PROSTAGLANDINS: STRUCTURE, SYNTHESIS, FUNCTIONS, INHIBITORS - BIOLOGY - 2025

The prostaglandins are hormone - like substances production and local action, extremely short life, composed of polyunsaturated fatty acids and oxygen, with a broad range of potent physiological effects. They are produced by most eukaryotes, and almost all organs and cell types.

Prostaglandins (abbreviated PG) owe their name to the fact that they were first isolated from the ovine prostate. They are members of a family of essential fatty acids called eicosanoids, alluding to their characteristic of having 20 carbons (the Greek root "eikosi", used to form this term, means twenty).

Source: Calvero.

Despite their multifunctionality, all prostaglandins have the same basic molecular structure. They are derived from arachidonic acid, which in turn is derived from phospholipids in cell membranes.

When required, they are released, used and degraded to inactive compounds, all without migrating from the tissues where they are synthesized.

Prostaglandins differ from hormones in: 1) not being produced by specialized glands; and 2) not be stored, and not be transported far from its synthesis site. This last fact is due to the fact that they degrade in a few seconds. However, they are sometimes called autocoids, or tissue hormones.

History

In 1930, R. Kurzrok and CC Lieb reported that the human uterine endometrium rhythmically contracted and relaxed when exposed to semen. In 1935, US von Euler reported that this type of contraction was due to the action of a hitherto unknown type of unsaturated lipid, which he called prostaglandin.

In 1957, S. Bergström and J. Sjövall reported for the first time the synthesis from arachidonic acid and the isolation in its crystalline form of a prostagandin (PGF _2α). In 1960, these authors reported having purified a second prostaglandin (PGE ₂).

Between 1962 and 1966, the teams of S. Bergström (in collaboration with B. Samuelsson) and DA van Dorp reported having achieved the synthesis of PGE ₂ from arachidonic acid and having elucidated the crystal structures of PGF _2α and PGE ₂.

These discoveries allowed the synthesis of prostaglandins in sufficient quantities to carry out pharmacological studies. In 1971, JR Vane reported that aspirin and non-steroidal anti-inflammatory agents inhibit prostaglandin synthesis.

For their research on prostaglandins, S. von Euler in 1970, and S. Bergström, B. Samuelsson, and R. Vane in 1982, received the Nobel Prize in Medicine and Physiology.

Structure

Prostaglandins are derived from a hypothetical lipid, called prostanoic acid, with 20 carbon atoms, of which those numbered from 8 to 12 form a cyclopentane ring, and those numbered from 1 to 7, and from 12 to 20, form respective chains parallel (called R1 and R2) that start from said ring.

There are 16 or more prostaglandins, mostly designated with the acronym PG, to which is added a third letter (A – I) that denotes the substituents of the cyclopentane ring, and a subscript composed of a number that denotes the amount of bonds doubles in R1 and R2, and sometimes also by a symbol, denoting other structural details.

Substituents on the cyclopentane ring can be, for example: A = α, β -unsaturated ketones (PGA); E = β-hydroxyketones (PGE); F = 1,3-diols (PGF). PGA – PGI are the primary groups of prostaglandins.

In the case of PGF ₂, the acronym indicates that it is a group F prostaglandin with two double bonds in R1 and R2. In the case of PGF _α, α indicates that the OH group of carbon 9 is on the same side of the cyclopentane ring as R1, while in that of PGF _β, β indicates the opposite.

Synthesis

Prostaglandin synthesis increases in response to stimuli that disrupt cell membranes, such as chemical irritants, infections, or mechanical trauma. Inflammatory mediators, such as cytokines and complement, trigger this process.

Hydrolysis by phospholipase A ₂ causes phospholipids in the cell membrane to transform into arachidonic acid, the precursor of most eicosanoids. Catalysis by cyclooxygenases (COX enzymes), also called prostaglandin H synthetases, converts arachidonic acid to PGH ₂.

