Classification and Precursor Dependency
Eicosanoids are derived from 20-carbon polyenoic fatty acids. Depending on the initial substrate, three main series of these substances are distinguished. The series is determined by the number of double bonds remaining in the side chains of the molecule after cyclization (two bonds are always consumed to form the ring).
- Series 1: Synthesized from eicosatrienoic acid (20:3). It is scarce in the body, so these products are formed in negligible amounts.
- Series 2 (Main): Synthesized from arachidonic acid (20:4, omega-6). Because this precursor is abundantly present in cell membrane phospholipids under a normal diet, series 2 eicosanoids predominate in humans (e.g., $PGE_2$, $TXA_2$).
- Series 3: Synthesized from eicosapentaenoic acid (20:5, omega-3), frequently 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
The synthesis process always begins with the release of the precursor fatty acid. Normally, polyenoic acids are tightly bound within membrane phospholipids (most commonly at the second carbon atom of glycerol). Hormones or mechanical stress activate the enzyme phospholipase $A_2$, which cleaves the fatty acid and releases it into the cytosol.
Free arachidonic acid can subsequently be metabolized via two alternative pathways:
- Cyclooxygenase Pathway: The enzyme prostaglandin synthase (possessing cyclooxygenase and peroxidase activities) incorporates oxygen and forms a cyclic structure. Initially, the unstable peroxide $PGG_2$ is formed, which is then reduced to $PGH_2$ in the presence of reduced glutathione. Depending on the tissue type, prostaglandins, prostacyclins, or thromboxanes are synthesized from $PGH_2$.
- Lipoxygenase Pathway: The action of lipoxygenase yields molecules with three conjugated double bonds — leukotrienes (e.g., $LTA_4$). They play a pivotal role in allergic reactions, 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 | Induces vasodilation and potently inhibits platelet aggregation. |
| Thromboxane ($TXA_2$) | Activated platelets | Induces vasoconstriction, stimulates platelet aggregation and thrombus formation. |
Under normal conditions, intact endothelium secretes $PGI_2$ and nitric oxide (NO), keeping the blood in a fluid state. If the vessel wall is damaged, prostacyclin production ceases, platelets contact exposed collagen and massively release $TXA_2$, leading to 'white thrombus' formation and cessation of bleeding.
Pharmacological Inhibition of Synthesis
Because eicosanoids are key inflammatory mediators (causing edema, pain, redness, and fever), blocking their synthesis is the basis of action for many drugs.
- Glucocorticoids (Steroid Drugs): Act at the earliest stage. They induce the synthesis of specific proteins — lipocortins — which inhibit the activity of phospholipase $A_2$. This halts the release of arachidonic acid 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 site, forming a covalent bond. As a result, the synthesis of prostaglandins and thromboxanes ceases, while the lipoxygenase pathway (leukotriene production) remains active.
Briefly: answers to topical questions
What are the isoforms of cyclooxygenase and what is the difference between them?
There are two isoforms of the cyclooxygenase enzyme.
| Sign | COX-1 (Constitutive/Physiological) | COX-2 (Inducible) |
|---|---|---|
| Expression | Constitutively expressed in the body | Normally inactive, expressed during inflammation |
| Localization | Normally present in the stomach, kidneys, and platelets | Expressed by inflammatory cells |
| Function | Regulation of physiological processes; synthesis of cytoprotective prostaglandins | Mediation of the inflammatory response |
| Inducers | — | Proinflammatory cytokines: IL-1, TNF-α |
COX-2 blockade is responsible for the therapeutic anti-inflammatory effect of NSAIDs. COX-1 blockade is associated with adverse effects, specifically impaired synthesis of protective prostaglandins and reduced gastric mucosal resistance.
Through which receptors on the target cell membrane do eicosanoids act?
Eicosanoids act in a paracrine or autocrine manner via specific membrane receptors on target cells.
- Eicosanoid receptors are located in the membrane adjacent to adenylate cyclase.
- Signaling frequently occurs via G proteins of the adenylate cyclase system.
- Depending on the receptor type and prostaglandin species, cAMP levels may change: for example, PGE1 increases cAMP levels, whereas PGE2 decreases them.
- Multiple receptor types exist for each eicosanoid.
- Literature also references thromboxane A2 receptors and PG receptors.
To remember their hemostatic effects: Thromboxane ($TXA_2$) is needed for Thrombosis (constricts vessels and aggregates cells), whereas Prostacyclin ($PGI_2$) maintains Circulation (dilates the lumen and prevents cell clumping).
Class and exam questions
Normally, these are local-action hormones with a very short half-life. However, during severe inflammation or other pathological conditions, their concentration sharply increases, they do not manage to be inactivated and enter the bloodstream, affecting the smooth muscle throughout the body.
Normally, these are local hormones with a very short half-life. However, in pathological states (e.g., systemic inflammation), synthesis is amplified manifold, their concentration spikes, and they begin to exert systemic effects throughout the body.
What is the effect of prostaglandin PGE2 on the stomach?
It performs the crucial function of gastric mucosal cytoprotection: it reduces hydrochloric acid secretion while stimulating the production of protective mucus.
What is the "slow-reacting substance of anaphylaxis"?
This is a complex of cysteinyl leukotrienes ($LTC_4$, $LTD_4$, $LTE_4$) synthesized by leukocytes and alveolar macrophages. They induce potent bronchial constriction and increase vascular permeability during allergic reactions.
What else to study on this topic
- Nomenclature and chemical structure of molecules (significance of letters A, E, F, D, I and substituents on the cyclopentane ring)
- Features of signal transduction via eicosanoid receptors and the role of the adenylate cyclase system (effect on cAMP)
- Specificity of enzyme repertoires across different tissues (why some cells synthesize only thromboxanes while others synthesize prostacyclins)
- Pathogenesis of atherosclerotic plaque formation and its effect on local prostacyclin synthesis
- Role of prostaglandins $PGE_2$ and $PGF_{2\alpha}$ in the initiation and stimulation of labor
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