────────┐
     ↓                  ↓
   LTB₄              LTC₄ (+ glutathione via LTC₄ synthase)
(BLT1/BLT2             ↓
 receptors)          LTD₄ (- γ-glutamyl)
Chemoattractant        ↓
for neutrophils      LTE₄ (- glycine)
                  [Cysteinyl leukotrienes = "slow-reacting
                   substances of anaphylaxis" = SRS-A]

12-LOX → 12-HPETE → 12-HETE (platelets; promotes smooth muscle proliferation)
15-LOX → 15-HPETE → Lipoxins (LXA₄, LXB₄): anti-inflammatory, resolve inflammation

Leukotriene effects:

Leukotriene	Receptor	Major Effect
LTB₄	BLT1, BLT2	Potent neutrophil/eosinophil chemoattractant; monocyte-endothelial adhesion
LTC₄, LTD₄	cysLT1, cysLT2	Bronchoconstriction (1000× more potent than histamine), mucus secretion, microvascular permeability
LTE₄	cysLT1	Sustained bronchoconstriction
Lipoxins	ALX (FPR2)	Anti-inflammatory; inhibit neutrophil, NK cell activation; resolve inflammation

Pathway 3: Cytochrome P450 (CYP450 Epoxygenase) Pathway

Arachidonic Acid
        ↓  CYP450 epoxygenase
      EETs (epoxyeicosatrienoic acids)
        ↓  soluble epoxide hydrolase
      diHETEs (dihydroxyeicosatrienoic acids)

        ↓  CYP450 ω-hydroxylase
      20-HETE (20-hydroxyeicosatetraenoic acid)

Product	Effect
EETs	Vasodilation, natriuresis, anti-inflammatory, antihypertensive, reduce cardiac hypertrophy
20-HETE	Blocks Ca²⁺-activated K⁺ channels in smooth muscle → vasoconstriction of renal arteries → hypertension

Pathway 4: Isoeicosanoid (Non-enzymatic) Pathway

AA undergoes non-enzymatic free-radical oxidation in the lipid bilayer → Isoprostanes (e.g., 8-iso-PGF₂α / iPF₂α-III). These are markers of oxidative stress and can act as vasoconstrictors via TP receptors.

Nomenclature Key

Symbol	Meaning
Series 1 (e.g., PGE₁)	From dihomo-γ-linolenic acid (C20:3, ω-6); 1 double bond in side chain
Series 2 (e.g., PGE₂)	From arachidonic acid (C20:4, ω-6); 2 double bonds - most abundant in humans
Series 3 (e.g., PGE₃)	From eicosapentaenoic acid/EPA (C20:5, ω-3); 3 double bonds - from fish oils; generally less pro-thrombotic
Capital letter (PGE)	Ring substituent configuration
Greek subscript (PGF₂α)	Position of -OH at C9 (α = below ring plane)

Pharmacological Inhibition Points

Drug/Agent	Target	Effect
Glucocorticoids	Phospholipase A₂ (via lipocortin induction)	Block ALL pathways (no AA released)
Aspirin	COX-1 and COX-2 (irreversible acetylation)	Block prostaglandins AND thromboxanes
Other NSAIDs (ibuprofen, naproxen)	COX-1 and COX-2 (reversible)	Same as aspirin but reversible
Selective COX-2 inhibitors (celecoxib)	COX-2 only	Reduce inflammation without platelet effects; ↑ cardiovascular risk (TXA₂ unopposed)
Montelukast, zafirlukast	cysLT1 receptor antagonists	Block LTC₄/LTD₄ effects (asthma treatment)
Zileuton	5-LOX inhibitor	Block leukotriene synthesis

Summary Table

Pathway	Key Enzyme	Products	Main Roles
COX	COX-1, COX-2	PGE₂, PGI₂, PGF₂α, PGD₂, TXA₂	Inflammation, fever, pain, platelet aggregation, vascular tone
5-LOX	5-LOX	LTB₄, LTC₄, LTD₄, LTE₄	Chemotaxis, bronchoconstriction, vascular permeability
12/15-LOX	12-LOX, 15-LOX	12-HETE, LXA₄, LXB₄	Platelet activation, anti-inflammatory resolution
CYP450	CYP epoxygenase/ω-hydroxylase	EETs, 20-HETE, diHETEs	Vascular tone, renal function, BP regulation
Non-enzymatic	Free radicals	Isoprostanes (8-iso-PGF₂α)	Oxidative stress markers, vasoconstriction

Sources: Basic Medical Biochemistry - A Clinical Approach, 6e (pp. 1134-1139) | Katzung's Basic and Clinical Pharmacology, 16e (pp. 515-524) | Goodman & Gilman's Pharmacological Basis of Therapeutics, 13e

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