Human cells produce two isoforms of cyclooxygenases, COX-1 and COX-2. These share 60% homology at the amino acid level and are similar in three-dimensional structure, however they are encoded by genes from different chromosomes.

COX-1 and COX-2 catalyze two reaction steps: 1) formation of the cyclopentane ring and addition of two O ₂ molecules, to form PGG ₂; 2) conversion of a hydroperoxide group to an OH group, to form PGH ₂. By the action of other enzymes, PGH ₂ is transformed into the other prostaglandins.

Despite catalyzing the same reaction steps, the differences in cell location, expression, regulation, and substrate requirements between COX-1 and COX-2 determine that each initiates the synthesis of structurally and functionally different prostaglandins.

Features

Since the spectrum of their modes of action and physiological effects is very broad, it is difficult to draw up an exhaustive and detailed list of the functions of prostaglandins.

In general, these functions can be classified based on the two COX enzymes involved (recently, the existence of a third COX enzyme has been raised).

COX-1 promotes the permanent synthesis of prostaglandins, necessary for daily body homeostasis, which modulate blood flow, contraction and relaxation of the muscles of the digestive and respiratory systems, temperature, the proliferation of the gastric and intestinal mucosa, the platelet function and antithrombogenesis.

COX-2 promotes the transient synthesis of prostaglandins, necessary for eventual physiological processes or for the healing of diseases or traumatic damages, which modulate inflammation, fever, pain, scarring, adaptation to kidney stress, trabecular bone deposition, ovulation, placentation, uterine contractions, and labor.

Receivers

To fulfill their wide variety of functions, prostaglandins must bind to specific receptors (surface proteins to which they bind) on target cells. The mode of action of prostaglandins is perhaps less dependent on their molecular structure than on these receptors.

There are prostaglandin receptors in all tissues of the body. Although these receptors have common structural features, they show specificity for primary groups of prostaglandins.

For example, PGE ₂ binds to receptors DP, EP _1, EP ₂, EP _3, and EP ₄; PGI ₂ binds to IP receiver; PGF _{2 α} binds to the FP receptor; TXA ₂ binds to the TP receptor.

Prostaglandins and these receptors work in conjunction with a group of regulatory molecules called G proteins, capable of sending signals across cell membranes, which is called transduction.

Through a complex molecular mechanism, G proteins act as switches that can be turned on or off.

Inflammation

The four classic symptoms of inflammation are edema, redness, high temperature, and pain. Inflammation is an immune system response to mechanical trauma, chemical agents, burns, infections, and various pathologies. It is an adaptation that normally allows tissues to heal and restore physiological balance.

Persistent inflammation may be involved in the development of tissue and organ damage, arthritis, cancer, and autoimmune, cardiovascular, and neurodegenerative diseases. Three prostaglandins, specifically PGE ₂, PGI ₂ and PGD ₂, play a fundamental role in the development and duration of inflammation.

PGE ₂ is the most abundant and functionally diverse prostaglandin. It is of great interest because it is involved in the four classic symptoms of inflammation.

It causes edema, redness, and increased temperature by increasing arterial dilation and vascular permeability. It produces pain because it acts directly on the nervous system.

PGI ₂ is a powerful vasodilator of great importance in the regulation of cardiac homeostasis. It is the most abundant prostaglandin in the synovial fluid of arthritic joints. PGD ₂ is present in both the nervous system and peripheral tissues. Both prostaglandins cause acute edema and pain.

Inhibitors

Acetylsalicylic acid (AAC), or aspirin, was marketed starting in 1899 by the German pharmaceutical company Bayer. In 1971, it was determined that aspirin works by inhibiting prostaglandin synthesis.

AAC forms, by acetylation, a covalent bond with the active site of cyclooxygenase enzymes (COX-1, COX-2). This reaction is irreversible, and generates an inactive AAC-COX complex. In this case, the cells must produce new COX molecules to resume prostaglandin production.

