Classification and Precursor Dependency
Eicosanoids are derived from 20-carbon polyunsaturated fatty acids. Depending on the initial substrate, three main series of these compounds are recognized. The series is determined by the number of double bonds remaining in the molecule's side chains after cyclization (two bonds are always consumed to form the ring structure).
- Series 1: Synthesized from eicosatrienoic acid (20:3). Since this precursor is scarce in the body, these products are formed in minimal quantities.
- Series 2 (Major): Synthesized from arachidonic acid (20:4, omega-6). Because this precursor is abundantly present in cell membrane phospholipids under normal dietary conditions, series 2 eicosanoids predominate in humans (e.g., $PGE_2$, $TXA_2$).
- Series 3: Synthesized from eicosapentaenoic acid (20:5, omega-3), often sourced from fish oil. Products of this series (e.g., $PGI_3$, $TXA_3$) have a distinct effect on blood clotting, notably strongly inhibiting platelet aggregation.
Broadly, all eicosanoids are divided into three major classes: prostaglandins (including prostacyclins), thromboxanes, and leukotrienes.
Initiation and Biosynthetic Pathways
Synthesis always begins with the release of the precursor fatty acid. Under normal conditions, polyunsaturated fatty acids are tightly bound within membrane phospholipids (most commonly at the second carbon atom of glycerol). Hormones or mechanical stress activate phospholipase $A_2$, which cleaves the fatty acid, releasing it into the cytosol.
Free arachidonic acid can then be metabolized via two alternative pathways:
- Cyclooxygenase pathway: The enzyme prostaglandin synthase (possessing both cyclooxygenase and peroxidase activities) incorporates oxygen to form a cyclic structure. It first produces the unstable peroxide $PGG_2$, which is then reduced to $PGH_2$ with the participation of reduced glutathione. Depending on the tissue type, prostaglandins, prostacyclins, or thromboxanes are synthesized from $PGH_2$.
- Lipoxygenase pathway: Action of the enzyme lipoxygenase yields molecules with three conjugated double bonds — leukotrienes (e.g., $LTA_4$). They play a key role in allergic reactions by causing bronchospasm and stimulating leukocyte chemotaxis.
Role in Hemostasis and Vascular Tone
Eicosanoids maintain a delicate balance between the procoagulant and anticoagulant systems of the blood.
| Eicosanoid | Site of Synthesis | Physiological Effect |
|---|---|---|
| Prostacyclin ($PGI_2$) | Intact vascular endothelial cells | Vasodilation, strongly inhibits platelet aggregation. |
| Thromboxane ($TXA_2$) | Activated platelets | Vasoconstriction, stimulates platelet aggregation and thrombus formation. |
Under normal conditions, intact endothelium releases $PGI_2$ and nitric oxide (NO) to keep the blood fluid. If the vessel wall is damaged, prostacyclin production ceases, platelets contact exposed collagen, and massively release $TXA_2$, leading to "white thrombus" formation and hemostasis.
Pharmacological Inhibition of Synthesis
Because eicosanoids are key inflammatory mediators (causing edema, pain, redness, and fever), blocking their synthesis is the basis of many pharmacological drugs.
- Glucocorticoids (Steroids): Act at the earliest stage. They induce the synthesis of specific proteins called lipocortins, which suppress the activity of phospholipase $A_2$. This halts arachidonic acid release and completely blocks the synthesis of all eicosanoids (both leukotrienes and prostaglandins).
- Acetylsalicylic Acid (Aspirin) and NSAIDs: Aspirin irreversibly inhibits the cyclooxygenase enzyme by transferring its acetyl group to the OH-group of the enzyme's active center, forming a covalent bond. As a result, prostaglandin and thromboxane synthesis stops, while the lipoxygenase pathway (leukotriene formation) remains active.