STRUCTURE AND PROPERTIES OF BIOMOLECULES - A. E. Zemlyakov - 2017

07. BIOREGULATORS: PROSTAGLANDINS AND THEIR ANALOGS

Prostaglandins and A number of related endogenous biologically active lipid compounds possessing hormone-like properties share A common biosynthetic precursor, arachidonic acid. For several prostaglandins, the starting Materials are arachidonic acid analogs containing three or five double bonds, specifically 20:3 ω6 and 20:5 ω3, respectively.

Arachidonic acid is a component of Phospholipids, from which it is released through the action of the enzyme phospholipase. Mediated by cyclooxygenase, it is converted into primary prostaglandins, which can subsequently be transformed into secondary Prostaglandins and thromboxanes. The action of lipoxygenases on arachidonic acid leads to the synthesis of Leukotrienes and their analogs, lipoxins.

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These groups of BIOREGULATORS are characterized by their ubiquitous distribution in mammalian Tissues. They are present in very low concentrations (~10^-10 g per 1 g of tissue) because there are no dedicated Organs for their production and storage; instead, they are synthesized by intracellular Enzymes in response to appropriate biological signals. Furthermore, prostaglandins undergo rapid biotransformation, with a half-life of approximately 30 seconds.

Typically, they exert their physiological effects directly at the site of synthesis. Not all tissues contain the complete set of enzymes belonging to the arachidonic acid cascade. Consequently, on the one hand, specific types of bioregulators are produced that exert localized, targeted effects; on the other hand, drugs like aspirin, which target specific pathways within this cascade, produce multifaceted effects on the Organism. For instance, alongside its anti-inflammatory effect, aspirin also exhibits antithrombotic activity (see below).

A number of pharmacological agents influence The formation of these classes of bioregulators, altering not only their total quantity but also the ratio between individual types and series. For example, nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase, leading to a decrease in The production of prostaglandins and thromboxanes and an increased yield of leukotrienes. Meanwhile, certain Flavonoids (such as rutin) suppress The Biosynthesis of leukotrienes. The anti-inflammatory action of glucocorticosteroids is likewise largely attributed to their ability to inhibit prostaglandin biosynthesis.

Swedish scientists played a pivotal role in the discovery of this group of biologically active compounds. In 1935, Ulf von Euler first isolated and identified The activity of prostaglandins. In 1982, the Nobel Prize in Physiology or Medicine for research on prostaglandins and their analogs was awarded to Professor S. Bergström, who isolated pure prostaglandins in 1957, and Professor B. Samuelsson, who established that prostaglandins, thromboxanes, and leukotrienes are formed as metabolic transformation products of arachidonic acid.

❖ Prostaglandins. The Structure of prostaglandins is based on prostanoic acid, which contains a cyclopentane ring. The name of this compound class originates from the Latin name for the Prostate Gland (Glandula prostatica), as early researchers mistakenly believed this organ produced prostaglandins.

Currently, more than 20 prostaglandins are known (abbreviated as PG). Depending on The Nature and position of their substituents, they are divided into groups designated by Latin letters (A–J). Within these groups, subgroups are distinguished based on the number of double bonds, indicated by numerical subscripts. For the PGF subgroup, the Greek letter subscripts α and β denote the configuration of the hydroxyl group at C9 in the cyclopentane ring.

✵ Biosynthesis of Prostaglandins. The key step in biosynthesis is The oxidation of arachidonic acid by cyclooxygenase, yielding the primary prostaglandins PGG₂ and PGH₂. The latter is subsequently cyclized into prostacyclin (PGI₂), reduced to PGF_2a, or isomerized into PGD₂ and PGE₂.

Further processes may include the dehydration of PGE₂ to the corresponding PGA₂ and PGB₂ derivatives.

Eicosatrienoic (20:3 ω6) and eicosapentaenoic (20:5 ω3) acids initiate the series of monoenoic and trienoic prostaglandins, respectively, such as PGE₁ and PGE₃. These corresponding derivatives differ in their biological activity from the prostaglandins of the arachidonic acid series.

✵ Cyclooxygenase. The enzyme cyclooxygenase belongs to membrane-bound Hemoproteins (Chromoproteins) and consists of two subunits, each with a Molecular Weight of 72 kDa.

There are two isoforms of this enzyme: cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). The former is constitutively expressed in normal Cells, whereas the latter is expressed in inflammatory cells. Their structures are very similar, sharing approximately 65% Amino Acid Sequence identity.

The enzyme catalyzes two sequential reactions: the oxidation of arachidonic acid to PGG₂ and the reduction of the hydroperoxide group to a hydroxyl group with the formation of PGH₂.