Inhibiting prostaglandin production reduces the inflammation and pain caused by them. However, other important functions are also affected.

Prostaglandins modulate the regeneration of the gastric mucosa that protects the stomach from its own acids and enzymes. The loss of integrity of this mucosa can cause the appearance of ulcers.

In addition to AAC, many other non-steroidal anti-inflammatory drugs (NSAIDs) work by inhibiting prostaglandin synthesis by inactivating COX enzymes.

Several NSAIDs (some of their trade names in parentheses) in common use are: acetaminophen or paracetamol (Tylenol ^®), diclofenac (Voltaren ^®), etodolac (Lodine ^®), ibuprofen (Motrin ^®), indomethacin (Indocin ^®), ketoprofen (Orudis ^®), meloxicam (Movimex ^®), naproxen (Naprosyn ^®), piroxicam (Feldene ^®).

Related diseases

Disorders in the production and action of prostaglandins are implicated in reproductive problems, inflammatory processes, cardiovascular diseases, and cancer.

Prostaglandins are very important in: 1) smooth muscle contraction and inflammation, which affects the menstrual cycle and labor; 2) the immune response, which affects the implantation of the ovum and the maintenance of the pregnancy; 3) vascular tone, which affects blood pressure during pregnancy.

Reproductive problems caused by failure to regulate prostaglandins include dysmenorrhea, endometriosis, menorrhagia, infertility, miscarriage, and pregnancy hypertension.

Prostaglandins control the body's inflammatory processes and the contraction of the bronchi. When inflammation lasts longer than normal, rheumatoid arthritis, uveitis (inflammation of the eye), and various allergic diseases, including asthma, can develop.

Prostaglandins control cardiovascular homeostasis and vascular cell activity. When prostaglandin activity is defective, heart attacks, thrombosis, thrombophilia, abnormal bleeding, atherosclerosis, and peripheral vascular disease can occur.

Prostaglandins have immunosuppressive effects and can activate carcinogens, favoring the development of cancer. Overexpression of the COX-2 enzyme can accelerate tumor progression.

Clinical use

Prostaglandins burst onto the clinical scene in 1990. They are essential for the treatment of glaucoma due to their powerful ability to lower intraocular pressure.

Prostacyclin (PGF ₂) is the most potent inhibitor of platelet aggregation that exists. It also breaks down platelet aggregations already present in the circulatory system. Prostacyclin is beneficial in the treatment of patients with pulmonary hypertension.

Synthetic PGE ₁ and PGE ₂ are used to induce labor. PGE _{1 is} also used to keep the ductus arteriosus open in childhood congenital heart disease.

Treatment with exogenous prostaglandins may help in cases where endogenous prostaglandin production is deficient.

Examples of prostaglandins

PGE ₂ is the prostaglandin present in a greater variety of tissues, therefore it has very varied functions. It is involved in the response to pain, vasodilation (protects against ischemia) and bronchoconstriction, gastric protection (modulates the secretion of acid and blood flow from the stomach), the production of mucus and fever.

In the endometrium, the concentration of PGE ₂ increases in the luteal phase of the menstrual cycle, reaching its maximum during menstruation, indicating that this prostaglandin has an important role in female fertility.

PGD ₂ is present in the central nervous system and peripheral tissues. It has homeostatic and inflammatory capacity. It is involved in the control of sleep and the perception of pain. It is involved in Alzheimer's disease and asthma.

PGF _{2 α} is present in smooth muscle of the bronchi, blood vessels and the uterus. It is involved in bronchoconstriction and vascular tone. It can cause abortions.

Thromboxanes A ₂ and B ₂ (TxA ₂, TxB ₂) are prostaglandins present in platelets. Prostacyclin (PGF ₂) is a prostaglandin present in the arterial endothelium.

TxA ₂ and TxB ₂ are vasoconstrictors that promote platelet aggregation. PGF ₂ is the opposite. The homeostasis of the circulatory system depends on the interaction between these prostaglandins.

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