Biosynthesis of eicosanoids
![](https://upload.wikimedia.org/wikipedia/commons/thumb/7/74/Arachidonic_acid_structure.svg/300px-Arachidonic_acid_structure.svg.png)
Eicosanoids (from the Greek eikosi - twenty) are compounds derived from polyene unsaturated fatty acids with a chain length of 20 carbons. These include prostanoids and leukotrienes. The group of prostanoids (sometimes inaccurately referred to as prostaglandins) includes prostaglandins, prostacyclins and thromboxanes. The general function of eicosanoids is to ensure cell signaling (they act on receptors coupled to G-proteins). The mechanism of action is paracrine or autocrine. They affect the contraction and relaxation of smooth muscle, blood clotting, pain or, for example, inflammation. The half-life of eicosanoids is extremely short, on the order of minutes.
Prostaglandins[edit | edit source]
Found in seminal plasma. Occur in almost all tissues (kidneys, myocardium, lungs, arterial walls, etc.), where they act as local hormones. They are synthesized by cyclization in the middle of the chain of twenty-carbon unsaturated fatty acids (e.g. arachidonic acid) to form a cyclopentane ring.
Three different eicosanoic acids (eicosapentaenoic acid ω3, 20:5; arachidonic acid ω6, 20:4; dihomo-γ-linolenic acid ω6, 20:3) give rise to three series of eicosadoids characterized by the number of double bonds in the side chains (e.g., PG1, PG2, PG3). Differences in substituents determine the different types within each series of prostaglandins and thromboxanes (see below), designated by the letters A, B, etc. (e.g., PGE1, PGE2, etc.).
Thromboxans[edit | edit source]
Thromboxanes, discovered in platelets (further leukocytes and mast cells), contain a six-membered oxygen heterocycle (pyran ring).
Leukotriens[edit | edit source]
First described in leukocytes. Leukotriene synthesis is influenced by lipoxygenase, there is no cyclization of the fatty acid chain. They are characterized by the presence of three conjugated double bonds.
Synthesis of eicosanoids[edit | edit source]
Arachidonate (eicosatetraenate) is essential for the synthesis of the most well-known eicosanoids, which is contained in membranes in the form of phosphatidylinositols. From there, it is cleaved by the action of phospholipase A2. When inflammatory conditions are treated with corticosteroids, the enzyme is inhibited, resulting in lower production of arachidonate.
Synthesis via cyclizing pathway (cyclooxygenase, glycooxygenase pathway)[edit | edit source]
In this way, prostaglandins, prostacyclins and thromboxanes are synthesized. The source of synthesis is arachidonate, or two 18C unsaturated essential acids (linoleic and α-linolenic), which can be converted to the desired 20-carbon compounds. Eicosanoids are formed from both ω6 and ω3 polyenoic acids.
The name of the cyclizing pathway is derived from the fact that a cycle is formed in the middle of the 20-carbon chain. This provides derivatives of the hypothetical prostanoic acid (trans-7-(2-octyl-1-cyclopentyl)heptanoic acid).
The first step of the cyclization pathway is the cyclization of arachidonate by prostaglandin endoperoxide synthase (cyclooxygenase). Cyclooxygenase is a "suicide" enzyme, as it is capable of stopping further synthesis by its autocatalytic destruction. The reaction occurs aerobically, forming endoperoxide. After the peroxide bridge is cleaved, prostaglandins and prostacyclins are formed by the action of other enzymes.
In the formation of thromboxanes containing an oxane ring, the endoperoxide structure is converted by the enzyme thromboxane synthase. During the synthesis of prostacyclins, prostacyclin synthase is used, forming prostacyclin I2. Other prostacyclins are derived from it.
The cyclization pathways of arachidonic acid (ARA) transformation are blocked by acetylsalicylic acid (acetylpyrine).
Synthesis via the lipoxygenase pathway[edit | edit source]
The lipoxygenase pathway produces linear hydroperoxyeicosatetraenolic acids (5-HPETE) and lipoxins. Some odorants are also synthesized via this pathway, e.g. cis-3-hexenal from linolenic acid with the typical scent of bent grass.
Arachidonate is oxidized under the catalysis of 5-lipoxygenase. Hydroperoxide substitution can occur at various sites in the molecule.
The main products of the pathway are active leukotrienes, synthesized in the following sequence: HPETE → LTA4 → LTC4 → LTD4 → LTE4 and LTB4. Leukotrienes with an index of 3 are produced from eicosatrienoic acid and leukotrienes with an index of 5 from eicosapentaenoic acid.
Lipoxins are LTC4 antagonists with antiphlogistic (anti-inflammatory) properties.
Function of eicosanoids[edit | edit source]
As mentioned above, prostaglandins mainly affect the contraction of smooth muscle (vessels, intestines, stomach, bronchi, etc.). The action of prostaglandins (series E and F) in the intestines affects the excretion of water and electrolytes, thus causing diarrhea. They also affect the renal tubules, blood pressure, change kidney perfusion, and cause the secretion of renin, angiotensin, and ADH. PGD2 induces sleep, while PGE2 has an effect on awakening. The series E prostaglandins cause relaxation of the muscles in the GIT and contraction of the muscles of the uterus. Prostaglandins inhibit the secretion of HCl in the stomach (which was already used by the ancient Chinese, who administered dried seminal plasma to patients), stimulate lipolysis, and affect many other processes in the body.
Prostacyclins have a similar effect to prostaglandins. It inhibits the secretion of HCl in the stomach, PGI2 inhibits platelet aggregation (thus acting as an anticoagulant).
Thromboxanes act against PGI2 in platelet aggregation; they increase arterial blood pressure and participate in the course of inflammatory processes.
Most leukotrienes have a pro-inflammatory effect, they chemotactically attract neutrophils, and can promote the production of reactive oxygen species. They are also the basis of anaphylactic reactions.
All eicosanoids are very quickly inactivated, usually by hydrolysis.
Use in pharmacotherapy[edit | edit source]
Pharmacological use is in almost diametric opposition to the wide range of processes in which eicosanoids participate in the human body. PGE1 is used in diseases of the coronary arteries, a number of PGE and synthetic analogues are used in gastric ulcers, affecting microcirculation in the gastric mucosa. PG are indicated by gynecologists and obstetricians to increase uterine tone and induce labor (PG changes the properties of uterine collagen using collagenase), abortion or regulation of menstrual bleeding. Widespread use is also offered in angiology or in the treatment of high blood pressure.
Links[edit | edit source]
Related articles[edit | edit source]
External links[edit | edit source]
References[edit | edit source]
- KOOLMAN, Jan – RÖHM, Klaus-Heinrich. Barevný atlas biochemie. 1. edition. Grada, 2012. ISBN 978-80-247-2977-0.
- MURRAY, Robert K. Harperova biochemie. 23. edition. H & H, 2002. 872 pp. ISBN 80-7319-013-3.
- LEDVINA, Miroslav. Biochemie pro studující medicíny. I. díl. 2. edition. Karolinum, 2009. 269 pp. ISBN 978-80-246-1416-8.