To initiate the enzymatic process, the heme is first oxidized by a hydroperoxide. Heme reduction is then driven by Electron transfer from a Tyrosine residue. The resulting tyrosine radical abstracts a hydrogen atom from arachidonic acid, thereby facilitating its oxidation.

✵ Biological effects of prostaglandins are diverse. These compounds predominantly affect smooth Muscle, gastric secretory function, Blood Circulation, and The Immune System. Specifically, PGЕ₁ and PGЕ₂ dilate bronchial Blood Vessels, whereas PGF₁ and PGD₂ induce bronchoconstriction. PGЕ₁ reduces the secretion of gastric juice and associated substances; PGЕ₂, PGА₁, and PGА₂ lower blood pressure and facilitate blood flow; and PGЕ₁ and PGF₂ stimulate labor. Prostacyclin significantly decreases platelet aggregation, enhances the anticoagulant action of heparin, and dilates blood vessels.

A significant portion of the BIOLOGICAL EFFECTS OF prostaglandins is mediated through interaction with specific receptors. For instance, activation of the EP₁ receptor (coupled to G_q Proteins) leads to bronchospasm and contraction of gastrointestinal smooth muscle, whereas interaction of PGЕ with the EP₂ receptor (coupled to G_s proteins) conversely causes bronchodilation and smooth muscle relaxation.

Prostaglandins also act as mediators of inflammation and allergic reactions (such as Bronchial Asthma) and influence various pathological processes in the body, including metastasis.

As medications, prostaglandins are used to induce and stimulate labor. Initially, medical practice relied on prostaglandins derived from the methyl ester of acetyl-PGА₂, extracted from certain species of coral. Today, despite being multi-step and complex, prostaglandins are produced synthetically.

❖ Thromboxanes are lipid bioregulators structurally and derivationally related to prostaglandins, synthesized in Blood Platelets. Unlike prostaglandins, they contain a tetrahydropyran ring in their structure. There are two main groups of thromboxanes: TXA and TXB.

The biosynthetic precursor of thromboxanes is PGН₂, which is converted into TXА₂ by thromboxane synthase; TXА₂, in turn, can be hydrolyzed to TXВ₂.

In many of their properties, thromboxanes are the opposite of prostaglandins. Unlike PGI₂, TXА₂ constricts blood vessels and triggers strong platelet aggregation. All of this can lead to blood clots and vascular atherosclerosis.

The blood-thinning effect of aspirin is attributed to the suppression of thromboxane synthesis (see below). Platelets, being anucleate cells, are unable to synthesize new molecules of this enzyme; consequently, thromboxane production is sharply inhibited for the entire lifespan of these cells.

❖ Leukotrienes. The name of this group of compounds comes from leukocytes, where they were first discovered, and the presence of a conjugated triene system of three double bonds.

As early as the first half of the 20th century, a substance exhibiting bronchoconstrictor activity was identified in the Lungs. This type of bronchospasm differed from histamine-induced bronchospasm by its slower onset and greater duration. The structure of these compounds was elucidated in the late 1970s under the leadership of Bengt Samuelsson.

Depending on their structure, leukotrienes are divided into several subgroups designated by Latin letters. The numeric subscript, as in the case of prostaglandins, indicates the number of double bonds. Leukotrienes of certain subgroups contain Cysteine amino acid residues (LTE) or cysteine-containing dipeptides (LTD and LTF) and tripeptides (LTC).

Biosynthetically, leukotrienes are derived from arachidonic acid, which is converted by 5-lipoxygenase into the highly unstable intermediate LTA₄. Further biotransformation leads to LTB₄. Alternatively, the epoxide ring in LTA₄ is opened via The addition of the tripeptide Glutathione to form LTC₄.

Leukotriene LTC₄, in turn, yields LTD₄ and LTF₄ upon Cleavage of Glycine or glutamic acid, whereas Hydrolysis with the removal of the dipeptide fragment produces LTE₄.

The most widespread are leukotrienes of types LTA and LTB, which have been found not only in animal cells but also in a number of plants, such as potatoes. These compounds do not accumulate in tissues; rather, they are synthesized in response to specific signals.

✵ Biological effects. Leukotrienes play a crucial role in the Pathogenesis of bronchial asthma. They promote inflammatory processes and bronchospasm. Specifically, so-called aspirin-induced asthma is linked to aspirin blocking prostaglandin production by inhibiting cyclooxygenase (see below), which can trigger the activation of 5-lipoxygenase and, consequently, airway narrowing resulting from increased leukotriene biosynthesis.

The action of this group of bioregulators is also associated with the anaphylactic effect—a rapid and life-threatening manifestation of an allergic reaction.

Specific receptors for leukotrienes have been identified, and interaction with these receptors accounts for a range of their physiological effects. Thus, amino acid-containing leukotrienes LTC₄–LTF₄ act on CysLT₁ receptors to induce bronchospasm, while their binding to CysLT receptors alters vascular tone and permeability. Activation by leukotriene LTB₄ stimulates chemotaxis and immune responses.

To treat bronchial asthma, medications have been developed that block leukotriene synthesis by inhibiting either the enzyme 5-lipoxygenase (zileuton) or leukotriene receptors (zafirlukast).

❖ Lipoxins. Alongside leukotrienes, other bioregulatory metabolites of arachidonic acid—lipoxins (LXA and LXB)—were discovered in leukocytes (1984, Bengt Samuelsson). These compounds feature four conjugated double bonds and three hydroxyl groups in their structure.

The key stages of their biosynthesis involve the sequential oxidation of arachidonic acid by 15-lipoxygenase and 5-lipoxygenase.

It has been shown that the interaction of LXA₄ with LXA₄R receptors leads to the inhibition of leukocyte chemotaxis (directed Cell movement). On the other hand, these lipoxins are capable of blocking CysLT₁ leukotriene receptors, thereby preventing The Development of bronchospasm and the inflammatory process.

❖ Nonsteroidal anti-inflammatory drugs (NSAIDs). This group of medications includes a range of substances that exhibit anti-inflammatory activity alongside analgesic and antipyretic effects, as well as various other physiological responses. The Mechanisms of action of these drugs are complex and multicomponent. However, a significant contribution to the comprehensive therapeutic efficacy of NSAIDs is made by the inhibition of prostaglandin and thromboxane production, primarily through the blockade of cyclooxygenase—the enzyme that catalyzes the first step of their biosynthesis. The inhibition of cyclooxygenase by aspirin was first demonstrated by the British professor John Vane (Nobel Prize in Physiology or Medicine, 1982).

✵ Aspirin. The anti-inflammatory properties of white willow bark (Salix alba) have long been known in traditional medicine.

In the 1830s, several research groups isolated the glycoside salicin from willow bark. In 1838, the Italian chemist Raffaele Piria obtained salicylic acid by oxidizing salicin. In the 1880s, the potent anti-inflammatory activity of this compound was established.

Acetylsalicylic acid was first synthesized in 1853 by the French chemist Charles Gerhardt, but this work did not lead to further Practical Applications. In 1897, the German chemist Felix Hoffmann, working for the Bayer company, developed a practical synthesis method for acetylsalicylic acid that caused less irritation to the gastric mucosa, and introduced it into medical practice under the trade name "aspirin".

Acetylsalicylic acid is a broad-spectrum medication. It exhibits anti-inflammatory, analgesic, and antipyretic activity. These effects are attributed to aspirin's ability to exert a comprehensive effect on the inflammation site: capillary permeability is reduced, the biosynthesis of inflammatory mediators (bradykinin, histamine, prostaglandins) is suppressed, and ATP synthesis is inhibited, thereby lowering the energy supply available for biochemical reactions.

Over recent decades, aspirin has been widely used as an antiplatelet agent to prevent thrombus formation in patients with myocardial infarction and other cardiovascular diseases, an effect also linked to the inhibition of thromboxane TXA₂ biosynthesis.

To prevent the Adverse effects of acetylsalicylic acid on The Stomach, it should be taken after meals in crushed form, washed down with plenty of fluids. In medical practice, special pharmaceutical formulations of aspirin that reduce irritation to the gastric mucosa are widely used, such as enteric-coated tablets and effervescent formulations typically containing sodium bicarbonate and citric acid to ensure rapid dissolution in Water.

✵ Other nonsteroidal anti-inflammatory drugs. Butadion is a drug with analgesic, antipyretic, and anti-inflammatory properties. As an inhibitor of prostaglandin biosynthesis, it surpasses aspirin. Since 1949, it has been used in the Treatment of rheumatism and polyarthritis.

Ibuprofen exhibits a similar therapeutic effect. This drug was developed in 1961 by the British chemist S. Adams. Today, it is one of the most widely used antipyretics. There is also evidence suggesting that it stimulates interferon production.

Voltaren (diclofenac sodium) and indomethacin are even more potent. All these drugs non-specifically inhibit the isomeric forms of the cyclooxygenase enzyme, which catalyzes the Formation of the entire pool of prostaglandins—both as inflammatory response mediators and PGE₁, which inhibits gastric acid secretion. Consequently, these medications exert an irritating effect on the gastric mucosa.

✵ Selective cyclooxygenase-2 inhibitors. Meloxicam is largely free of the aforementioned drawback, as it selectively blocks only cyclooxygenase-2, which is responsible for the synthesis of prostaglandin inflammatory mediators.